The ESDO BULLETS by the Young Group of the European Society of Digestive Oncology provide regular overviews and summaries of the latest publications in GI oncology from major journals. We cover topics which are interesting for digestive oncology specialists as well as for clinicians with multi-disciplinary background.
The bullets provide direct links to each publication. We hope you find this summary of the latest developments in digestive cancers of benefit to you in your practice and kindly ask you to share our content with your circles.
In CRC patients with synchronous resectable metastases, resection of the primary tumor does not improve OS (SYNCHRONOUS and CCRe-IV trials).
In multicenter, randomized trial 393 CRC patients with synchronous unresectable metastases were randomized to primary tumor resection (PRT) or No PRT. Chemotherapy was not administered to 6.4% in the no PTR group and 24.1% in the PTR group. The mOS was 16.7 mo in the PTR group and 18.6 mo in the No PTR group (p = .191). Comparable OS in both groups was also confirmed in multivariate analysis (HR, 0.94; HR 95% CI, 0.74 to 1.21], p = .65) Serious AE were more frequent in the No PTR group (10.2% v 18.0%; p = .027).
Rahbari NN, et al. J Clin Oncol. 2024 May 1;42(13):1531-1541. https://ascopubs.org/doi/10.1200/JCO.23.01540
Chromoendoscopic screening achieves only a modest reduction in esophageal cancer (EC) incidence and mortality.
From January 2012 to September 2016, a community-based cluster randomized controlled trial including permanent residents age 45-69 years in a high-risk region for EC in northern China was conducted. The participants were randomly assigned in a 1:1 ratio to the screening group (Lugol’s chromoendoscopy) or control group (no screening). In total, 33,847 participants were included in the analysis: 17,104 in the screening group, 15,165 (88.7%) of whom underwent screening, and 16,743 in the control group. During a maximum follow-up of 9 years, EC incidence in the screening and control groups were 60.9 and 72.5 per 100,000 person-years, while mortality were 29.7 and 32.4 per 100,000 person-years, respectively. Compared with the control group, the incidence and mortality of the screening group reduced by 19% (adjusted [HR], 0.81 [95% CI, 0.60 to 1.09]) and 18% (adjusted [HR], 0.82 [95% CI, 0.53 to 1.26]), respectively, in the intention-to-treat analysis. In conclusion, the trial suggests there is a tendency towards EC incidence and mortality reductions with chromoendoscopic screening, however a more efficient strategy for EC screening and subsequent patient management should be established.
Liu M, et al. J Clin Oncol. 2024 May 10;42(14):1655-1664. https://ascopubs.org/doi/10.1200/JCO.23.01284
The addition of durvalumab to 1L chemotherapy does not worsen patient-reported outcome in advanced biliary tract cancer (TOPAZ-1)
In the global, randomized, double-blind phase III trial, 685 patients with unresectable locally-advanced or metastatic biliary cancer were randomized (1:1) to durvalumab or placebo, both combined with 1 CTx cisplatin plus gemcitabine for up to 6 cycles, followed by maintenance therapy every 4 weeks. Previous report indicated an improvement of OS in the experimental arm. The current analysis of secondary endpoints showed no significant differences in patient-reported outcomes (PROs), assessed using the QLQ-C30 and QLQ-BIL21 questionnaires. The median time to deterioration of global health status or quality of life (by ≥10 points) was 7.4 mo in the durvalumab arm and 6.7 mo in the placebo arm (HR 0.87; 95% CI 0.69-1.12). The adjusted mean change from baseline was 1.23 (95% CI, 0.71-3.16) in the durvalumab arm and 0.35 (–1.63-2.32) in the placebo arm.
Burris HA 3rd, et al. Lancet Oncol. 2024 May;25(5):626-635. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00082-2
Overall survival benefit of the STRIDE regimen is maintained with longer follow up in unresectable hepatocellular carcinoma patients (HIMALAYA update).
In the phase III HIMALAYA study, 1171 participants with unresectable HCC, were randomized to either STRIDE (Single dose tremelimumab, 4-weekly durvalumab), durvalumab monotherapy, or sorafenib. With longer follow-up data available, the 36-mo OS rate for STRIDE was 30.7% vs 19.8% for sorafenib. The 48-mo OS rate was equally improved for STRIDE at 25.2% vs 15.1% for sorafenib. OS HR for STRIDE versus sorafenib remained at 0.78 (95% CI 0.67-0.92). The long-term OS benefit of STRIDE was observed across clinically relevant subgroups. Of these long-term survivors (≥ 36mo after randomization) with STRIDE (n = 103), 57.3% had no reported subsequent anticancer therapy. These data present the longest OS follow-up to date from a pivotal phase III study in uHCC, and demonstrate the sustained long-term survival benefits of STRIDE, with over one in four participants remaining alive at 4 years.
Sangro B, et al. Ann Oncol. 2024 May;35(5):448-457. https://www.annalsofoncology.org/article/S0923-7534(24)00049-8
Chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases: A prospective multicentric randomized trial (TRANSMET). Abstract 3500. R Adam, France
In highly selected patients (40% non-eligible) with unresectable colorectal liver metastases, liver transplantation after response to induction chemotherapy and no subsequent progression (N=38/47 of initially randomized) is feasible and provide with 73% 5-years OS as compared with 9% 5-years survival in chemotherapy alone (N=47) (HR 0.16; 95%CI 0.07-0.33). Most patients (68%) received chemotherapy after liver transplant.
Surgery versus thermal ablation for small-size colorectal liver metastases (COLLISION): An international, multicenter, phase III randomized controlled trial. Late-Breaking Abstract 3501. MR Meijerink, Netherlands
Focusing on peripheral small (≤3cm) liver metastases, which are both eligible to surgery and thermal ablation, 148 resections vs 147 multiple-thermal ablations+/-limited surgery were performed. After a median follow-up of 28.8 months, thermal ablation arm displayed a reduced morbidity and mortality (0%) with no difference in local or distant PFS nor OS difference as compared with surgery alone (2.1% mortality).
Primary outcome analysis of the ORCHESTRA trial: A randomized phase III trial of additional tumor debulking to first-line palliative systemic therapy for patients with multiorgan metastatic colorectal cancer. Abstract 3502. EC Gootjes, Netherlands
A significant fraction of the 454 screened patients dropped out for progression under the pre-operative treatment (>90% CAPOX and 75% with bevacizumab). Peritoneum was involved in 33% of patients. Despite successful surgical procedure in 137 patients (>80% of the disease removed), palliative chemotherapy+tumor debulking brings no survival benefit as compared with chemotherapy alone after 32.3 months of follow-up: OS 30.0 vs 27.5months and PFS 10.5 vs 10.4 months.
FU/FA maintenance therapy with or without panitumumab (pmab) in RAS wild-type metastatic colorectal cancer (mCRC) (PanaMa, AIO KRK 0212): Updated efficacy analyses. Abstract 3506. DP Modest, Germany
Maintenance FU with or without Panitumumab? You choose! PanaMa met its primary endpoint as PFS is significantly higher in maintenance treatment arm with FU/FA+panitumumab 8.8 vs 5.8 HR 0.73 [95%CI: 0.56-0.94] p=0.05 BUT time to failure strategy is the same 17.1 vs 15.7 months, HR=0.98 (95%CI 0.68 – 1.42), p=0.92.
Acquired gene alteration patterns and post-progression survival: PARADIGM study analysis. Abstract 3507. H Uetake, Japan
RAS mutation at time of use is critical. Gene alterations are more frequent in FOLFOX-Panitumumab setting as compared with FOLFOX-Bevacizumab. Patients from the FOLFOX-panitumumab group with RTK/RAS alterations had shorter PPS than those without alterations (13.2 vs 18.8 mo, HR 1.88 [95% CI: 1.28–2.76]).
ARC-9: A randomized study to evaluate etrumadenant based treatment combinations in previously treated metastatic colorectal cancer Abstract 3508. ZA Wainberg, USA
In 2nd or 3rd line, Etrumadenant+Zimberelimab+mFOLFOX+Bevacizumab (N=75) versus Regorafenib (N=37) with possible cross-over met its primary endpoint PFS 6.24 vs 2.07months HR 0.27 [0.17-0.43] p<0.0001 (OS 19.68 vs 9.49 months, HR 0.37, 95% CI 0.22-0.63, p = 0.0003), even in patients previously treated with bevacizumab BUT all included patients were candidate for FOLFOX rechallenge.
What is the best strategy for locally advanced esophageal cancer, especially at the esogastric junction? We discussed this question at the ESDO Masterclass 2022 in Brussels. Our answer at that time was that we were looking forward to the ESOPEC trial results. Here they are!
Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial). Late-Breaking Abstract 1. Jens Hoeppner, Germany
Primary endpoint was overall survival assessed in an intention to treat analysis. ESOPEC enrolled 438 patients (221 FLOT; 217 CROSS) male sex 89.3%, median age 63 with locally advanced tumor: cT3/4 80.5%; cN+ 79.7%.
Neoadjuvant treatment was started in 403 patients (207 FLOT; 196 CROSS). Surgery was performed in 371 patients (191 FLOT; 180 CROSS). In case of residual disease, patients received adjuvant chemotherapy in the CROSS arm. In the FLOT group 52.5% of patients completed the adjuvant treatment. In the CROSS arm 67.7% of patients completed the neoadjuvant treatment although 98% of patients received the total radiotherapy dose of 41.4 Gray.
The 3-year OS rates were 57.4% (95% CI 50.1 – 64.0%) for FLOT and 50.7% (95% CI 43.5 – 57.5%) for CROSS. With median OS time of 66 months 95%CI [36-non achieved] for FLOT and 37 months 95%CI [27-43] for CROSS (HR 0.70, 95% CI 0.53-0.92, p=0.012).
With a median follow-up of 55 months, this result was confirmed in per protocol analysis. FLOT was favored in most subgroups analyzed, except node negative tumors and elder patients. The 5-year OS rates were 50.6% for FLOT and 38.7% for CROSS. R0 resection was achieved in 94.2% of patients in FLOT and 95.0% in CROSS. Resected tumors were ypN+ in 48.7% of cases in FLOT and 44.4% in CROSS. Pathologic complete remission ypT0N0 was obtained in 16.8% of patients for FLOT vs 10.0% for CROSS.
Some limitations were discussed:
*CROSS arm in ESOPEC had lower outcomes than in the CROSS trial whereas the treatment was completed in most cases. We should keep in mind that the CROSS trial included only 65% of N+ patients and included also squamous cell carcinoma (Van Hagen, NEJM 2012), which respond very well to chemoradiation (Bedenne, JCO 2007).
*ESOPEC, which was designed before Checkmate 577 results, did not include Nivolumab as a standard of care in case of residual disease after CROSS + surgery (Kelly, NEJM 2021).
*FLOT regimen is an intensive treatment which cannot be administered to frail patients.
Conclusion: the ESOPEC trial establishes FLOT as the new standard for fit patients with locally advanced esophageal cancer.
* ESO-GASTRICA phase II/III study of peri-operative nivolumab (nivo) and ipilimumab (ipi) in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: Results of the neoadjuvant pathologic complete response (pCR) rate (ECOG-ACRIN EA2174). Abstract 4000. JR Eads, USA
A trial to help us interprete ESOPEC at the time of immunotherapy!
275 patients (G/GEJ adenoca T1N+, T2-3N0-2M0) in step 1: neoadjuvant chemoradiation 41.4-50.4 Gy with Paclitaxel-Carboplatin with (n = 138) or without Nivolumab (n = 137). 22% of drop-out rate before surgery performed 7 weeks after CRTx.
The primary endpoint of pCR not different:
21.0% in CROSS-like Arm A (95% CI, 14.5-28.8),
24.8% in CROSS+Nivo Arm B (95% CI, 17.8-32.9), p = 0.27.
50.7% drop-off rate is 51% in CROSS-type arm A and 43% in CROSS+Nivo arm.
Step 2 ongoing - randomization after surgery for adjuvant nivo with or without ipi.
* Effect of chemotherapy/targeted therapy alone vs. chemotherapy/targeted therapy followed by radical surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction: The IKF-575/RENAISSANCE phase III trial. Late-Breaking Abstract 4001. S-E Al-Batran, Germany
For now, surgery is not recommended in metastatic gastric cancer care.
RENAISSANCE: 139 pts (G/GEJ adenoca, M1):
69 pts in 4x FLOT chemo → surgery → 4-8x FLOT (± nivo/trastuzumab)
vs 72 pts in 8-12x FLOT chemo (± nivo/trastuzumab)
mOS not different: 18.5 mo [95% CI, 11.9-27.7] in the FLOT+ surgery
vs 23.3 mo [16.6-31.9] in FLOT only
HR 1.037 (95% CI 0.691-1.556)
Patients with retroperitoneal metastatic lymph nodes may benefit from surgical.
Non-responders to CTx (mOS, 13 vs. 22 months) or with peritoneal disease (mOS, 12 vs. 19 months) experienced a detrimental effect from surgery. Complete disease resection was achieved in 54% of patients.
* Ramucirumab plus paclitaxel as switch maintenance versus continuation of oxaliplatin-based chemotherapy in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction (GEJ) cancer: The ARMANI phase III trial. Late-Breaking Abstract 4002. F Pietrantonio, Italy
Early Paclitaxel+Ramucirumab after FOLFOX/CAPOX induction: efficient but toxic, is it really maintenance?
Patients with advanced G/GEJ, HER2-ve, disease control after 12w of FOLFOX/CAPOX, randomized to:
Paclitaxel-Ramucirumab, Arm A (N=144), or FOLFOX/CAPOX for extra 3 mo, then fluoropyrimidine maintenance, Arm B (N=136).
Primary endpoint, mPFS was 6.6 mo (95% CI 6.0-7.8] in Arm A
vs 3.5 mo (95% CI 2.8-4.2) in Arm B
HR 0.64 (0.49-0.81) p<0.001.
The secondary endpoint OS: 12.6 mo (11.5-15.0) in Arm A
vs 10.4 mo (8.0-13.1) in Arm B.
