A new retrospective analysis published in the International Journal of Cancer on January 12, 2024 provides evidence that ramucirumab-containing second-line therapy may be effective for patients with advanced gastroesophageal cancer who progressed after first-line immunochemotherapy. The study, funded by Eli Lilly and Company, analyzed data from 83 patients enrolled in the randomized phase II AIO-STO-0417 trial who received second-line treatment after progression on first-line mFOLFOX plus nivolumab and ipilimumab.
The purpose of this retrospective analysis was to evaluate the efficacy of second-line VEGFR-2 inhibition with ramucirumab plus chemotherapy after treatment failure on first-line immunochemotherapy in patients with advanced gastric or gastroesophageal junction adenocarcinoma. As immunotherapy has recently been incorporated into first-line treatment for these cancers, there is a need to understand optimal sequencing strategies and the potential benefits of antiangiogenic therapy after progression on immunotherapy.
The study took place across 27 centers in Germany that participated in the AIO-STO-0417 trial. Patients included in this analysis had advanced, histologically proven HER2-negative gastric or gastroesophageal adenocarcinoma and had received at least one administration of both chemotherapy plus anti-PD-1 and anti-CTLA-4 therapy as first-line treatment within the AIO-STO-0417 trial, followed by second-line systemic treatment. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
The 83 patients were divided into two groups based on their second-line therapy: 38 patients received ramucirumab-containing regimens (RAM group) and 45 patients received treatment without ramucirumab (control group). Baseline characteristics were generally similar between the two groups, though the control group had a slightly higher proportion of patients with ECOG 0 performance status (49% vs 37%) and fewer patients with signet ring cell histology (31% vs 42%). PD-L1 combined positive score (CPS) ≥1 was present in 42% of the RAM group and 44% of the control group.
In the RAM group, the most common second-line regimen was ramucirumab plus paclitaxel (85%). The median duration of second-line treatment was 2.1 months in the RAM group compared to 1.6 months in the control group. The primary endpoints analyzed were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR).
In the overall population, median OS from the start of first-line therapy was similar between groups (12.5 months for RAM vs 14.2 months for control). However, median PFS for second-line therapy favored the RAM group at 4.5 months compared to 2.9 months in the control group. ORR was 16% in the RAM group versus 13% in the control group, while DCR was 40% versus 31%, respectively.
Notably, subgroup analyses revealed more pronounced benefits with ramucirumab in certain populations. Among patients who had responded (complete or partial response) to first-line immunochemotherapy, those receiving second-line ramucirumab had substantially improved outcomes compared to the control group, including:
- Median OS from start of first-line therapy: 28.9 vs 16.5 months - Median OS from start of second-line therapy: 9.6 vs 7.5 months - Median PFS: 5.6 vs 2.9 months - DCR: 53% vs 29%
Additionally, in patients with PD-L1 CPS ≥1 tumors, second-line ramucirumab therapy was associated with improved outcomes:
- Median OS from start of first-line therapy: 11.5 vs 8.0 months - Median OS from start of second-line therapy: 6.5 vs 3.9 months - Median PFS: 4.5 vs 1.6 months - ORR: 25% vs 10% - DCR: 44% vs 30%
In contrast, patients with PD-L1 CPS <1 tumors did not appear to derive significant benefit from ramucirumab-containing second-line therapy compared to the control group.
The authors concluded that prior exposure to first-line FOLFOX plus dual checkpoint inhibition followed by ramucirumab plus chemotherapy shows promising potential to advance the treatment paradigm in advanced gastroesophageal cancer, with the most favorable responses and survival outcomes observed in patients with initial response to first-line therapy and positive PD-L1 expression.
There are several important limitations to consider when interpreting these results. As a retrospective analysis of a relatively small patient cohort, the study was not powered to demonstrate statistically significant differences between groups. The variety of chemotherapy regimens used in combination with ramucirumab as second-line treatment introduces potential confounding. Additionally, toxicity and safety data for the second-line therapies were not reported.
Nevertheless, this analysis generates an intriguing hypothesis about the potential synergism between prior immunotherapy exposure and subsequent VEGF-targeted therapy. The authors propose several potential mechanisms to explain the observed benefits of ramucirumab after progression on immunochemotherapy:
1) Ramucirumab may help reverse resistance to immunotherapy by modulating the tumor microenvironment. VEGF signaling promotes an immunosuppressive environment, and VEGFR-2 blockade with ramucirumab could potentially restore a more immunocompetent milieu.
2) The effects of PD-1 blockade may persist for months after the last dose of anti-PD-1 therapy. Subsequent anti-angiogenic therapy with ramucirumab could therefore act on tumors that are still experiencing sustained PD-1 checkpoint inhibition, potentially enhancing efficacy.
3) PD-L1 expression may serve as a biomarker for tumors more likely to benefit from the immunomodulatory effects of anti-angiogenic therapy.
The potential clinical impact of these findings, if validated in larger prospective studies, could be significant. Currently, ramucirumab plus paclitaxel is a standard second-line option for advanced gastroesophageal cancer regardless of PD-L1 status or prior therapy. This study suggests that patients who initially respond to immunochemotherapy and have PD-L1 positive tumors may derive particular benefit from ramucirumab-containing second-line regimens.
Furthermore, these results support further investigation of treatment strategies that integrate immunotherapy and anti-angiogenic approaches. Several ongoing phase III trials are evaluating combinations of immune checkpoint inhibitors and VEGF-targeted agents in gastroesophageal cancer, including the LEAP-15 study of pembrolizumab plus lenvatinib and the INTEGRATE IIb study of regorafenib plus nivolumab.
If the synergism between immunotherapy and anti-angiogenic therapy is confirmed in larger trials, it could potentially impact treatment sequencing decisions and lead to new combination strategies. The authors suggest that future studies should incorporate evaluation of predictive biomarkers like PD-L1 expression, tumor mutational burden, and microsatellite instability status to help identify patients most likely to benefit from integrated immunotherapy and anti-angiogenic approaches.
In conclusion, while the retrospective nature and small sample size of this analysis limit definitive conclusions, it provides hypothesis-generating data on the potential efficacy of ramucirumab-containing therapy after progression on immunochemotherapy in advanced gastroesophageal cancer. The results suggest that certain subgroups, particularly immunotherapy-responsive and PD-L1 positive patients, may derive substantial benefit from this treatment sequence. Larger prospective studies are needed to confirm these findings and further elucidate optimal treatment strategies integrating immunotherapy and anti-angiogenic approaches for patients with advanced gastroesophageal cancer.
References
Masetti M, Al-Batran SE, Goetze TO, et al. Efficacy of ramucirumab combination chemotherapy as second-line treatment in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction after exposure to checkpoint inhibitors and chemotherapy as first-line therapy. Int J Cancer. 2024;154(12):2142-2150. doi:10.1002/ijc.34894
