Combination extends OS in immunotherapy-resistant advanced non-small cell lung cancer
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CHICAGO — A new combination therapy benefitted certain patients with immunotherapy-resistant advanced non-small cell lung cancer, according to randomized phase 2 study results presented at ASCO Annual Meeting.
Pembrolizumab (Keytruda, Merck) plus ramucirumab (Cyramza, Eli Lilly) extended OS compared with standard of care for individuals previously treated with chemotherapy and immunotherapy, results of the Lung-MAP Nonmatched Sub-Study S1800A showed.
This is the first trial of a second-line regimen with no chemotherapy backbone to suggest a potential survival benefit compared with standard of care, Karen L. Reckamp, MD, director of medical oncology at Cedars-Sinai Cancer and associate director of clinical research at Cedars-Sinai, and colleagues reported.
Reckamp characterized the results as “a game changer” for the field and the patients who may derive benefit from this regimen.
“Seeing a 3-month improvement in OS in the refractory setting is pretty impressive,” Reckamp told Healio. “The survival curves start to split very early and the benefit starts from the beginning, which we don’t always see with immunotherapy. And the HR of 0.69 is very respectable as far as being a clinically meaningful result.”
Background and methods
Most patients with advanced NSCLC receive immunotherapy as part of their primary therapy.
“Most of these tumors will progress and develop resistance,” Reckamp said. “We really have limited options for patients once there is tumor growth on prior immunotherapy.”
The combination of immune checkpoint inhibitors and VEGF/VEGF receptor inhibition has demonstrated encouraging activity in multiple tumor types through immune modulation, according to study background.
Reckamp and colleagues assessed the combination of pembrolizumab — a monoclonal antibody that targets PD-1 — and ramucirumab — a fully human monoclonal antibody and VEGFR2 antagonist — for patients with advanced NSCLC who previously received immune checkpoint inhibitor therapy.
The analysis included patients with ECOG performance status of 0 or 1 with acquired resistance to immune checkpoint inhibition.
All study participants received prior immune checkpoint inhibitor therapy for a minimum 84 days but developed disease progression during or after therapy. Study participants also experienced disease progression on prior platinum-based doublet therapy — either sequential or in combination with immune checkpoint inhibition.
The analysis included 137 eligible patients.
Researchers randomly assigned 69 patients to pembrolizumab (200 mg every 3 weeks for up to 35 cycles) in combination with ramucirumab (10 mg/kg every 3 weeks). The other 68 received standard of care, which consisted of investigator’s choice of docetaxel plus ramucirumab (n = 45) or docetaxel, pemetrexed and gemcitabine (n = 23).
OS served as the primary outcome measure. Secondary endpoints included response, duration of response, investigator-assessed PFS and toxicity.
Results
Results showed significantly longer OS in the pembrolizumab-ramucirumab group (median, 14.5 months vs. 11.6 months; HR = 0.69; 95% CI, 0.38-0.97). The OS benefit persisted in most subgroups.
However, researchers reported no statistically significant difference in PFS (median, 4.5 months vs. 5.2 months; HR = 0.86; 95% CI, 0.57-1.31) or objective response rate (22% vs. 28%) between the pembrolizumab-ramucirumab and standard-of-care groups.
The discordance between OS and the other efficacy measures has been observed in prior immunotherapy trials, Reckamp said.
The regimen also exhibited a manageable safety profile, according to investigators.
Grade 3 or higher treatment-related adverse events occurred among 42% of patients assigned pembrolizumab-ramucirumab and 60% of those assigned standard of care.
Researchers reported nine grade 3 to grade 5 immune-related adverse events in the experimental group.
“When we use a nonchemotherapy-containing regimen, we generally see less grade 3 to grade 5 toxicity, and that was the case in this study,” Reckamp said. “We saw some vascular toxicities, as you would expect with a combination containing ramucirumab.”
Subgroup analyses showed patients with squamous cell and mixed histology — as well as those with certain co-mutations, such as STK11 and KEAP1 — potentially deriving more benefit. PD-L1 status did not appear to predict benefit.
Implications
A larger trial designed to confirm the benefit of pembrolizumab-ramucirumab in this setting is in the planning stages, Reckamp said.
“I have confidence that this result is meaningful, and I think a larger trial will help us see the magnitude and potentially the subgroups who will most benefit from this combination,” Reckamp told Healio. “I’m excited that we might have new therapies that go beyond standard chemotherapy.”
Perspective
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This study is significant in that it points to a potentially better option for patients after disease progression on first-line therapy, which often includes checkpoint inhibitors like pembrolizumab. The suggestion is that the addition of a VEGF inhibitor antibody — in this case ramucirumab — can improve OS when combined with pembrolizumab, one of the most used checkpoint inhibitors. A phase 3 trial is needed to conform these results.
Perspective
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Sally C. Lau, MD, MPH
This is the first prospective study in NSCLC demonstrating activity of PD-1/VEGF inhibitors among patients previously treated with a PD-1 inhibitor.
Interestingly, outcomes patterns were discordant, showing a significant improvement in OS but not PFS or response. A similar pattern was seen with PD-1 inhibitors alone in previously treated NSCLC. The similarities suggest that the anti-tumor effect with combination PD-1/VEGF inhibitors is immune mediated rather than anti-angiogenesis alone.
Preclinical evidence showed that the addition of VEGF inhibitors increased CD8+ T-cell infiltration and reduced myeloid-mediated immunosuppression. Bevacizumab (Avastin, Genentech) in combination with atezolizumab (Tecentriq, Genentech) and chemotherapy is an accepted standard in the first-line setting. But given the chemotherapy backbone, the effect of VEGF inhibition was difficult to tease out.
In this randomized phase 2 study, Reckamp and colleagues provided promising evidence that PD-1/VEGF combinations alone are active in NSCLC. Exploratory results on subgroups with genomic alterations, tumor mutational burden and PD-L1 are yet to be presented and may define its future place in therapy for advanced NSCLC. Further elucidating the mechanisms through which VEGF inhibition can overcome resistance to PD-1 inhibitors will help identify predictive biomarkers, such as myeloid signatures, and allow a personalized approach to immunotherapy treatments in NSCLC.
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Reckamp KL, et al. Abstract 9004. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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