HR 0.75 (0.58-0.97) p=0.028.
Neutropenia ≥G3 higher in Arm A (26.2%), neuropathy G1-2: 61.7% in Arm A vs 45% in Arm B.
* A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer (GIANT): ECOG-ACRIN EA2186. Abstract 4005. E Dotan, USA
In patients ≥70 yo with advanced pancreatic adenocarcinoma, considered vulnerable, no survival difference between 1L: biweekly Gem-Nab-Paclitaxel (Arm A) vs reduce-dosed FU-Nal-IRI (Arm B)
GIANT enrolled 176 vulnerable patients, median age was 77 yo [70-90], 80% ECOG 0-1.
mOS: 4.7 mo [4.1-7.4] in Arm A vs. 4.4 mo [3.1-8.9] in Arm B; p =0.72.
When patients could complete 2 cycles of treatment, mOS: 8.0 mo.
No difference between 70-74 yo patients and patients ≥75 yo.
≥G3 toxicities: 51% (G4: 8%) in Gem-Nab-Paclitaxel vs 58% (G4: 15%) in FU-Nal-IRI.
* Early results of the PASS-01 trial: Pancreatic adenocarcinoma signature stratification for treatment-01. Late-Breaking Abstract 4004. JJ Knox, Canada
Patients with advanced pancreatic adenocarcinoma should be treated accordingly to their treatment sensitivity.
PASS-01 enrolled 160 patients, with 140 randomized to 1L Gemcitabine-nab-Paclitaxel (GnP) or mFOLFIRINOX (mFFX), followed by molecularly matched therapy after PD.
mPFS (PP): 5.1 mo GnP vs 4.0 mo for mFFX (p=0.14)
Best response PR/SD for GnP: 29/45% vs 24/35% for mFFX.
mOS (ITT): 9.7 mo with GnP vs 8.4 mo with mFFX, p=0.04.
Multiple core biopsies were performed and a correlate-guided therapy was delivered in 32 (50%) patients. Biomarkers were able to prospectively stratify patients in terms of outcome and sensitivity to chemotherapy. This prospective data supports the PRODIGE24 analysis presented in Rapid oral session #4015 by NJ Dusetti.
* NRG Oncology/RTOG 0848: Results after adjuvant chemotherapy +/- chemoradiation for patients with resected periampullary pancreatic adenocarcinoma (PA). Abstract 4005. KA Goodman, USA
Adjuvant chemoradiation may be useful in head pancreatic cancer, especially in N+ patients.
354 operated patients randomized to adjuvant treatment: 174 to the chemotherapy arm (CTx, gemcitabine or combination chemo), and 180 to the CTx +chemoradiation with 5-FU/capecitabine (CTx+CRTx) arm.
In all patients, 5y OS similar in both arms: 23% in CTx vs 28% CTx+CRTx; HR 0.96 (95% CI 0.79-1.18).
In all patients, 5y DFS better for CTx+CRTx: 15% in CTx vs 21% CTx+CRTx; HR 0.82 (95% CI 0.68-0.99).
No difference in DFS & OS in N+, but CTx + CRTx superior in N- patients.
In N- patients, mOS: 3.0y (95% CI 2.3-4.0) in CTx vs 3.9y (95% CI 2.5-NR) in the CTx + CRTx; HR 0.57 (95% CI 0.33-0.98), p=0.38.
For N- patients, mDFS: 1.5y (95%CI 0.8-2.7) in the CTx arm vs 2.3y (95% CI 1.4-NR) in the CTx + CRTx arm, HR 0.52 (95% CI 0.32-0.85), p=0.004.
* Addition of stereotactic body radiotherapy (SBRT) to systemic chemotherapy in locally advanced cholangiocarcinoma (CC) (ABC-07): Results from a randomized phase II trial. Abstract 4006. MA Hawkins, UK
No signal for radiotherapy in advanced cholangiocarcinoma.
69 patients randomized with a median follow-up time was 20.7 months.
mOS: 19.4 mo (95% CI 11.2-24.6) for SBRT + CTx (CisGem) vs 14.2 mo (95% CI 7.0-NR) for CTx only (CisGem); HR 0.79 (95% CI 0.41-1.51; p = 0.47).
PFS events were 7 (16%) local and 24 (53%) metastatic relapses for SBRT+CTx, vs 7 (29%) and 7 (29%) in the CTx only arm, respectively.
* International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI). Abstract 4007. AB El-Khoueiry, USA
Anti-PD1 + anti-VEGF TKI in patients with advanced HCC after ICI
This phase II trial enrolled 95 patients with advanced HCC to 2L regorafenib + pembrolizumab stratified upon prior ICI treatment: Cohort 1 = atezolizumab + bevacizumab; Cohort 2 = other ICI. Median follow up was 7.1 months.
Median PFS: 2.8 mo vs 4.2 mo in Cohort 1 and Cohort 2, respectively.
ORR and DCR: 5.9% vs 11.1% and 48.5% vs 63.0%, respectively.
* Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW. Late-Breaking Abstract 4008. PR Galle, Germany
Nivolumab-Ipilimumab a 1L option in advanced hepatocellular carcinoma
668 patients were randomized between 1L nivolumab + ipilimumab (n = 335) and lenvatinib or sorafenib (n = 333).
mOS: 23.7 mo [95% CI 18.8–29.4] in nivo+ipi vs 20.6 mo [95%CI 17.5–22.5] in lenvatinib or sorafenib; HR 0.79 (95%CI 0.65–0.96); 0.0180 p< 0.0001.
ORR and mDOR superior for nivo+ipi: 36 vs 13%; 30.4 vs 12.9 mo.
G3-4 toxicities: 41% in nivo+ipi and 42% in lenvatinib or sorafenib.
Cetuximab monotherapy maintenance fails to show PFS noninferiority in comparison to continuous FOLFIRI + Cetuximab in 1L RAS/BRAF-wt mCRC (ERMES).
In a multicenter, open-label, randomized, phase III non-inferiority trial, 593 mCRC RAS/BRAF wild-type patients were randomly assigned to arm A (296 pts: continuous FOLFIRI + Cetuximab) or to arm B (297 pts: FOLFIRI + Cetuximab for 8 cycles, followed by cetuximab monotherapy). Of these, 154 and 183 patients received treatment beyond the 8th cycle in arms A and B, respectively (modified per protocol population, mPP). The coprimary endpoints were: noninferior PFS in the mPP population (>8 cycles) and a lower incidence rate of G3-4 AEs for arm B compared with arm A. The cetuximab maintenance arm failed to show non-inferiority of PFS. In the mPP population, mPFS was 10.0 and 12.0 months (HR 1.3 [95% CI 1.03-1.64]; P for noninferiority = .43), while mOS was 35.7 vs 30.7 months (P = .119) in arms B and A, respectively. In the ITT (≥one cycle) population, mPFS was 9.0 vs 10.7 months (P = .39), and mOS 31.0 vs 25.2 months (P = .32), respectively. The G3-G4 toxicity rate during the maintenance phase was 20.2% vs 35.1% in arms B and A, respectively. Thus, FOLFIRI + Cetuximab should be continued until disease progression, but dose de-escalation could be an option in selected cases to reduce toxicity.
Pinto C, et al. J Clin Oncol. 2024 Apr 10;42(11):1278-1287.
https://ascopubs.org/doi/10.1200/JCO.23.01021
Combination of anti-PD-1 Ab plus HDAC inhibitor plus anti-VEGF shows promising activity in refractory MSS/pMMR colorectal cancer (CAPability-01).
The randomized phase II trial tested the efficacy of combining anti-PD-1 Ab (sintilimab) with a histone deacetylase (HDAC) inhibitor (chidamide), with or without VEGF inhibition (bevacizumab), in 48 patients with unresectable chemotherapy-refractory advanced MSS/pMMR CRC. The primary endpoint of PFS rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% for the entire study population. Secondary endpoint results included mPFS of 3.7 months, ORR of 29.2%, DCR of 56.3%, and mDOR of 12.0 months. The triplet arm showed greater 18wPFS rate (64.0% vs 21.7%, P = .003), higher ORR (44.0% vs 13.0%, P = .027), and longer mPFS (7.3 vs 1.5 months, P = .006). The most common adverse events observed included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia, and diarrhea.
Wang F, et al. Nat Med. 2024 Apr;30(4):1035-1043.
https://www.nature.com/articles/s41591-024-02813-1
Cabozantinib plus atezolizumab fails to demonstrate OS benefit over sorafenib in hepatocellular carcinoma (COSMIC-312 final analysis).
COSMIC-312, an international, open-label, phase III study in 1L advanced HCC, randomized 837 patients (2:1:1) to either a combination of cabozantinib 40 mg qd plus atezolizumab 1200 mg q3w, sorafenib 400 mg bid, or single-agent cabozantinib 60 mg qd. mOS was 16.5 months for the combination treatment group and 15.5 months for the sorafenib group (HR 0.98 [96% CI 0.78–1.24]; stratified log-rank P = .87). mPFS was 6.9 months for the combination treatment group, 4.3 months for the sorafenib group, and 5.8 months for the single-agent cabozantinib group (HR 0.74 [99% CI 0.56–0.97] for combination treatment vs. sorafenib; HR 0.78 [99% CI 0.56–1.09], P = .05, for single-agent cabozantinib vs. sorafenib). No new safety signals were noted. The 1L PFS benefit of cabozantinib plus atezolizumab over sorafenib, reported in the primary analysis, was confirmed with longer follow-up. The reason why the PFS improvement did not translate into an OS benefit in the overall population might be multifactorial and remains open for discussion.
Yau T, et al. Lancet Gastroenterol Hepatol. 2024 Apr;9(4):310-322.
https://www.thelancet.com/journals/langas/article/PIIS2468-1253(23)00454-5
Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma (5-year follow-up from CheckMate 040).
In phase I/II, open-label, non-comparative, nivolumab monotherapy was tested in 80 sorafenib-naive and 154 sorafenib-experienced patients with advanced HCC. ORR was 20% and 14%, mOS was 26.6 months and 15.1 months, and the 5-year OS rates were 14% and 12% in the sorafenib-naive and sorafenib-experienced patients, respectively. No new safety signals were identified. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year.
El-Khoueiry AB, et al. Ann Oncol. 2024 Apr;35(4):381-391.
https://www.annalsofoncology.org/article/S0923-7534(23)05115-3/fulltext
The ABC factors - tumor anatomy, biologic (CA19-9) and conditional (performance status) factors - were independent prognostic factors for OS in localized PDAC.
In this retrospective cohort study, 1835 patients with localized PDAC treated with initial (m)FOLFIRINOX at five high-volume centers in the US and the Netherlands were included (2012-2019). Tumor stage at diagnosis was potentially resectable in 18.9%, borderline resectable in 28.9% and locally advanced in 52.2% of patients. The baseline CA19-9 was >500U/ml in 32.5%. Performance status was ≥1 in 60.7%. Independent poor prognostic factors for OS were borderline resectable disease (HR 1.26 [95% CI 1.06-1.50]), locally advanced disease (HR 1.71 [95%CI 1.45-2.02]), CA19-9 >500U/ml (HR 1.36 [95% CI 1.21-1.52]) and performance status ≥1 (HR 1.31 [95%CI 1.16-1.47]). Patients were assigned 1 point for each poor ABC factor and 2 points for locally advanced disease. The median OS for patients with score 0-4 was 49.7, 29.9, 22.0, 19.1 and 14.9 months with corresponding 5-year OS rates of 47.0%, 28.9%, 19.2%, 9.3% and 4.8%, respectively. In conclusion, the ABC factors were independent prognostic factors for OS in patients with localized PDAC treated with initial (m)FOLFIRINOX. Staging of patients with localized PDAC at diagnosis should be based on anatomy, CA19-9 and performance status.
Dekker EN, et al. J Clin Oncol. 2024 Apr 20;42(12):1357-1367.
https://ascopubs.org/doi/10.1200/JCO.23.01311
Neoadjuvant nivolumab or nivolumab plus relatlimab combined with chemoradiotherapy in resectable esophageal/gastroesophageal junction cancer.
This phase Ib trial investigated neoadjuvant immunotherapy in resectable stage II/III esophageal or GEJ cancer. 16 patients received nivolumab alone (Arm A), while another 16 received nivolumab plus relatlimab (anti-LAG3; Arm B), followed by preoperative (immuno)chemoradiotherapy. The study met its primary endpoint of safety in Arm A, while Arm B required modification (elimination of ICI during chemoradiotherapy) due to cases of toxicity (pericarditis and adrenal insufficiency). TRAE of ≥G3 were observed in 31% and 44% of patients, respectively. pCR and major pathological response rates were 40% and 53.5% in Arm A, and 21.4% and 57.1% in Arm B. In both arms combined, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Clearance of ctDNA and high PD-L1 and LAG-3 levels were associated with improved outcomes.
Kelly RJ, et al. Nat Med. 2024 Apr;30(4):1023-1034.
https://www.nature.com/articles/s41591-024-02877-z
The addition of atezolizumab to 1L chemotherapy did not yield a significant PFS benefit in advanced anal cancer (SCARCE C17-02 PRODIGE 60).
In this French phase II, non-comparative trial, 97 participants with advanced squamous cell carcinoma of the anus were randomized in a 2:1 ratio to receive either atezolizumab plus the modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen or mDCF alone. The primary endpoint was 12-mo PFS in the atezolizumab + mDCF group (35% for the null hypothesis and 50% for the alternative hypothesis). The primary efficacy endpoint was not met in the ITT population, with 12-mo PFS rates of 45% (90% CI 35-55) and 43% (90% CI 29-58) in atezolizumab + mDCF and mDCF groups, respectively. However, in participants with PD-L1 CPS ≥5, the 12-mo PFS rates were 70% (95% CI 47-100) in the atezolizumab + mDCF and 40% (95% CI 19-85) in the DCF group. AEs of ≥G3 were observed in 61% and 42% of patients, respectively.
