For refining the knowledge for treatment approaches for GI malignancies, ESMO2020 represented an interesting platform for the breakthrough data for patients with colorectal cancer, gastric cancer, pancreatic cancer, gastroesophageal junction cancer, and more. Whilst, ESMO2020 has presented immunotherapy as a beneficial treatment option for current GI patients who have poor survival, it has also represented immune checkpoint inhibitors as the potential therapeutic option for the first-line therapies in GI cancers.
Some of the key abstracts, along with their key summary and insights, include:
CHECKMATE-577 study
Study title: Adjuvant Nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiation therapy (CRT): First results of the CheckMate 577 study.
Summary: Bristol Myers Squibb presented very interesting and promising data from its Checkmate 577 study. The results concluded that Nivolumab is the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement in DFS vs. placebo (DFS was doubled: 22.4 mo vs. 11 mo); (HR 0.69 [96.4% CI 0.56 -0.86]; P = 0.0003) in resected EC/GEJC following neoadjuvant CRT. Also, there was a 31% reduction in the risk of recurrence of death and a doubling in median DFS. DFS has shown benefits across multiple pre-specified subgroups. Nivolumab was found to be well tolerated with an acceptable safety profile. These results have been shown as being the first advancement in years (second global after melanoma) for this group of patients. Qol was found to be similar between placebo and Nivolumab treated patients.
Expert insights: “Nivolumab significantly reduced the risk of relapse in these patients; however, the results are independent of PD-L1 status and may not apply to patients treated only with neoadjuvant chemotherapy. Immature OS data is available, and mature OS data will be of great relevance. DFS and OS are used as primary endpoints. DFS is not currently validated as a major endpoint for these cancers.”
DelveInsight believes that these results are remarkable with double DFS. These results show that Nivolumab may potentially be the first adjuvant as a new standard of care.
KEYNOTE-590 study
Study title: Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study.
Summary: Merck also presented these results during ESMO2020. As per the ESMO release, most esophageal cancer patients in the trial had squamous cell carcinoma (73%), and those with adenocarcinoma were a small subgroup. The results in the subgroup of patients with adenocarcinoma were an experimental analysis, but in the adenocarcinoma subgroup, median overall survival (OS) was 11.6 months and 9.9 months (hazard ratio [HR] =0.74), and median progression-free survival (PFS) was 6.3 months and 5.7 months (HR=0.63) in the Pembro+Chemo and Chemo group, respectively. The OS- and PFS-benefit observed in the adenocarcinoma subgroup was consistent with the benefit observed in the overall patient population.
Expert insights: “This combination has shown significant increases in RR, PFS, and OS. This may become a new standard of care. However, the results are independent of CPS status, despite being a key in the statistical plan as preplanned analysis, and also squamous histology and CPS≥10 may get a maximum benefit. The standard arm is not frequently used as SOC, but it is acceptable.”
“I expect that this study may change practice for patients with metastatic squamous cell carcinoma or adenocarcinoma of the esophagus who have PD-L1 CPS≥10 tumors, for whom pembrolizumab added to chemotherapy will become the standard of care in the first-line”.
"The results of these trials offer oncologists new treatment options. In the first line settings, there is a clear change in our standard of care, in which patients with high PD-L1 expression will be candidates for immune checkpoint inhibitors plus chemotherapy. However, more data are needed on the subgroups who benefit from the treatment (e.g. PD-L1 CPS groups and MSI).”
CHECKMATE 649 & ATTRACTION-4 study
Study title: Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study
Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study
Summary: Results from checkmate 649 from the BMS study showed that Nivolumab and chemotherapy improved OS (14.4 vs. 11.1) and PFS (7.7 vs. 6.0), and ORR (60% vs. 45%) as well in patients with PD-L1 combined positive score (CPS) ≥5 tumors. Improvements were also observed in patients with PD-L1 CPS≥1 tumors in the overall patient populations.
Similar to the Checkmate 649 study, the Attraction 4 trial was conducted in Asian patients by BMS/Ono without specific CPS value and was designed for all patients. First-line treatment with nivolumab plus chemotherapy improved the co-primary progression-free survival endpoint, but not overall survival. (ORR: 58% vs 48%, mPFS: 7.7 vs 6.0, mOS: 17.5 vs 17.2).
Expert views: “The results of these Nivolumab trials represent a paradigm shift in the treatment of 1L advanced gastroesophageal adenocarcinoma. The OS benefit in checkmate 649 is a gamechanger. Further analysis of biomarker selected subgroups is required to understand the value of Nivolumab in all patients.”
DelveInsight believes that overall survival rates not improved for attraction-4 may be a setback for this trial. Conclusions may warrant further analysis. QoL data is not currently available but is essential.
“The results are clinically very relevant. Based on CHECKMATE-649 trial, the addition of nivolumab to chemotherapy will become the standard of care for first-line treatment. The open question is the effect in patients who have a PD-L1 CPS <5.”