Kim S, et al. Lancet Oncol. 2024 Apr;25(4):518-528.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00081-0/
The combination of pembrolizumab and Lenvatinib did no show sufficient efficacy in patients with advanced well-differentiated NETs.
In this prospective, phase II trial a total of 20 patients with advanced GI/thoracic NETs (nine small intestine, five lung, two thymic, two unknown primary, one cecal, one presacral primaries) received a combination of Lenvatinib (20mg p.o. daily) plus Pembrolizumab (200mg i.v. every 3 weeks). Pancreatic NETs were excluded due to high response rate to lenvatinib monotherapy in this tumor type. Only patients with evidence of progression within 8 months of study entry and at least 2 prior lines of systemic therapy were included. Two patients (10%) achieved PR (atypical lung and small intestine primaries). mPFS was 8 months (95% CI 5.8-10.2 months). 12 patients (60%) experienced AE G3 events, of those ten were arterial hypertension. 14 patients (70%) required dose reductions or discontinued one of the medications. In conclusion, the combination of Pembrolizumab and Lenvatinib did not show sufficient response in patients with advanced NETs to warrant continued enrollment on trial.
Al-Toubah T, etl al. ESMO Open. 2024 Apr;9(4):102386.
https://www.esmoopen.com/article/S2059-7029(24)00154-6/fulltext
☆ Baseline ctDNA based molecular hyperselection of optimal candidates for panitumumab plus mFOLFOX in mCRC (biomarker analysis of PARADIGM study).
This prespecified exploratory biomarker analysis of the phase 3 PARADIGM study (n = 733) evaluated the association between ctDNA gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition (including KRAS, NRAS, PTEN and extracellular domain EGFR-mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions). mOS was prolonged with panitumumab + mFOLFOX6 vs bevacizumab + mFOLFOX6 in patients with ctDNA that lacked such gene alterations in the panel (negative hyperselection): 40.7 vs 34.4 mo (HR 0.76 [95% CI 0.62–0.92]). However, mOS was similar or inferior with panitumumab in patients exhibiting any ctDNA gene alteration, with mOS of 19.2 vs 22.2 mo, respectively (HR 1.13 [95% CI 0.83–1.53]). ORR, depth of response, and the curative resection rate also favored panitumumab in the negative hyperselected patients. Remarkably, these findings occurred regardless of tumor sidedness. The results suggest that the primary tumor location only serves as surrogate predictor of the anti-EGFR benefit, as it shaped by the intricate mutational landscape.
Shitara K, et al. Nat Med. 2024 Mar;30(3):730-739.
https://www.nature.com/articles/s41591-023-02791-w
☆ KRAS G12 mutational status does not influence the survival on trifluridine/tipiracil (FTD/TPI) with or without bevacizumab in patients with refractory mCRC (SUNLIGHT).
In a retrospective analysis of phase 3 trial that demonstrated the superiority of FTD/TPI plus bevacizumab over FTD/TPI alone, the impact of KRAS G12 mutational status on OS was studied. Similar OS was observed in patients without and with KRAS G12 mutation (HR 1.09 [0.87-1.4] and those with KRAS G12 vs other RAS mutations (HR 1.03 [95% CI 0.76-1.4]). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRAS mutational status
Tabernero J, et al. ESMO Open. 2024 Mar;9(3):102945.
https://linkinghub.elsevier.com/retrieve/pii/S2059-7029(24)00713-0
☆ Neoadjuvant FOLFIRINOX shows no additional benefit compared to upfront surgery in patients with resectable pancreatic ductal adenocarcinoma (NORPACT-1).
In a multicentre, phase 2 trial, 140 patients with resectable pancreatic adenocarcinoma were randomly assigned to the neoadjuvant FOLFIRINOX group (4 cycles; n=77), or the upfront surgery (n=63). 79% of patients in the neoadjuvant group received preoperative therapy. The rate of 18-mo OS in the ITT analysis was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group vs 73% (95% CI 62–84) in the upfront surgery group (p=.032). OS did not differ significantly between the study arms: the ITT mOS in the neoadjuvant group was 25.1 vs 38.5 mo in the upfront surgery group (HR 1.52 [95% CI 1.00–2.33]; p=.050), while the pre-protocol mOS was 23.0 vs 34.4 mo (HR 1.46 [95% CI 0.99–2.17]; p=.058). The NORPACT-1 trial did not show a survival benefit from neoadjuvant FOLFIRINOX (with a trend favoring upfront surgery) in resectable PDAC.
Labori KJ, et. al. Lancet Gastroenterol Hepatol. 2024 Mar;9(3):205-217.
https://www.thelancet.com/journals/langas/article/PIIS2468-1253(23)00405-3/abstract
☆ The addition of paclitaxel to 2L gemcitabine does not improve OS in metastatic pancreatic cancer (GEMPAX).
In a multicenter open-label, phase 3 trial, 211 patients with mPDAC were randomly assigned (2:1) to gemcitabine + paclitaxel (GEMPAX), or to gemcitabine monotherapy. There was no significant difference in OS, the primary endpoint – mOS: 6.4 vs 5.9 mo in in the GEMPAX and gemcitabine arm, respectively (HR 0.87 [95% CI, 0.63-1.20]; p=.41). PFS was longer in the GEMPAX group: mPFS 3.1 vs 2.0 mo, respectively (HR 0.64 [95% CI 1.9-2.3]; p=.0067). The ORR was 17.1% vs 4.2%, respectively. GEMPAX increased the rate of grade ≥3 AE (58% vs 27%), especially neuropathy.
De La Fouchardière C, et al. J Clin Oncol. 2024 Mar 20;42(9):1055-1066.
https://ascopubs.org/doi/10.1200/JCO.23.00795
☆ Transcriptional signature of resectable pancreatic adenocarcinoma indicates patients who achieve similar survival with adjuvant gemcitabine monotherapy and mFOLFIRINOX (PRODIGE-24).
GemPred is an investigational transcriptomic signature predictive of the efficacy of gemcitabine. Its predictive value was analyzed retrospectively in patients with pancreatic adenocarcinoma participating in the PRODIGE-24 phase 3 trial, a study that compared adjuvant mFOLFIRINOX and gemcitabine. FFPE surgical specimens of 350 patients were RNA-sequenced for GemPred prediction. In total, 25.5% cancers were found to be GemPred+ (potentially gemcitabine-sensitive). Among patients in the gemcitabine arm, GemPred+ individuals had significantly superior DFS and cancer-specific survival (CCS) as compared to GemPred– patients (mDFS 27.3 vs 10.2 mo; HR 0.43 [95% CI 0.29-0.65], p<.001; mCSS 68.4 vs 28.6 mo; HR 0.42 [95% CI 0.27-0.66], p<.001). GemPred status had no prognostic value in the mFOLFIRINOX arm. GemPred+ patients had less grade ≥3 AE with gemcitabine (40%) than with mFOLFIRINOX (76%). GemPred-positive signature may thus indicate patients who are candidates for adjuvant treatment with gemcitabine, thus sparing them from the toxicity associated with mFOLFIRINOX.
Nicolle R, et al. J Clin Oncol. 2024 Mar 20;42(9):1067-1076.
https://ascopubs.org/doi/10.1200/JCO.22.02668
☆ The addition of Trastuzumab to 1L Gemcitabine-Cisplatin improves 6-month PFS in HER2-positive advanced biliary adenocarcinoma (TAB trial).
In a multicenter, open-label, single arm, phase II study, 876 patients with metastatic or locally advanced unresectable biliary adenocarcinoma (GBC, IHCC and EHCC) were screened for HER2 status. 118 (13.4%) patients were found to be positive (IHC 3+ or 2+ with FISH+), of which 90 patients received trastuzumab combined with gemcitabine + cisplatin. The addition of trastuzumab to chemotherapy produced the 6-month PFS rate (the primary endpoint) of 66.7% (95% CI 56.7-76.7). The 6-mo OS, 12-month OS and the mOS were 81.1%, 39.1%, and 9.96 mo (95% CI 9.25-10.66), respectively. ORR was 55.5%. The treatment was well tolerated.
Ostwal V, et al. J Clin Oncol. 2024 Mar 1;42(7):800-807.
https://ascopubs.org/doi/abs/10.1200/JCO.23.01193
☆ Adjuvant treatment with sintilimab (anti-PD1 Ab) improved RFS compared to active surveillance in HCC patients with microvascular invasion (MVI).
A randomized, phase 2 study investigated the efficacy and safety of adjuvant anti-PD1 Ab, sintilimab, following hepatectomy in HCC patients with MVI. 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n=99), or undergo active surveillance (n=99). Sintilimab significantly prolonged RFS compared to the surveillance (mRFS 27.7 vs 15.5 mo, respectively; HR 0.53 [95% CI 0.36-0.79]; p=.002). Further follow-up is needed to evaluate OS. Sintilimab was well tolerated (G3-4 TRAE in 12% patients).
Wang K, et al. Nat Med. 2024 Mar;30(3):708-715.
https://www.nature.com/articles/s41591-023-02786-7
☆ Regorafenib plus nivolumab show clinical activity in 1L treatment of unresectable hepatocellular carcinoma (uHCC): RENOBATE trial.
This multicenter, single-arm, phase 2 trial tested regorafenib–nivolumab as 1L treatment for uHCC. Forty-two patients received nivolumab 480 mg every 4 weeks and regorafenib 80 mg daily (3-weeks-on/1-week-off schedule). The study met its primary endpoint with an ORR per RECIST 1.1 of 31.0%. Median PFS was 7.4 mo. The 1-year OS rate was 80.5% and the mOS was not reached. Treatment was well tolerated.
Kim HD, et al. Nat Med. 2024 Mar;30(3):699-707.
https://www.nature.com/articles/s41591-024-02824-y
☆ The use of antivirals associates with improved survival in patients with resectable hepatitis virus-related HCC.
An international cohort study investigated the utilization and impact of antivirals in HBV- and HCV-related HCC. Among 1906 participants who underwent curative resection of HCC (55% HBV-related, 45% HCV-related HCC), 47% received antiviral therapy. The use of antivirals increased over time for HCV-related HCC (from 24% before 2015 to 74% from 2015), but decreased for HBV-related cases (from 65% before 2010 to 47% after 2015). 10-y OS was superior in patients who received antivirals compared to those who did not (in HBV: 61% vs 58%, in HCV: 82% vs 38%). Use of antivirals before or within 6 mo after HCC diagnosis was independently associated with improved survival.
Huang DQ, et al. J Clin Oncol. 2024 Mar 1;42(7):790-799
https://ascopubs.org/doi/10.1200/JCO.23.00757
☆ The addition of Sugemalimab (anti-PD-L1 Ab) to chemotherapy improves PFS and OS in advanced esophageal squamous cell carcinoma (ESCC)
In a multicenter, randomized phase 3 trial, 540 patients with unresectable, locally advanced, recurrent or metastatic untreated ESCC were randomized to receive either sugemalimab (anti-PD-L1 Ab) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin with 5-FU) every 3 weeks for up to 6 cycles. The dual primary endpoints (PFS and OS) were met. After a median follow-up of 15.2 mo, mPFS (6.2 vs 5.4 mo; HR 0.67 [95% CI 0.54-0.82]; p = .0002) and mOS (15.3 vs 11.5 mo; HR 0.70 [95% CI 0.55-0.90]; p = .0076) were higher in the sugemalimab group. A consistent benefit was observed across different PD-L1 expression levels. The addition of sugemalimab also improved ORR (60.1% vs 45.2%). There were no unexpected safety signals.
Li J, et al. Nat Med. 2024 Mar;30(3):740-748.
https://www.nature.com/articles/s41591-024-02797-y
The addition of Pembrolizumab to perioperative chemotherapy increases the pCR rate, but does not improve the event-free survival (EFS) in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585).
In a multicentre, randomised, placebo-controlled, phase III study, 1007 patients with locally advanced gastric or gastro-esophageal adenocarcinoma (≥cT3 i/lub N+) were randomly assigned to either the pembrolizumab plus perioperative chemotherapy group, or the placebo plus perioperative chemotherapy group. Adjuvant pembrolizumab or placebo was given for additional 11 maintenance cycles after completing chemotherapy. 80% of patients received cisplatin-fluoropyrimidine-based chemotherapy, while 20% received the FLOT regimen. The primary endpoints were: pCR rate, EFS and OS. Pembrolizumab was superior to placebo for pCR (12.9% vs 2.0; p<.00001), but there was no significant difference in EFS (mEFS: 44.4 mo vs 25.3 mo; HR 0.81 [95% CI 0,67-0.99; p=.0198]). The mOS was 60.7 mo in the pembrolizumab group, and 58.0 in the placebo group (HR 0.90 [95% CI 0.73-1.12; p=.174]). The safety of the therapy was similar in both arms.
Shitara K, et al. Lancet Oncol. 2024 Feb;25(2):212-224.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00541-7
The addition of Atezolizumab to perioperative Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel (FLOT) improves postoperative stage and histopathologic regression in resectable esophagogastric adenocarcinoma (DANTE).
In a multicentre phase II/III trial, 295 patients with resectable esophagogastric adenocarcinoma (≥cT2 and/or N+) were randomized to receive either 4 cycles of pre- and postoperative FLOT with atezolizumab (followed by 8 cycles of atezolizumab maintenance), or FLOT alone. The addition of atezolizumab improved tumor downstaging (ypT0: 23% vs 15% [p=.044]; ypN0: 68% vs 54% [p=.012], and pCR rate (24% vs 15% [p=.032). The benefit of immunotherapy was more pronounced in MSI-H and PD-L1 CPS ≥10 tumors. The treatment safety, surgical morbidity and mortality were similar in both arms. Survival data is not available yet.
Lorenzen S, et al. J Clin Oncol. 2024 Feb 1;42(4):410-420.
https://ascopubs.org/doi/abs/10.1200/JCO.23.00975
The sequential nab-Paclitaxel/Gemcitabine-mFOLFOX regimen improves 12-mo survival as compared to the standard nab-P/Gem 1L treatment in metastatic pancreatic cancer.
In this multi-institutional, open-label, phase II trial, 157 patients with untreated mPDAC were randomized to receive either nab-P/Gem on days 1, 8, and 15 followed by mFOLFOX on day 29 of a 6-week cycle, or nab-P/Gem on days 1, 8, and 15 of a 4-week cycle (control group). The primary end point of 12-mo OS rate was met with 55.3% (95% CI 44.2-66.5) in the experimental arm vs 35.4% (95% CI: 24.9-46) in the control group (P= .02). The mOS equally favored the experimental regimen with 13.2 mo (95% CI, 10.1 to 16.2) vs 9.7 mo (95% CI, 7.5-12) (HR 0.68; 95% CI 0.48-0.95). Increased efficacy came at the cost of an increased incidence of ≥G3 neutropenia and thrombocytopenia and two treatment-related deaths (2.6%).
Carrato A, et al. NEJM Evid 2024;3(2).
https://evidence.nejm.org/doi/full/10.1056/EVIDoa2300144
Digital PCR (dPCR)-based ctDNA detection proves highly prognostic of patients’ outcomes in localized CRC.
In a nationwide Danish study, ctDNA was used to monitor minimal residual disease (MRD). Single-target dPCR was used as a faster and cheaper method than NGS for ctDNA detection (the monitored mutation was selected after baseline tumor and germline whole-exome sequencing). Plasma samples were collected from 851 stage II-III CRC patients within 60 days post-operation, and from a subset of 246 patients serially every 3-4 mo for up to 36 mo. Both post-operative and serial ctDNA detection were prognostic of recurrence: HR 11.3 (95% CI 7.8-16.4, P<.001), and HR 30.7 (95% CI 20.2-46.7, p<.001), respectively. The dynamics of the ctDNA growth were prognostic of survival (HR 2.6; 95% CI 1.5-4.4, p=.001). Post-op ctDNA detection was lowest for patients later diagnosed with peritoneal (20%) or lung metastases (19%), and highest for metastases at multiple sites (44%). A cumulative ctDNA+ detection rate was 87% at the end of sample collection in patients who recurred (vs 10% in patients without recurrence).
Henriksen TV, et al. Ann Oncol. 2024 Feb;35(2):229-239.
https://www.annalsofoncology.org/article/S0923-7534(23)05073-1/fulltext
Long-term organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy (TNT): OPRA trial update.
324 patients with stage II/III rectal cancer were randomly assigned to receive TNT with: 4-month induction FOLFOX/CAPOX chemotherapy followed by long-course CRTx (n = 158), or long-course CRTx followed by 4 month consolidation FOLFOX/CAPOX chemotherapy (CRT-CNCT, n = 166). Patients achieving CR or near-CR were offered a watch-and-wait strategy (W&W). The 5-y DFS rates were 71% (95% CI 64%–79%) in the INCT-CRT group and 69% (95% CI 62%–77%) in the CRT-CNCT group (p=.68). Among W&W patients, regrowth occurred in 44% in the INCT-CRT group, and 29% in the CRT-CNCT group. Overall, 5-year TME–free survival was 39% (95% CI 32%–48%) and 54% (95% CI 46%–62%), respectively (p=.012). Among 81 patients with tumor recurrence, regrowth occurred in 94% within 2 years and in 99% within 3 years. 5-y DFS was similar among patients who underwent TME after restaging (64%; 95% CI 53%–78%) and those on a W&W, who underwent TME after regrowth (64%; 95% CI 53%–78%; p=.94).
Verheij FS, et al. J Clin Oncol. 2024 Feb 10;42(5):500-506.
https://ascopubs.org/doi/10.1200/JCO.23.01208
Multiplex immunofluorescent staining analysis of intratumoral immune infiltrate could refine risk stratification in stage II–III colorectal cancer.
In this retrospective analysis, multiplex immunofluorescent staining of tissue microarrays was performed to assess the densities of CD8+, CD20+, FoxP3+, and CD68+ cells in the intraepithelial and intrastromal compartments from tumor samples of patients with stage II–III CRC from the SCOT trial (2340 cases – discovery cohort) and the QUASAR 2 trial (1069 cases – validation cohort). Immune marker predictors were analyzed by multiple regression to assess the prognostic and predictive values of markers for CRC recurrence-free interval. The study demonstrated that quantification of intrastromal FoxP3 improves upon the known prognostic value of intraepithelial CD8 in stage II–III colorectal cancer, with performance as good as or better than the consensus Immunoscore. Associations of other assessed markers with recurrence-free interval were moderate.
Frei AL, et al. Lancet Oncol. 2024 Feb;25(2):198-211.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00560-0/fulltext
Novel mutations are found to impact outcomes of 1L treatment in advanced CRC.
Retrospective analysis of phase III CALBG/SWOG 80405 trial aimed to identify novel mutated genes that affecting the outcomes of 1L treatment (ChT with bevacizumab or cetuximab) in patients with mCRC. Primary tumor DNA from 548 patients was sequenced, and the effect of mutations on OS was analyzed, adjusting for MSI status, BRAF V600E, RAS mutations, treatment arm, sex, and age. mOS was similar in BRAF non-V600E mutated and BRAF wild-type patients (31.9 vs 31.2 mo, respectively). Mutated LRP1B (found in 10.7% of patients) was associated with better OS compared to LRP1B wild-type status (HR 0.57; 95% CI 0.40-0.80). In patients treated with cetuximab, OS was worse in patients with RNF43 mutations (5.6% of patients; mOS 11.5 vs 30.1 mo in mutated and wild-type pts, respectively), while the negative impact of RNF43 mutations was less prominent in patients receiving bevacizumab (mOS 25.0 vs 31.3 mo in mutated and wild-type pts, respectively). KRAS mutations were more frequent in Black than in White patients (53% vs 27%), while BRAF V600E mutation less common in Black than in White patients (5% vs 14%).
Innocenti F et al. Clin Oncol. 2024 Feb 1;42(4):399-409.
https://ascopubs.org/doi/10.1200/JCO.23.00825
Liver MRI prompts significant changes in treatment plans for colorectal liver metastases in patients scheduled for surgery on the basis of CT imaging.
In a prospective, international study involving 298 patients with CRC liver metastases scheduled for local therapy based on contrast-enhanced CT, performance of liver contrast-enhanced MRI with DWI revealed a substantial impact on treatment plans. 31% patients experienced modifications in their treatment strategies following MRI: 13% required more extensive local therapy, 4% necessitated less extensive intervention, and 11% had their curative-intent local therapy indications revoked due to excessive disease extent (9%) or benign lesions (3%). These findings highlight the critical role of liver MRI in guiding personalized treatment decisions for patients with colorectal liver metastases.
Gorgec B, et al. Lancet Oncol. 2024 Jan;25(1):137-146
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00572-7/fulltext
The immunoscore biopsy (ISB) is validated as a biomarker to predict recurrence in patients undergoing Watch-and-wait (W&W) strategy for rectal cancer.
A multicenter international, retrospective validation cohort study of 249 W&W rectal cancer patients aimed to evaluate the utility of the ISB performed on pretreatment biopsies to predict time to recurrence (TTR) after completion of neoadjuvant treatment. Recurrence-free rates at 5 years were 91.3%, 62.5%, and 53.1% with ISB High, ISB Intermediate, and ISB Low, respectively (HR in Low vs High: 6.51 [95% CI 1.99-21.28]; log-rank P=.0004). ISB categories (High v Intermediate v Low) were significantly associated with a gradual scaling of the risk of both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage, cN stage and was the strongest predictor for TTR. These findings could pave the way for prospective therapeutic trials guided by ISB to adjust monitoring and/or therapy of W&W patients.
El Sissy C, et al. J Clin Oncol. 2024 Jan 1;42(1):70-80
https://ascopubs.org/doi/full/10.1200/JCO.23.00586
Tislelizumab results in better patients’ survival than 2L chemotherapy in advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302).
In a global open-label phase III trial, 108 patients with advanced/metastatic ESCC were randomized to 2L therapy with tislelizumab (anti-PD1 Ab), or chemotherapy (paclitaxel, docetaxel or irinotecan). OS was prolonged with tislelizumab in comparison to chemotherapy: mOS 11.2 vs 6.3 mo, respectively (HR 0.55; 95% CI 0.35-0.87). While PFS was similar (mPFS 2.3 vs 2.7 mo), ORR was greater with tislelizumab (20.0% vs 11.3%). Tislelizumab had a more favorable safety profile.
Ajani J, et al. ESMO Open. 2024 Jan;9(1):102202.
https://www.esmoopen.com/article/S2059-7029(23)01443-6/fulltext
Clinical features and outcomes of advanced HER2+ esophageal/GEJ cancer with brain metastasis.
Brain metastases (BRM) are uncommon in gastroesophageal cancer. In a retrospective study, among 515 patients with advanced E/GEJ cancer, HER2 overexpression was associated with increased risk of BRM (OR 2.45 [95% CI 1.10-5.46]). HER2-postive status was also associated improved PFS (HR 0.35 [95% CI 0.16-0.80]) and improved OS (HR 0.20, 95% CI 0.08-0.54) on 1L systemic therapy in patients with BRM.
Liang K, et al. ESMO Open. 2024 Jan;9(1):102199.
https://www.esmoopen.com/article/S2059-7029(23)01440-0/fulltext
Use of HIPEC in patients undergoing cytoreductive surgery (CRS) for gastric cancer and synchronous peritoneal metastases does not improve OS (GASTRIPEC-I Trial).
In a randomized phase III trial, 105 gastric cancer patients with peritoneal carcinosis were randomly assigned to CRS + HIPEC (CRS + H), or CRS alone (CRS-A). In 55 patients, treatment stopped before CRS due to disease progression/death. OS was the similar in both groups (mOS 14.9 vs 14.9 mo for CRS + H and CRS-A, respectively; p = .1647). mPFS was 7.1 vs 3.5 mo, respectively (p = .047), and metastasis-free survival 10.2 vs 9.2 mo, respectively (p =.0286). No increase in AEs was observed in the CRS + H group.
Rau B, et al. J Clin Oncol. 2024 Jan 10;42(2):146-156.
https://ascopubs.org/doi/10.1200/JCO.22.02867
☆ Addition of pembrolizumab to 1L trastuzumab + chemotherapy improves PFS in HER2+ gastric or gastro-esophageal junction adenocarcinoma (KEYNOTE-811).
In a randomized, phase III trial, 698 patients with HER2-positive gastro-esophageal adenocarcinoma were randomly assigned to receive pembrolizumab or placebo, combined with 1L chemotherapy (CAPOX or cisplatin/5-FU) + trastuzumab. Dual primary endpoints were PFS and OS. Compared with placebo, pembrolizumab significantly improved PFS: mPFS 10.0 vs 8.1 mo (HR 0.73 [95% CI 0.61-0.87]) at the third interim analysis. A subgroup analysis indicted that the improvement in PFS was pronounced if PD-L1 CPS was ≥1 (HR 0.71 [95% CI 0.59-0.86]), but was not apparent if CPS was <1 (HR 1.03 [95% CI 0.65-1.64]). OS has not meet the prespecified criteria for significance (mOS was 20.0 vs 16.8 months; HR 0.84 [95% CI 0.70-1.01]), and will continue to final analysis. TRAE of ≥G3 were observed in 58% and 51% patients, respectively.
Janjigian YY, et al. Lancet. 2023 Dec 9;402(10418):2197-2208.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736
Combination nivolumab with 1L chemotherapy decreases the risk of deterioration of quality of life in patients with advanced gastric/GEJ or esophageal adenocarcinoma (CheckMate 649).
In the CheckMate 649 trial, which explored the efficacy of 1L nivolumab + chemotherapy in patients with advanced GC/GEJ or esophageal adenocarcinoma, patient-reported outcomes (PROs) analysis revealed that the combination of nivolumab with chemotherapy showed a decreased risk of definitive HRQoL deterioration and a stable or better on-treatment HRQoL than chemotherapy alone. Final results showed that patient-reported symptom burden was not increased with nivolumab plus chemotherapy.
Moehler M, et al. J Clin Oncol. 2023 Dec 10;41(35):5388-5399.
https://ascopubs.org/doi/10.1200/JCO.23.00170
☆ The combination of lenvatinib plus pembrolizumab fails to improve survival compared to lenvatinib plus placebo in patients with advanced hepatocellular carcinoma (LEAP-002 trial).
In a global, double-blind, phase III trial, 794 patients with advanced unresectable HCC (stage BCLC-C and B) were randomized to receive 1L lenvatinib + pembrolizumab (the experimental arm) or lenvatinib + placebo (the control arm). The addition of pembrolizumab to lenvatinib failed to improve either of the primary endpoints: OS (mOS: 21.2 vs 19.9 mo, respectively; HR 0.84, 95% CI 0.71-1.00) or PFS (mPFS 8.2 vs 8.0 mo, respectively; HR 0.87, 95% CI 0.73-1.02). ORR according to RECIST 1.1 was 26% and 18%, respectively. TRAE of grade ≥3 were observed in 63% and 58% in the experimental and control arms, respectively. Combination of lenvatinib + pembrolizumab cannot be recommended as the 1L therapy of advanced HCC.
Llovet JM, et al. Lancet Oncol. 2023 Dec;24(12):1399-1410.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00469-2/fulltext
Tislelizumab provides non-inferior survival benefit when compared with Sorafenib in 1L advanced hepatocellular carcinoma (RATIONALE-301).
In a global, open-label, randomized phase III trial, 674 patients with histologically confirmed HCC (BCLC B or C; Child-Pugh class A status) were randomized to tislelizumab (anti-PD1 antibody) or sorafenib. Noninferiority of OS (the primary endpoint) between tiselizumab and sorafenib was tested against the non-inferiority margin of 1.08. mOS for tislelizumab was 15.9 vs 14.1 mo for sorafenib (HR = 0.85; [95.003% CI, 0.71-1.02]). The ORR was 14.3% vs 5.4%, and median DoR was 36.1 vs 11.0 mo (95% CI, 6.2-14.7), respectively. Median PFS was 2.1 vs 3.4 mo for tislelizumab vs sorafenib, respectively (HR = 1.11 [95% CI, 0.92-1.33]). Tislelizumab demonstrated a favorable safety profile. Tislelizumab was confirmed to be noninferior to sorafenib in OS.