“The improvement in progression-free survival was clinically relevant, and the ATTRACTION-4 trial strongly supports the results of CheckMate 649. Overall survival was not improved, possibly because all-comers were treated or because patients in Asia receive more subsequent therapies than Western populations.”
KEYNOTE-177 study
Study title: Health-related quality of life (HRQoL) in patients treated with pembrolizumab vs chemotherapy as first-line treatment in microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC): Phase III KEYNOTE-177 study.
Summary: In ESMO 2020, Merck presented HRQoL data from patients in MSI-H/dMMR mCRC patients. HRQol results complement the superior PFS with the previously reported results. As per the company’s release, compliance at baseline was more than 90% in pembro and SOC arms and remained high at week 18 (>85% and >75%, respectively). There were significant differences in score variations {QLQ-C30 GHS/QoL score (LSM difference: 8.96; 95% CI, 4.24-13.69; P=0.0002) and EQ-5D VAS score (LSM difference: 7.38; 95% CI, 2.82-11.93; P=0.0016)} at week 18 vs. baseline which were in favor of pembrolizumab. Prolonged TTD for patients receiving pembro vs. SOC was observed for GHS/QoL, physical functioning, social functioning, and fatigue.
Expert Insights: Nearly 5% of metastatic colorectal cancer cancers represent the sub-segment of MSI-H/dMMR tumors, but these tumors are associated with decreased survival rates and are less responsive to conventional chemotherapies, representing the potential unmet need in this segment.
“DelveInsight believes that these findings support the use of pembrolizumab as SoC in 1L patients and can be considered the best upfront option. However, OS data is still awaited. Data regarding the patients being germline Lynch vs. somatic MSI-H mutated not available and may not matter since the outcomes for BRAF mut and WT were the same. Future may hold checking potential combinations for immune checkpoint inhibitors as they are needed to open the field of MSS tumors to these therapeutic options and in the field of MSI tumors to foresee a possibility of having efficacious combinations to further improve the outcome of checkpoint inhibitors.”
CAVE mCRC study
Study title: Avelumab plus cetuximab in pretreated RAS wild type metastatic colorectal cancer patients as a rechallenge strategy: The phase II CAVE (Cetuximab-AVElumab) mCRC study.
Summary: Merck presented the efficacy of avelumab and cetuximab in RAS WT mCRC pts treated in the first line with chemotherapy (CT) in combination with anti-EGFR drugs. The results showed the primary endpoint of the being met with mOS 13.1 mo and mPFS 3.6 mo. Among 65 pts evaluable for response, 1 pt (1.5%) experienced CR, 3 pts (4.6%) PR, 32 pts stable disease (SD) (49.2%); 29 pts PD (44.6%). Grade-3 adverse events were reported in 22% of patients. Overall, this rechallenge strategy was found to be effective, well-tolerated, and feasible. The study concludes that with the limitations of a single-arm, non-randomized phase II trial, the results of the present study provide a signal of the clinically relevant activity and safety that needs to be expanded in further clinical trials, in which cetuximab plus avelumab would be compared to 3L SOC therapy.
Expert insight: “The study has met the primary endpoint with a certain (not impressive) confirmed activity, RAS/BRAF mutations in the detection of ctDNA may be a useful selection tool, but results are hardly cross-trial comparable to other Phase II trials. Clarity regarding the added value of anti-PDL1 is beyond the reach of this trial, and responses were obtained in MSI-high tumors, results in the MSS group are still of major interest. DelveInsight believes that overall more data is required to finally derive to a conclusion for this combination.”
LEAP-005 study
Study title: LEAP-005: Phase II study of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors.
Summary: First results for Phase II LEAP-005 by Merck/Eisai were presented during ESMO2020. Lenvatinib plus pembrolizumab has shown promising benefits in patients with pretreated solid tumors, including 3L gastric cancer (GC) and 3L colorectal cancer (CRC) (non-MSI-H/mismatch repair proficient) and others. Each cohort included 31 patients, except for the CRC cohort (n=32), intending to expand the number of patients treated up to 100 for cohorts in which sufficient efficacy was observed. The efficacy results were encouraging among all tumor types with ORRs increasing from 10% in GC to 22% in CRC. Corresponding disease control rates were 48% in GC and 47% in CRC. The longest duration of response was 10.4+ months, recorded in a patient with CRC. The toxicity levels were also manageable.
Expert insights: “Data from this combination was found to be quite promising for the ovarian and colorectal cancer, given that they have been historically challenging to treat, and it's been hard to show evidence that anti-PDL1 drugs alone are active. However, in-depth biomarker studies to understand the combination mechanisms and finding predictive biomarkers of efficacy as TMB, gene signatures, etc. warrants further investigation.”
DelveInsight believes that overall, these trials have shown promising new options, leaving few questions open for this segment of patients. With concluding ESMO2020 at a good note, these trials have shown prospects of a new standard of care for the GI cancers very shortly.