Qin S, et al. JAMA Oncol. 2023 Dec; 9(12): 1651–1659.
https://jamanetwork.com/journals/jamaoncology/fullarticle/2810119
Artificial intelligence-based pathology may predict response to atezolizumab - bevacizumab in patients with hepatocellular carcinoma (HCC).
Atezolizumab–bevacizumab response signature (ARBS) defined using molecular biology profiling techniques was previously shown to predict PFS in patients with advanced HCC treated with atezolizumab–bevacizumab. In the current multicenter retrospective study, AI-based pathology reporting system was developed to predict ABRS (ABRS-P) directly from digital histological slides. ARBS-P was then tested as a predictive marker for PFS in patients treated with atezolizumab–bevacizumab. Study of samples from 840 patients illustrated a moderate correlation between the ABRS (molecular) parameter and the ABRS-P (AI-based pathology) score: r=0.62 (mean p<.0001) in the training series, and r=0.60 (p<.0001) and r=0.53 (p<.0001) in two validation series. In 122 patients treated with atezolizumab + bevacizumab, those with ABRS-P-high tumors (n=74) showed significantly longer mPFS (12 mo [95% CI 7–not reached]) than those with ABRS-P-low tumors (n=48; mPFS 7 mo [95% CO 4–9]; p = .014).
Zeng Q, et al. Lancet Oncol. 2023 Dec;24(12):1411-1422.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00468-0/fulltext
Combination of tucatinib and trastuzumab in patients with previously treated HER2–positive metastatic biliary tract cancer (mBTC) appears effective and safe (SGNTUC-019 basket study).
In a global open-label phase II basket trial, 30 patients with mBTC with HER2 overexpression and/or amplification were treated on a 21-day cycle with tucatinib (an oral selective HER2 inhibitor) plus trastuzumab. Patients had received a median of 1 prior treatment line in the advanced setting and were naïve to HER2-targeting agents. Confirmed ORR per investigator assessment was 46.7% (90% CI, 30.8 to 63.0), with a DCR of 76.7% (90% CI, 60.6 to 88.5) and PFS of 6.0 mo (90% CI, 5.5 to 6.9). Treatment was well tolerated.
Nakamura Y, et al. J Clin Oncol. 2023 Dec 20;41(36):5569-5578.
https://ascopubs.org/doi/10.1200/JCO.23.00606
Avasopasem, a selective dismutase mimetic, demonstrates promising activity in patients with pancreatic adenocarcinoma treated with stereotactic body radiotherapy.
In a phase Ib/II trial, avasopasem (an agent used to protect normal cells from, and sensitize cancer cells to radiation) was tested in 42 patients treated with SBRT with localized pancreatic adenocarcinoma. The primary objective was to identify the optimal dose of SBRT with avasopasem or placebo as determined by the late-onset EffTox method (it determines an optimal dose of radiotherapy considering both efficacy and toxicity). Late-onset EffTox responses were observed in 89% and 100% patients treated at 50 and 55 Gy in the avasopasem group, respectively, while the responses were described in 50% and 75% of the patient in the control group at 50 and 55 Gy, respectively. Combination of avasopasem and SBRT in locally advanced pancreatic cancer will be validated in a larger phase II trial.
Taniguchi CM, et al. Lancet Oncol. 2023 Dec;24(12):1387-1398.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00478-3/fulltext
☆ Combination of sotorasib plus panitumumab resulted in a longer progression-free survival than standard treatment in patients with chemorefractory colorectal cancer harboring a KRAS G12C mutation (CodeBreaK 300).
In a multicenter, randomized, phase 3 trial, 160 patients with chemorefractory metastatic CRC harboring KRAS G12C mutation received sotorasib (960 mg or 240 mg once daily) combined with panitumumab, or the investigator’s choice of trifludine-tipiracil or regorafenib (standard care). All patients received prior treatment with fluoropyrimidine, oxaliplatin and irinotecan. The median PFS was 5.6, 3.9 and 2.2 mo in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively (HR 0.49 [95% CI, 0.30-0.80; P = 0.006] for the 960 mg sotorasib-pani vs the control group; HR 0.58 [95% CI, 0.36-0.93; P = 0.03] for the 240 mg sotorasib-pani vs the control group). ORR was 26.4%, 5.7%, and 0% in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. The OS analysis is immature. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib + panitumumab.
Fakih MG, et al. N Engl J Med. 2023 Dec 7;389(23):2125-2139.
https://www.nejm.org/doi/10.1056/NEJMoa2308795
Real-world data suggest that the efficacy of trifluridine/tipiracil (FTD/TPI), when combined with bevacizumab, is independent of the RAS mutational status in metastatic CRC.
Data from 123 patients from five Austrian cancer centers were retrospectively collected. Eligible patients had previously received FTD/TPI + bevacizumab (any treatment line) and had available info on their molecular profile. Median OS was similar in the RAS wild-type [9.63 mo (95% CI 8.055-13.775)] and the RAS-mutant cohorts [8.78 mo (95% CI 8.055-11.014)], which was confirmed in a multivariable model adjusting for potential confounders; HR 1.05 (95% CI 0.618-1.785; p = .857). OS was 8.88 mo (95% CI 7.332-12.92) in patients with KRAS G12 mutation, compared to 9.47 mo (95% CI 8.088-11.375) in patients with RAS WT/non-KRAS G12 disease [HR: 0.822 (95% CI 0.527-1.282; p = .387)]. This suggests that the addition of bevacizumab to FTD/TPI may overcome the resistance to FTD/TPI monotherapy that was described in KRAS G12-mutant mCRC in past reports.
Doleschal B, et al. ESMO Open. 2023 Nov 15;8(6):102064.
https://www.esmoopen.com/article/S2059-7029(23)01305-4/fulltext
Both Panitumumab + Fluorouracil/Leucovorin and Panitumumab + FOLFOX are effective and safe 1L treatment options in Elderly Patients With RAS and BRAF wild-type Metastatic Colorectal Cancer (PANDA Trial).
An open-label, randomized phase II non-comparative study explored the safety and efficacy of panitumumab added to mFOLFOX (arm A) or LV-FU (arm B) as 1L treatment for patients aged ≥70 y.o. with unresectable RAS/BRAF wild-type mCRC. The primary endpoint was PFS, assuming a null hypothesis of mPFS at ≤6 mo. The study met its primary endpoint in both arms. mPFS was 9.6 and 9.0 mo for arm A and B, respectively (p < .001 in each arm). A post-hoc evidence indicated ORR of 69% and 52%, respectively, while mOS was 23.5 and 22.0 mo, respectively. As expected, 5-FU + LV + PAN was associated with a better safety profile. The overall rate of ≥G3 chemotherapy-related AE was 60% and 37%, respectively. Both mFOLFOX and 5-FU/LV + PAN are reasonable options as initial therapy of elderly patients with RAS/BRAF wild-type mCRC.
Lonardi S, et al. J Clin Oncol. 2023 Dec 1;41(34):5263-5273.
https://ascopubs.org/doi/10.1200/JCO.23.00506
A novel multimodal ctDNA-based blood test shows a promising accuracy in the detection of CRC.
A multimodal ctDNA-based blood test that integrates genomics, epigenomics and fragmentomics, plus proteomic profiling (in a refined version) was evaluated as a potential CRC screening method. The study tested two groups of individuals: people with a positive fecal immunochemical test (FIT) test, and patients diagnosed with CRC (623 persons in total). Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection was 84%, 94% and 96% for stage I, II and III CRC, respectively. Sensitivity to detect advanced premalignant lesions was 23% with a refined version of the test (integrating proteomics).
Bessa X, et al. Ann Oncol. 2023 Dec;34(12):1187-1193.
https://linkinghub.elsevier.com/retrieve/pii/S0923-7534(23)04010-3
Majority of older patients experience good QoL and stay independent after colorectal cancer surgery (GOSAFE study).
A prospective international study evaluated risk factors for failing to achieve a good quality of life (QoL) and functional recovery in patients >70 years undergoing elective surgery for CRC. Complete data were available for 625 patients (435 colon and 190 rectal cancer), median age 79.0 y. At 3-6 months, 68.9-70.3% patients experienced equal/better QoL (72.8-72.9% colon, 60.1-63.9% rectal cancer). With regards to QoL, preoperative Flemish Triage Risk Screening Tool (fTRST) ≥2 and postoperative complications are associated with decreased QoL after colectomy, whereas a Charlson Age Comorbidity Index ≥7, ECOG ≥2, severe complications, fTRST ≥2 and palliative surgery are risk factors for not achieving functional recovery.
Montroni I, et al. J Clin Oncol. 2023 Dec 1;41(34):5247-5262.
https://ascopubs.org/doi/10.1200/JCO.22.02195
☆ Pembrolizumab + chemotherapy exhibits a significant improvement in overall survival in HER2-negative advanced gastric (KEYNOTE-859).
In a global multicenter randomized double-blind phase III trial, 1579 participants were randomly assigned to receive pembrolizumab + chemotherapy (n=790) or placebo + chemotherapy (n=789). The investigator’s choice of chemotherapy was CAPOX in 86% and Cisplatin-Fluorouracil in 14% of cases. mOS was longer in the pembrolizumab group in the ITT population (12.9 vs 11.5 mo; HR 0.78 [95% CI 0.70–0.87]; p<.0001), in participants with PD-L1 CPS of ≥1 (13.0 vs 11.4 mo; HR 0.74 [95% CI 0.65–0.84]; p<.0001), and in participants with PD-L CPS of ≥10 (15.7 vs 11.8 mo; 0.65 [95% CI 0.53–0.79]; p<.0001). Toxicity was manageable and no new safety signals were identified.
Rha SY, et al. Lancet Oncol. 2023 Nov;24(11):1181-1195.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00515-6/fulltext
KRAS and BRAF V600E mutations associate with different prognostic values in MSS and MSI stage III colon cancer (ACCENT/IDEA analysis).
In a pooled analysis of 7 trials evaluating the duration of adjuvant chemotherapy in resected stage III colon cancer, the prognostic impact of MMR status, and KRAS (codon 12 & 13) and BRAF V600E mutations was tested. In MSS tumors, KRAS and BRAF V600E mutations, as compared to KRAS/BRAF wild-type status, negatively impacted time-to-recurrence (TTR; HR 1.58 and 1.31, respectively, both p<.001; 5-y DFS 66%, 62% and 73%, respectively). The presence of KRAS and BRAF mutations was also detrimental for OS (HR 1.35 & 2.06, respectively; p<.0001 for both) and survival after recurrence (HR 1.25 & 2.87, respectively; p<.0001 for both). In MSI tumors, no influence of KRAS or BRAF mutations on TTR was seen (HR 0.99 & 0.98; 5-y DFS 76%, 76% and 75% in KRAS mut, BRAF V600E mutant, and KRAS/BRAF wild-type groups, respectively); however, BRAF V600E mutation had a negative effect on OS (HR 1.36, p=.042), and KRAS and BRAF mutations worsened survival after recurrence (HR 1.52, p=.07, and HR 1.99, p<.001)."
Taieb J, et al. Ann Oncol. 2023 Nov;34(11):1025-1034.
https://www.annalsofoncology.org/article/S0923-7534(23)00804-9/fulltext
☆ In esophageal cancer, prolonged time to surgery after neoadjuvant CRT does not improve histological complete response, but may lead to worse patients’ survival (NeoRes II).
The multi-centered trial aimed to assess whether standard (4-6 weeks) or prolonged (10-12 weeks) time to surgery (TTS) in patients with esophageal cancer after neoadjuvant CRT was associated with a better histological response. In total, 249 patients with esophageal cancer were randomized: 125 to standard and 124 to prolonged TTS. The primary endpoint, the rate of complete histological response (pCR) in patients with adenocarcinoma, was not significantly different between the standard (21%) and prolonged (26%) TTS cohorts (p=.429). Similarly, pCR rate in patients with resected squamous cell cancers was comparable in both treatment arms (55% vs 46% in the standard and prolonged TTS cohorts, respectively; p=.545) Tumor regression, resection margins and number of resected lymph nodes did not differ either. However, a trend of worse survival was found after prolonged TTS (HR 1.35; 95% CI 0.94-1.95, p=.107), suggesting caution in routinely delaying surgery for >6 weeks after neoadjuvant CRT.
Nillson K, et al. Ann Oncol. 2023 Nov;34(11):1015-1024.
https://www.annalsofoncology.org/article/S0923-7534(23)00825-6/fulltext
☆ Adjuvant atezolizumab plus bevacizumab improves recurrence free survival versus active surveillance in patients with high-risk hepatocellular carcinoma (IMBRAVE-050).
In a randomized phase III trial, 668 patients with high-risk surgically resected or ablated hepatocellular carcinoma were randomly assigned to either atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) for 17 cycles, or to active surveillance. High-risk features included: tumor size >5 cm, tumor number >3, vascular invasion (micro- or macrovascular) and poor tumor differentiation (G3-4). At the prespecified interim analysis, recurrence-free survival (the primary end-point) was improved in the adjuvant arm compared with active surveillance (median RFS not achieved in either arm; HR = 0.72 [95% CI 0.53–0.98], p=.012). Both atezolizumab and bevacizumab were discontinued because of adverse events in 9% of patients who received atezolizumab plus bevacizumab. Longer follow-up for both recurrence-free and overall survival is needed to assess the benefit–risk profile more fully.
Qin S, et al. Lancet. 2023 Nov 18;402(10415):1835-1847.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01796-8/fulltext
Nimotuzumab, an anti-EGFR antibody, plus gemcitabine improves outcomes in KRAS wild-type locally advanced or metastatic pancreatic cancer.
A Chinese randomized phase III trial evaluated the efficacy of the addition of nimotuzumab (anti-EGFR Ab) to first-line gemcitabine in patients with KRAS wild-type locally advanced or metastatic pancreatic cancer. 82 individuals with KRAS wild-type tumors were eligible. Nimotuzumab + gemcitabine, as compared to gemcitabine monotherapy, resulted in numerically superior OS, the primary end-point (mOS 10.9 vs 8.5 mo; HR 0.66 [95% CI, 0.42 to 1.05]; p=.08 ). Since the proportional hazards assumption was violated due to the separation of survival curves only after 6 mo, the authors used the restricted mean survival time (RMST) model to calculate the survival differences. The experimental arm resulted in a superior RMST (18.05 vs 11.4 mo in the experimental group and control groups, respectively, ratio = 0.62, [95% CI 0.40-0.97]; p=.036). While the experimental arm produced superior PFS (mPFS: 4.2 vs 3.6 mo; HR 0.60 [95% CI 0.37-0.99]), ORR and DCR rates were similar in both arms (7% vs 10%, and 68% vs 63% in the investigational and control arms, respectively).
Qin S, et al. J Clin Oncol. 2023 Nov 20;41(33):5163-5173.
https://ascopubs.org/doi/10.1200/JCO.22.02630
In a large pan-cancer cohort, pancreatic acinar cell carcinoma (PACC) was identified as the cancer type with the highest prevalence of BRCA2 germline pathogenic variants and genomic features of HRD.
Somatic and germline analyses were performed in 28,780 patients with cancer, 49 of whom were diagnosed with PACC. Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 (n = 1), BRCA2 (n = 12), PALB2 (n = 2), ATM (n = 2), and CHEK2 (n = 1). BRCA2 germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma, high-grade serous ovarian carcinoma, prostate cancer, and breast cancer. Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs tested with WGS. These data suggest that PACC should be considered as part of the spectrum of BRCA-related malignancies.
Mandelker D, et al. J Clin Oncol. 2023 Nov 20;41(33):5151-5162.
https://ascopubs.org/doi/10.1200/JCO.23.00561
The combination of first-line regorafenib, nivolumab, and FOLFOX shows promising activity in advanced esophagogastric adenocarcinoma.
In a single-arm, single-center phase 2 trial, patients with HER2-negative metastatic esophagogastric adenocarcinoma received 1L chemotherapy FOLFOX6 combined with nivolumab and regorafenib. The primary endpoint was 6-mo PFS in the per-protocol analysis (expected in at least 24/35 pts). The study was positive with 25 of 35 patients (71%) progression-free at 6 mo. Other findings included: 12-mo PFS of 51%, mPFS of 13.0 mo, 12-mo OS of 85%, and ORR of 76%. Serious TRAE occurred in 26% patients, with no treatment-related deaths observed. A randomized phase 3 clinical trial is planned.
Cytryn SL, et al. Lancet Oncol. 2023 Oct;24(10):1073-1082.
https://linkinghub.elsevier.com/retrieve/pii/S1470-2045(23)00358-3
MRI is insufficient to accurately predict pCR in patients with locally advanced rectal cancer treated with TNT.
A prospective imaging substudy of NRG-GI002 (a parent phase 2 study evaluating novel radiosensitizers in rectal cancer) assessed the utility of Magnetic Resonance Tumor Regression Grade (MR-TRG) to predict pCR in patients with locally advanced rectal cancer treated with total neoadjuvant treatment (TNT). The study evaluated the data of 121 patients. MR-TRG scores were associated with pCR (p < .01) and pathologic neoadjuvant response score (p < .0001). There was a moderate agreement between MR-TRG and the pathologic response score with a kappa of 0.43. However, the PPV for pCR was only 40% (95% CI, 26 to 53), and the NPV was 84% (95% CI, 75 to 94). The authors conclude that, although MR-TRG can objectively measure regression magnitude during TNT, MRI alone is insufficient to accurately identify pCR.
Hall WA, et al. J Clin Oncol. 2023 Oct 10;41(29):4643-4651.
https://ascopubs.org/doi/10.1200/JCO.22.02525
Pathologic lymph node regression after neoadjuvant chemotherapy is an independent predictive factor for survival in esophageal cancer.
A multicenter study from the UK aimed to evaluate how pathologic lymph node (LN) regression after neoadjuvant chemotherapy influences survival after surgery for esophageal adenocarcinoma. In total, 17930 LNs from 763 patients were examined using a three-point classification system (complete, partial and poor/no response). Of these patients, 8.1% had a complete response, 20.3% partial response, 39.7% poor/no response and 31.8% were LN negative. Mortality was reduced in patients with complete LN response (HR 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). Pathologic lymph node regression after neoadjuvant chemotherapy is an independent predictive factor for survival and may provide important information beyond pathologic TNM staging and primary tumor regression grading.
Moore JL, et al. J Clin Oncol. 2023 Oct 1;41(28):4522-4534.
https://ascopubs.org/doi/10.1200/JCO.23.00139
Individual Participant Data (IPD) Network Meta-Analysis (NWA) of Neoadjuvant Chemo- or Chemoradiotherapy in Esophageal or Gastroesophageal Junction (GEJ) Carcinoma confirms overall survival benefit for both strategies over surgery alone.
The MANATEC-02 collaborative group conducted an IPD-NWA to evaluate whether neoadjuvant chemotherapy and chemoradiotherapy have a differential effect on survival for esophageal or GEJ carcinoma and, in particular, across histology, location, and sex. This NWA included 26 published randomized controlled trials, that completed accrual before the end of 2015, comparing at least two of the following strategies: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). IPD were obtained for nearly 5.000 patients. Neoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS (larger OS benefit for females) and tumor location for CS (larger OS benefit for GEJ). A strong OS difference between CS and CRS was not identified.
Faron M, et al. J Clin Oncol. 2023 Oct 1;41(28):4535-4547.
https://ascopubs.org/doi/10.1200/JCO.22.02279
Immune checkpoint blockade does not eliminate the risk of de novo cancer in Lynch syndrome carriers but influences the types of new primary malignancies.
A retrospective analysis examined the incidence on new primary neoplasia in 172 cancer-affected patients with Lynch syndrome who had received ≥1 immune checkpoint blockade cycle, ICB (66% treated for metastatic disease). Following immunotherapy, 21 (12%) individuals developed subsequent malignancies (91% of which were dMMR). The median time to the development of new malignancy was 21 mo (interquartile range, 6-38). Among the 21 new malignances in the ICB-treated patients, 57% were skin malignancies (median to development after the 1st neoplasm: 4.5 mo), and 43% were visceral tumors (median to development after the 1st neoplasm: 43.0 mo). Additionally, premalignant polyps were found in 39% of ICB-treated patients who underwent surveillance colonoscopy. A comparison of the pre- and post-immunotherapy follow-up periods revealed that ICB did not reduce the risk overall rate of tumor development, however it altered the pattern of new cancer types: ICB reduced the incidence of visceral tumors, while it increased the incidence of skin neoplasms.
Harrold EC, et al. Nat Med. 2023 Oct;29(10):2458-2463.
https://www.nature.com/articles/s41591-023-02544-9
Trastuzumab combined with ramucirumab and paclitaxel showed appreciable efficacy with consistent safety profiles as 2nd line treatment for HER2-positive gastric or gastroesophageal junction(G/GEJ) cancer
In the phase II study, 50 patients with HER2-positive G/GEJ cancer were treated with trastuzumab combined with ramucirumab and paclitaxel following progression under trastuzumab-containing chemotherapy. With a median follow-up duration of 27.5 months, median PFS and OS were 7.1 months (95% CI, 4.8 to 9.4) and 13.6 months (95% CI, 9.4 to 17.7), respectively. ORR was 54 % (27 of 5) including one complete response and DCR was 96% (48 of 50). Safety profiles were consistent with previous reports.
Kim CG, et al. J Clin Oncol. 2023 Sep 20;41(27):4394-4405.
https://ascopubs.org/doi/full/10.1200/JCO.22.02122
Phase II FIRE-4.5 trial shows no superiority of 1L treatment with FOLFOXIRI-cetuximab compared to FOLFOXIRI-bevacizumab in patients with BRAF V600E mutant metastatic colorectal cancer.
In the randomized, open-label phase II trial, 109 patients with mCRC harboring the BRAF V600E mutation were randomized 2:1 to the cetuximab-FOLFOXIRI or bevacizumab-FOLFOXIRI 1L treatment arms. The primary endpoint ORR was 51% in the cetuximab-based experimental arm, and 67% in the bevacizumab-based control arm (OR 1.93; 80%CI, 1.06-3.52; p=.92 [one sided]). Median PFS was significantly inferior (6.7 mo vs 10.7 mo; HR 1.89; p=.006) and median OS showed a trend toward shorter survival in cetuximab-treated patients (12.9 mo vs 17.1 mo; HR 1.4; p=.20). Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAF V600E-mutant mCRC.
Stintzing S, et al. J Clin Oncol. 2023 Sep 1;41(25):4143-4153.
https://ascopubs.org/doi/full/10.1200/JCO.22.01420
Camrelizumab plus Rivoceranib outperforms Sorafenib in patients with advanced hepatocellular carcinoma (CARES-310).
In the randomized, international phase 3 trial involving 543 patients with unresectable HCC the combination of camrelizumab (anti-PD1) + rivoceranib (mTKI) outperformed sorafenib as the first-line treatment. The results demonstrated improvements in progression-free survival and overall survival — mPFS: 5.6 mo vs 3.7 mo (HR 0.52 [95% CI 0·41–0·65], one-sided p<0.0001); mOS: 22.1 mo vs 15.2 mo for camrelizumab + rivoceranib and sorafenib, respectively (HR 0.62 [95% CI 0.49–0.80]; one-sided p<.0001). Grade ≥3 TRAEs were observed in 81% of patients in the experimental arm (the most common being hypertension, hand-foot syndrome, elevated AST or ALT), and 52% in the control group.
Qin S, et al. Lancet. 2023 Sep 30;402(10408):1133-1146.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00961-3
Stereotactic Body Radiation Therapy (SBRT) demonstrates effectiveness in the treatment of intermediate-stage hepatocellular carcinoma (the TRENDY Trial).
In a multicenter, randomized, phase 2 trial, patients with HCC eligible for transarterial chemoembolization (TACE) were randomized between TACE-DEB and stereotactic body radiation therapy (SBRT; 6 fr x 8-9Gy). The trial was closed prematurely due to slow patient enrollment, with 16 patients in the TACE-DEB group and 12 in the SBRT group. While there was no significant difference in Time to Progression (the primary end-point; median TTP 12 mo for TACE- DEB and 19 mo for SBRT; p=.15), SBRT showed better local tumor control (median LC 12 mo for TACE- DEB and >40 mo for SBRT; p=.075). The median OS was 36.8 months for TACE-DEB and 44.1 months for SBRT (p=.36). Both treatments resulted in high response rates (>80%). Adverse events were observed in 19% of patients in the TACE-DEB group, but none in the SBRT group. The study suggests that SBRT may be effective in controlling locally advanced HCC that are not eligible for surgery.
Romero AM, et al. Int J Radiat Oncol Biol Phys. 2023 Sep 1;117(1):45-52.
https://www.redjournal.org/article/S0360-3016(23)00308-5/
Zolbetuximab + CAPOX combination provides benefit in first line treatment of CLDN18.2-positive unresectable and metastatic gastric/GE junction adenocarcinoma (the global phase 3 GLOW trial).
Zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma, met both primary and key secondary endpoints. 507 patients were randomized 1:1 to zolbetuximab + CAPOX or placebo + CAPOX. Results showed statistically and clinically significant improvement in mPFS (8.21 mo vs. 6.80; HR = 0.687; 95% CI, 0.544–0.866; P = 0.0007) and mOS (14.39 mo vs. 12.16 mo; HR = 0.771; 95% CI, 0.615–0.965; P = 0.0118). These results further support the survival benefits observed in the recent phase 3 SPOTLIGHT trial were zobetuximab was combined with a mFOLFOX backbone in the same treatment setting.
Shah MA, et al. Nat Med. 2023 Aug;29(8):2133-2141. https://www.nature.com/articles/s41591-023-02465-7
Risk-adapted neoadjuvant chemoradiotherapy in rectal cancer (OCUM study).
In the multicenter study, patients with rectal cancer (cT2–4, any cN, cM0) were classified according to minimal distance between the tumor, suspicious lymph nodes or tumor deposits, and mesorectal fascia on pelvic MRI. Patients with distance > 1 mm underwent upfront total mesorectal excision TME (low-risk group); those with distance ≤ 1 mm and/or cT4 and cT3 tumors in the lower rectal third received neoadjuvant chemoradiotherapy (nCRT) followed by TME (high-risk group). 530 patients underwent upfront TME and 354 patients received nCRT followed by TME. Results indicated 5-year locoregional recurrence (LR) rates of 4.1% (95% CI, 2.7 to 5.5) for patients treated per protocol, 2.9% (95% CI, 1.3 to 4.5) after up-front surgery, and 5.7% (95% CI, 3.2 to 8.2) after nCRT followed by surgery. The 5-year rate of distant metastases was 15.9% (95% CI, 12.6 to 19.2) and 30.5% (95% CI, 25.4 to 35.6), respectively. In a subgroup analysis of 570 patients with lower and middle rectal third cII and cIII tumors, the 5-year LR rate was 3.8% (95% CI, 1.4 to 6.2) after up-front surgery. In 271 high-risk patients, the 5-year rate of LR was 5.9% (95% CI, 3.0 to 8.8) and of metastases 34.5% (95% CI, 28.6 to 40.4). The findings support avoidance of nCRT in low-risk patients and suggest that in high-risk patients, neoadjuvant therapy should be intensified to improve prognosis.
Ruppert R, et al. J Clin Oncol. 2023 Aug 20;41(24):4025-4034. https://ascopubs.org/doi/full/10.1200/JCO.22.02166
The combination of Durvalumab-Tremelimumab with mFOLFOX6 in 1L RAS-mutant mCRC is tolerable and shows promising clinical activity (MEDITREME trial).
A phase Ib/II included 48 patients with RAS-mutant microsatellite stable mCRC, treated in 1L with mFOLFOX6 + durvalumab (750 mg q2w) + tremelimumab (75 mg q4w). Patients with stable or responding tumors after 3 months of combination therapy, continued on maintenance durvalumab (750 mg q2w) for a maximum of 1 year. This study reached its primary objective, with 3-month PFS of 90.7%, 6-mo PFS of 60% and mPFS of 8.2 months. ORR was 63%. Higher tumor mutational burden and lower genomic instability were seen in responders. Transcriptomic analysis underlined that high immune signature and low epithelial–mesenchymal transition were associated with better outcome.
Thibaudin M, et al. Nat Med. 2023 Aug;29(8):2087-2098. https://www.nature.com/articles/s41591-023-02497-z
Identification of molecular signature predictive of ICI benefit in MSI-H mCRC.
A translational study retrospectively evaluated genomic (DNA) and transcriptional (RNA) markers for predicting response to immunotherapy (anti-PD1 ± anti-CTLA4) in 116 patients with MSI-H mCRC. Tumor mutation burden, MSIsensor score, or specific cellular contingents within the tumor bulk did not predict ICI resistance. In contrast, PFS by immune RECIST (iPFS) was negatively influenced by multiplex MSI signature involving mutations in 19 microsatellites (HR = 3.63, 95% CI 1.65-7.99), and fibrotic, non-epithelial transforming growth factor beta (TGFB)-related RNA markers (HR = 1.75; 95% CI 1.03-2.98).
Ratovomanana T, et al. Ann Oncol. 2023 Aug;34(8):703-713.
https://www.annalsofoncology.org/article/S0923-7534(23)00695-6/fulltext
Association of alcohol intake with the risk of early-onset colorectal cancer.
In this Korean trial, the risk of early-onset CRC and the association between average daily alcohol consumption were investigated among over 5 million individuals aged between 20-49 years. 8314 cases of early-onset CRC were identified. Moderate (10 to <30 g/d for men, 10 to <20 g/d for women) and heavy (≥30 g/d for men, ≥20 g/d for women) drinkers showed an increased risk of early-onset CRC compared with light drinkers (aHR, 1.09 [95% CI, 1.02 to 1.16] and aHR, 1.20 [95% CI, 1.11 to 1.29], respectively). Subgroup analysis by tumor location showed positive dose-response significance for early-onset distal colon and rectal cancers, but not for proximal colon cancer.
Jin EH, et al. J Clin Oncol. 2023 Aug 1;41(22):3816-3825. https://ascopubs.org/doi/10.1200/JCO.22.01895
Erdafitinib demonstrates clinical activity across a range of GI cancers harboring FGFR alterations (RAGNAR study).
In phase II, single-arm, basket trial, erdafitinib (pan-FGFR TKI) demonstrated clinical benefit in tumors harboring predefined FGFR1–4 alterations (mutations or fusions). The trial included previously treated patients with no alternative standard therapy available who were diagnosed with advanced pancreatic cancer (n = 18, ORR = 56%, DCR = 94%, mPFS 7.0 mo, mOS 19.7 mo), cholangiocarcinoma (n = 31, ORR = 52%, DCR = 97%, mPFS 8.3 mo, mOS 14.7 mo), gastric cancer (n = 8, ORR = 13%, DCR = 63%, mPFS 2.4 mo, mOS 3.6 mo), and esophageal cancer (n = 8, ORR = 13%, DCR = 38%, mPFS 1.4 mo, mOS 7.0 mo). The most common ≥G3 TRAE were stomatitis (12%), hand-foot syndrome (6%), and hyperphosphatemia (5%).
Pant S, et al. Lancet Oncol. 2023 Aug;24(8):925-935.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00275-9/fulltext
Zanidatamab in gemcitabine-refractory HER2-amplified advanced biliary tract cancer (HERIZON-BTC-01).
In a single-arm phase 2b study, zanidatamab (a bispecific Ab targeting two distinct HER2 epitopes) was assessed in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer who had experienced disease progression on gemcitabine-based therapy. Among 80 patients with HER2 2+ or 3+ expression in IHC, zanidatamab resulted ORR of 41%, mPFS of 5.5 mo, and a 9-mo OS rate of 69.9%.
Harding JJ, et al. Lancet Oncol. 2023 Jul;24(7):772-782.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00242-5/fulltext
Trastuzumab deruxtecan in HER2-positive advanced gastric or gastroesophageal junction cancer pretreated with trastuzumab-containing regimens (DESTINY-Gastric02).
In a single-arm phase 2 study conducted in Western countries, trastuzumab deruxtecan was evaluated in the 2L+ setting in 79 patients with HER2-positive advanced gastric or gastroesophageal junction cancer who had previously been treated with a trastuzumab-containing regimen. In an updated analysis, trastuzumab deruxtecan demonstrated ORR of 42% (including CR in 5% pts), mPFS of 5.6 mo, and mOS of 12.1 mo.
Van Cutsem E, at al. Lancet Oncol. 2023 Jul;24(7):744-756.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00215-2/fulltext
Neoadjuvant FOLFOX is noninferior to CRT in treatment of locally advanced rectal cancer (PROSPECT).
PROSPECT was a multicenter randomized noninferiority trial of neoadjuvant FOLFOX6 versus combined chemo- and radiation therapy, which enrolled adults with locally advanced rectal cancer (cT2N+, cT3N0, or cT3N+), who were candidates for sphincter-sparing surgery. 1128 patients started treatment, of those 585 were assigned to the FOLFOX group (6 cycles) and 543 to the chemoradiotherapy group (CRT: 50,4 Gy with 5-FU or capecitabine). Adjuvant chemotherapy was optional in each arm. Patients with suboptimal responses to FOLFOX (<20% tumor regression) selectively received preoperative CRT (used in 9% participants in the FOLFOX arm). At a median follow-up of 58 mo, FOLFOX was noninferior to CRT for DFS (HR = 0.92, 90.2% CI, 0.74-1.14, p=0.005 for noninferiority). 5-year DFS was 80.8% in the FOLFOX and 78.6% in the chemoradiotherapy group. No significant differences in OS were found.
Schrag D, et al. N Engl J Med 2023; 389:322-334. https://www.nejm.org/doi/full/10.1056/NEJMoa2303269
Patient-Reported Outcomes (PROs) during and after treatment for locally advanced rectal cancer in the PROSPECT Trial (Alliance N1048)
Within the PROSPECT trial, patients were asked to provide patient-reported outcomes (PROs), which included 14 symptoms from the PRO-CTCAE at baseline, during neoadjuvant therapy and at 12 months after surgery. In total, 940 patients contributed PRO-CTCAE data. During neoadjuvant treatment, significantly lower rates of diarrhea and better overall bowel function were reported in the FOLFOX cohort, while anxiety, appetite loss, constipation, depression, fatigue, neuropathy, and vomiting were lower with 5-FU CRT (p<0.05). At 12 months post-surgery, patients assigned to FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function compared to 5-FU CRT (p<0.05). In conclusion, for patients with locally advanced rectal cancer choosing between neoadjuvant FOLFOX and 5-FU CRT, the distinctive PRO profiles inform treatment selection and shared decision making.
Basch E, at al. J Clin Oncol. 2023 Jul 20;41(21):3724-3734.
https://ascopubs.org/doi/full/10.1200/JCO.23.00903
Fruquintinib improves survival in patients with heavily pretreated metastatic colorectal cancer (FRESCO-2).
In an international randomized phase 3 study, fruquintinib (an oral inhibitor of VEGFRs 1-3) was compared to a placebo in 691 patients with metastatic colorectal cancer who had previously received all standard approved therapies, including trifluridine-tipiracil and/or regorafenib. Fruquintinib demonstrated improvements in OS (mOS = 7.4 vs 4.8 mo, respectively; HR= 0.66, 95% CI 0.55-0.80) and PFS (mPFS = 3.7 vs 1.8 mo, respectively; HR = 0.32, 95% CI 0.27-0.39) compared to the placebo. Grade ≥3 adverse events occurred in 63% of patients who received fruquintinib (mainly hypertension, asthenia, and hand-foot syndrome), while the rate was 50% for those on placebo.
Dasari A, at al. Lancet. 2023 Jul 1;402(10395):41-53.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00772-9/fulltext
Choice of 1L treatment in patients with initially unresectable CRC with liver metastases (CAIRO5).
In a phase 3 study, 530 patients with initially unresectable colorectal cancer liver metastases were randomized to receive different systemic treatments based on the primary tumor location and RAS/BRAF mutational status. For right-sided or RAS/BRAF V600E-mutated tumors, FOLFOXIRI + bevacizumab demonstrated superiority over FOLFOX or FOLFIRI + bevacizumab in terms of PFS (mPFS 10.6 vs 9.0 mo, respectively; HR = 0.76, 95% CI 0.60-0.98), ORR (54% vs 33%; p = 0.0004), and complete local treatment rate. In left-sided and RAS/BRAF V600E wild-type tumors, similar PFS were achieved with either bevacizumab or panitumumab, both in combination with FOLFOX or FOLFIRI (mPFS 10.8 vs 10.4 months, respectively; HR = 1.11, 95% CI 0.84-1.48). The addition of panitumumab resulted in a higher ORR compared to bevacizumab (80% vs. 53%; p < 0.0001), although the complete local treatment rate did not differ. OS data are pending.
Bond MJG, et al. Lancet Oncol. 2023 Jul;24(7):757-771.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00219-X/fulltext
Anti–EGFR rechallenge combined with trifluridine-tipiracil improves PFS in refractory RAS wild-type mCRC.
In an Italian phase II trial, 62 patients with refractory RAS-wt mCRC who had achieved a response to 1L chemotherapy plus an anti-EGFR antibody were randomized in a 1:1 ratio to receive trifluridine-tipiracil ± panitumumab as part of their late-line therapy. The addition of panitumumab to FTD/TPI improved PFS compared to FTD/TPI alone (mPFS 4.0 vs 2.5 mo; HR = 0.48; 95% CI, 0.28-0.82). Pretreatment plasma RAS/BRAF wild-type ctDNA was associated with a clinical benefit from panitumumab. Among patients whose tumors were wild-type for KRAS, NRAS, BRAF V600E, EGFR, ERBB2, MAP2K1, and PIK3CA (comprising 65% of the participants), mPFS of 6.4 mo was achieved with trifluridine-tipiracil + panitumumab.
Napolitano S, et al. JAMA Oncol. 2023 Jul 1;9(7):966-970.
https://jamanetwork.com/journals/jamaoncology/fullarticle/2805081
BILIARY CANCER
Pembrolizumab in combination with gemcitabine and cisplatin provides survival benefit in 1L treatment of advanced biliary tract cancer (KEYNOTE-966)
KEYNOTE-966 was a global, randomized, double-blind phase 3 trial conducted in patients with previously untreated, unresectable, locally advanced or metastatic biliary tract cancer (BTC). Participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine and cisplatin. 1564 patients were screened for eligibility, 1069 of whom were randomly assigned. The study met its primary endpoint on median OS: 12.7 mo (95% CI, 11.5–13.6) vs 10.9 mo (9.9–11.6) with HR = 0.83 (95% CI, 0.72–0.95; one-sided p = .0034).
Kelly RK, et al. Lancet. 2023 Jun 3;401(10391):1853-1865.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00727-4
COLORECTAL CANCER
Adjuvant oxaliplatin does not improve survival in older patients with CRC
In a pooled analysis of 8 randomized trials comparing adjuvant oxaliplatin-containing vs fluoropyrimidine-based adjuvant CTx in high-risk patients with stage II–III colorectal cancer, the use oxaliplatin did not improve OS (HR = 1.02; 95% CI, 0.82-1.27) or DFS (HR = 0.87; 95% CI, 0.76-1.00) in elderly patients (≥70 y.o). Improvements were seen in non-elderly patients with HRs = 0.74 (95% CI, 0.64-0.84) for OS and = 0.74 (95%, CI 0.69-0.79) for DFS.
Dottorini L, et al. J Clin Oncol. 2023 Jun 20;41(18):3300-3303.
https://ascopubs.org/doi/10.1200/JCO.23.00354
Consensus molecular subtypes (CMS) impact outcomes in RAS wild-type metastatic CRC treated with 1L maintenance 5-FU and folinic acid with or without panitumumab
In retrospective analysis of phase II PanaMa trial, consensus molecular subtypes (CMS) influenced outcomes (ORR, PFS, OS) in patients with RAS wild-type mCRC treated with maintenance 5-FU and folinic acid ± panitumumab after mFOLFOX6 + panitumumab. Better outcomes were observed for CMS2 (canonical subtype) and CMS4 (mesenchymal), while CMS1 (MSI immune) and CMS3 (metabolic) subtypes were associated with less favorable PFS & OS. Addition of panitumumab to the 5-FU maintenance in CMS2/4 improved PFS (CMS2: HR = 0.58, 95% CI, 0.36-0.95, p = .03; CMS4: HR = 0.63, 95% CI, 0.38-1.03, p = .07) and OS (CMS4: HR = 0.54; 95% CI, 0.30-0.96, p = 0.04), but produced no benefits in survival in CMS1/3.
Stahler A, et al. J Clin Oncol. 2023 Jun 1;41(16):2975-2987.
https://ascopubs.org/doi/10.1200/JCO.22.02582
Plasmatic BRAF-V600E allele fraction is a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments
In multicenter study, the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) were evaluated for the combination of a BRAF inhibitor + anti-EGFR ± MEK inhibitor. In total, 47 patients were included in the discovery cohort & 29 patients in the validation cohort. In the discovery cohort, median PFS and OS were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS (HR 2.97, 95% CI 1.55-5.69; p = 0.001) and worse OS (HR 3.28, 95% CI 1.58-6.81; p = 0.001) than low-BRAF AF patients (<2%, n = 24). An exploratory analysis of predictive value revealed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, p < 0.01).
Ros J, et al. Ann Oncol. 2023 Jun;34(6):543-552.
https://www.annalsofoncology.org/article/S0923-7534(23)00112-6/fulltext
Early detection of molecular residual disease and risk stratification for stage I to III colorectal cancer via circulating tumor DNA methylation
In longitudinal cohort study of 299 patients with stage I to III colorectal cancer (CRC), circulating tumor DNA status was evaluated with 6 DNA methylation markers. At postoperative month 1, ctDNA-positive patients were 17.5 times more likely to relapse than were ctDNA-negative patients (HR, 17.5; 95% CI 8.9-34.4; p < .001). After adjuvant chemotherapy, ctDNA-positive patients had a significantly shorter recurrence-free survival when compared to the ctDNA-negative patients (HR, 13.8; 95% CI, 5.9-32.1; p < .001). Longitudinal ctDNA analysis after the post-definitive treatment showed that ctDNA-positive patients had poorer recurrence-free survival than ctDNA-negative patients (HR, 20.6; 95% CI, 9.5-44.9; p < .001). Post-definitive treatment analysis detected CRC recurrence earlier than radiologically confirmed recurrence, with a median lead time of 3.3 months (IQR, 0.5-6.5 months).
Mo S, et al. JAMA Oncol. 2023 Jun 1;9(6):770-778.
https://jamanetwork.com/journals/jamaoncology/article-abstract/2803768
BILIARY CANCER
In Asian open-label phase IIb trial, addition of nal-IRI to FU/LV (LV5FU2) significantly improved PFS in patients with previously treated advanced BTC (central review mPFS: 4.2 mo for nal-IRI + FU/LV vs 1.2 mo for FU/LV alone; HR 0.61, 95% CI 0.44-0.86, p=0.004).
Hyung J, et al. JAMA Oncol 2023;9(5), 692-699
https://jamanetwork.com/journals/jamaoncology/article-abstract/2802825
In a phase 2 basket trial, dabrafenib (BRAFi) + trametinib (MEKi) demonstrated tumor-agnostic activity in previously treated BRAF V600E-mutated advanced cancers. The trial enrolled 43 patients with biliary tract cancers (investigator-assessed ORR 53% [all PR], mPFS 9.0 mo, mOS 13.5 mo) and 3 persons with small intestine adenocarcinoma (ORR 67%, mPFS 9.5 mo, mOS 21.8 mo).
Subbiah V, et al. Nat Med 2023, 29, 1103–1112.
https://doi.org/10.1038/s41591-023-02321-8
COLORECTAL CANCER
In phase III randomized trial, 492 patients with mCRC after 1 or 2L of palliative treatment received FTD/TPI + bevacizumab or FTD/TPI alone (1:1 ratio). The addition of anti-VEGF-A prolonged PFS (mPFS: 5.6 vs 2.4 mo; HR 0.44; 95% CI 0.36-0.54, p<0.001), and OS (mOS: 10.9 vs 7.5 mo; HR 0.61; 95% CI 0.49-0.77, p < 0.001). No new safety signals were identified.
Prager GW, et al. N Engl J Med 2023; 388:1657-1667.
https://www.nejm.org/doi/full/10.1056/NEJMoa2214963
In a global open label, phase 2 study enrolled 117 patients with chemo-refractory HER2+/RAS WT unresectable or metastatic CRC. In 84 patients treated with Tucatinib (oral HER2 targeted TKI) + Trastuzumab (iv anti-HER2 mAb) combo the confirmed ORR per blinded independent central review was 38.1% (95% CI 27.7-49.3), of which 3 patients achieved a complete response.
Strickler JH, et al. Lancet Oncol. 2023 May;24(5):496-508.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00150-X/fulltext
In phase II single-arm trial, patients with BRAF V600E mutant mCRC were treated in 1L with encorafenib (BRAFi) + binimetinib (MEKi) + cetuximab (anti-EGFR Ab). Triplet therapy had a manageable safety profile and resulted in ORR of 47.4% (all PR), mPFS 5.8 mo, and mOS 18.3 mo.
Van Cutsem E, et al. J Clin Oncol 2023, 41:14, 2628-2637.
https://ascopubs.org/doi/full/10.1200/JCO.22.01693
ESOPHAGEAL CANCER
In a global, randomized, placebo-controlled phase III trial the combination of chemo + Tislelizumab (anti-PD-1) provided superior OS (mOS: 17.2 vs 10.6 mo; HR 0.66; 95% CI 0.54-0.80; p<0.0001). Benefit was observed across all prespecified patient subgroups, including PD-L1 expression and investigator-chosen chemo regimen.
Xu J, et al. Lancet Oncol. 2023 May;24(5):483-495.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00108-0/fulltext
GASTRIC CANCER
Zolbetuximab significantly prolongs PFS & OS compared to placebo, when combined with mFOLFOX6 in Claudine 18.2 positive/HER2 negative 1st line locally advanced or metastatic gastric & GE Junction adenocarcinoma treatment (SPOTLIGHT)
In a global, randomized, placebo-controlled phase III trial the combination of mFOLFOX6 + Zolbetuximab (first-in-class CLDN18.2 targeted mAb) proved superior in terms of PFS (mPFS: 10.61 vs 8.67 mo) and OS (mOS: 18.23 vs 15.54 mo) when compared to mFOLFOX6 + placebo. The HR for disease progression or death was 0.75 (95% CI 0.60-0.94; p=0.0066). CLDN 18.2 is a tight junction protein specifically expressed in 40% of HER2 negative adenocarcinomas in the upper GI tract.
Shitara K, et al. Lancet. 2023 May 20;401(10389):1655-1668.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00620-7/fulltext
PANCREATIC CANCER
Paraaortic lymph node (PALN) metastasis do not negatively impact survival of patients with resectable pancreatic head adenocarcinoma
In a retrospective German study, among 148 patients who underwent upfront resection for PDAC, 125 (85%) received paraaortic lymphadenectomy. In this group, PALN metastases did not negatively impact OS (mOS 18.9 for PALN(+) vs 19.0 mo for PALN(-); HR 1.3; 95% CI 0.7-2.6, p=0.392), or DFS (mOS 14.0 for PALN(+) vs 10.7 mo for PALN(-); HR 1.7; 95% CI 0.9-3.2, p=0.076). The authors conclude that the presence of PALN metastases is not a contraindication for resection of pancreatic head cancer.
Petrova E, et al. Eur J Surg Oncol, vol 49(5): 996-1000.
https://www.ejso.com/article/S0748-7983(22)01358-0/fulltext
Toripalimab combined with definitive chemoradiotherapy in locally advanced oesophageal squamous cell carcinoma
In Chinese single-arm phase II trial, definitive chemoradiotherapy (50,4 Gy with 5 weekly cycles of cisplatin + paclitaxel) combined with toripalimab (anti PD-1, concurrent with CRTx and continued up to 1 y) demonstrated encouraging activity in locally advanced unresectable ESCC (1-y OS: 78.4%, 1-y PFS: 54.5%).
Zhu Y, et al. Lancet Oncol., Volume 24, Issue 4, 371 – 382
https://doi.org/10.1016/S1470-2045(23)00060-8
In randomized phase III trial, the addition of zolbetuximab (anti-CLDN18.2 antibody) to 1L mFOLFOX6 chemotherapy improved PFS and OS in patients with CLDN18.2-positive, HER2-negative unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma – mPFS: 10.61 vs 8.67 mo, HR = 0.75, 95% CI 0.60–0.94; p=.0066; mOS: 18.23 vs 15.54 mo, HR = 0.75, 95% CI 0.60–0.94; p=.0053.
Shita K, et al. Lancet (2023)
https://doi.org/10.1016/S0140-6736(23)00620-7
In retrospective analysis of phase II PanaMa trial, consensus molecular subtypes (CMS) influenced outcomes (ORR, PFS, OS) in patients with RAS wild-type mCRC treated with 5-FU and folinic acid with or without panitumumab after mFOLFOX6 + panitumumab induction. More favorable outcomes were observed for CMS2 (canonical) and CMS4 (mesenchymal) subtypes, while CMS1 (MSI immune) and CMS3 (metabolic) subtypes were associated with less favorable PFS and OS. The addition of panitumumab to the maintenance chemotherapy improved PFS in CMS2 and OS in CMS4, but produced no benefits in CMS1/3.
Stahler A, et al. J Clin Oncol. (2023)
https://ascopubs.org/doi/full/10.1200/JCO.22.02582
In a single-arm phase II trial, neoadjuvant pembrolizumab was administered to dMMR/MSI-H cancer patients (27 with CRC and 8 with non-colorectal cancers) up to 6 months before surgery, with an option to continue for 12 months after surgery. The trial produced high rates of ORR (82%) and pathological CR (65% in resected cases). 17 patients were managed without surgery, with 2 cases of PD.
Ludford K, et al. J Clin Oncol. 2023 41:12, 2181-2190
https://ascopubs.org/doi/abs/10.1200/JCO.22.01351
In resected pancreatic ductal adenocarcinoma adjuvant nab-paclitaxel + gemcitabine did not improve independently assessed disease-free survival (iDFS) as compared to gemcitabine alone (the primary end-point – median iDFS: 19.4 vs 18.8 mo, HR = 0.88; 95% CI, 0.729 to 1.063; P = .18). Mature OS favored nab-paclitaxel + gemcitabine versus gemcitabine (mOS: 41.8 vs 37.7 mo; HR = 0.80; 95% CI, 0.678 to 0.947; P = .0091).
Tempero MA, et al. J Clin Oncol. 2023 41:11, 2007-2019
https://ascopubs.org/doi/10.1200/JCO.22.01134
In randomized Chinese phase III trial, the use of adjuvant Hepatic Arterial Infusion Chemotherapy (HAIC; 1 or 2 cycles of FOLFOX) improved disease-free survival after radical resection of HCC with microvascular invasion) – median DFS: 20.3 mo for HAIC vs 10.0 mo for routine follow-up; HR = 0.59; 95% CI, 0.43 to 0.81; P = .001). No significant difference in OS was detected.
Li S-H et al. J Clin Oncol. 2023 41:10, 1898-1908
https://ascopubs.org/doi/full/10.1200/JCO.22.01142
In randomized phase III, the addition of pembrolizumab to 1L chemotherapy (cisplatin for up to 8 cycles and gemcitabine with no maximum duration) modestly improved OS in patients with advanced biliary tract cancer (mOS: 12.7 mo vs 10.9 mo, HR = 0.83; 95% CI 0.72–0.95; P = .0034). No significant differences in ORR or PFS were observed.
Kelly RK, et. al. Lancet 2023 (online)
https://doi.org/10.1016/S0140-6736(23)00727-4
Pembrolizumab added to fluoropyrimidine- and platinum-containing chemotherapy (PF or CAPOX) improved ORR, PFS and OS in patients with advanced HER2-negative gastric/esophagogastric junction adenocarcinoma (mOS: 12.9 mo with pembro + chemo vs 11.5 mo with placebo + chemo, HR = 0.78, 95% CI 0.70-0.87; P < 0.0001). Results were consistent across PD-L1 expression subgroups.
Rha SY, et al. Annals of Oncology, Volume 34, Issue 3, 319 - 320
https://doi.org/10.1016/j.annonc.2023.01.006
Meta-analysis of randomized phase III trials indicated superiority of PD-1 antibody plus chemotherapy to chemotherapy alone in terms of OS and ORR in patients with advanced esophageal squamous cell carcinoma with low PD-L1 expression.
Wu XH, et al. J Clin Oncol. 2023 41:9, 1735-1746
https://ascopubs.org/doi/10.1200/JCO.22.01490
Results of a large Japanese study indicate that germline pathogenic variants in homologous recombination genes (BRCA1, BRCA2, PALB2, ATM) significantly increase the risk of gastric cancer, but only in carriers that were infected with Helicobacter pylori.
Usui Y, et al. N Engl J Med 2023; 388:1181-1190
https://www.nejm.org/doi/full/10.1056/NEJMoa2211807
In large retrospective analysis of real world data and results of phase III RECOURSE trial, OS was not prolonged with treatment with trifluridine/tipiracil versus placebo in patients with KRAS G12-mutant metastatic colorectal cancers (HR = 0.97; 95% CI 0.73–1.20; P = 0.85). In contrast, FTD/TPI was highly effective in KRAS G13-mutant CRC. The predictive influence of KRAS mutational status was confirmed in vitro.
Van de Haar J, et. al. Nature Medicine, volume 29, 605–614 (2023).
https://www.nature.com/articles/s41591-023-02240-8
In FOxTROT randomized phase III trial 6 weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy for operable colon cancer (cT3-4, N0-2, M0) produced histopathologic down-staging, improved resectability, and reduced the 2-year recurrence rate (16.9% preoperative chemotherapy vs 21.5% control; HR = 0.72 [95% CI, 0.54 to 0.98]; P = .037). Preoperative panitumumab did not enhance the benefit. The advantage of preoperative chemotherapy was not seen in dMMR cancers.
Morton D, et al. J Clin Oncol. 2023 41:8, 1541-1552
https://ascopubs.org/doi/full/10.1200/JCO.22.00046
In randomized, phase II trial comparing temozolomide versus capecitabine/temozolomide in patients with advanced pancreatic NETs (G1-G2), capecitabine + temozolomide significantly improved progression-free survival. No change in OS was detected.
Kunz PL, et al. J Clin Oncol. 2023 41:7, 1359-1369
https://ascopubs.org/doi/10.1200/JCO.22.01013
In phase 2 randomized trial the addition of bevacizumab to FOLFIRI in 2nd line treatment of advanced neuroendocrine carcinomas (gastroenteropancreatic or of unknown primary origin) did not improve 6-month overall survival.
Walter D, et al. Lancet Oncol. 2023 Mar;24(3):297-306
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00001-3/fulltext
In randomized, phase III trial treatment with pembrolizumab improves ORR, PFS and OS vs placebo in Asian patients with advanced hepatocellular carcinoma who progressed or did not tolerate sorafenib.
Qin S, et al. J Clin Oncol. 2023 41:7, 1434-1443
https://ascopubs.org/doi/full/10.1200/JCO.22.00620
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