J Clin Oncol 2022 Jun 03
Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A.
Abstract
Purpose
Resistance to immune checkpoint inhibition (ICI) in advanced non-small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types.
Methods
In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity.
Results
Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC.
Conclusion
This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.
Related Questions
What are your top takeaways in Thoracic Cancers from ASCO 2025?
More presentations that were interesting for the future, than immediately impactful in thoracic oncology this year at the ASCO meeting. Immediately impactful: 8006 and 8008 – Both in SCLC. 8006- IMforte trial suggesting improvement in survival with the addition of maintenance lurbinectedin to atezo...
What treatment options would you consider for a patient with stage IV NSCLC harboring a KRAS-G12A mutation who has progressed after chemoimmunotherapy and prefers to avoid additional chemotherapy?
Unfortunately, I think the only way to avoid additional chemotherapy would be in the context of a clinical trial, where non-KRAS G12C inhibitors are being studied. From the perspective of a standard of care, I would still recommend chemotherapy. We don't have granular data to suggest dual checkpoint...
Are there any unique toxicity concerns with combination of ramucirumab/pembrolizumab as compared with other available treatments for metastatic NSCLC?
Unique toxicities issues were not seen with ramucirumab and pembrolizumab. The adverse events aligned with known side effects of the individual agents as previously reported. Toxicities were less than those seen in the standard of care arm. Many patients are interested to learn about a potential reg...
How will you decide who to offer ramucirumab + pembro after progression on chemoimmunotherapy?
In S1800A, overall survival benefit was relatively consistent across subgroups including TMB levels and PD-L1 strata. I would take into account the patient’s prior response to ICI (extent and duration) and the side effects from the ICI therapy. For instance, I would favor chemotherapy for those with...
Is S1800A data sufficient to adopt ramucirumab + pembrolizumab in your clinical practice immediately, or is phase 3 data needed?
The control arms in S1800A were docetaxel + Ram (67%) but the other 33% received single-agent docetaxel, gemcitabine, etc. The primary endpoint was overall survival which was reached, but for what it was worth no difference in PFS. In my opinion, it is possible that the modest survival benefit with ...
Are there differences in efficacy of ramucirumab + pembrolizumab based on extent and duration of response to first line chemo/pembro?
S1800A required that patients have at least 84 days (~4 cycles) of time on treatment before progression on anti-PD-L1 therapy. This will exclude patients who had rapid progression. Other than this entry criterion for all patients, the trial stratified by PD-L1 status, but did not select for prior IC...
What do you view as the role for docetaxel+ramucirumab for patients with metastatic NSCLC in light of LUNG-MAP S1800A data?
I still think, at this moment, docetaxel/ramucirumab should be considered standard of care (more below). I would not yet transition to pembro/ram for everyone. A broader issue raised by this trial is whether anti-VEGF drugs, or immunotherapy regimens, alter the efficacy of concurrent or subsequent c...
What are your top takeaways in Thoracic Cancers from ASCO 2022?
1. Abst 8502 - Quality metrics and survival after lung cancer surgery: More efficient work-ups and consistently high quality resections will likely do more to improve lung cancer survival than any adjuvant or neo-adjuvant therapy we can come up with. This is low-hanging, low-cost fruit. 2. Abst 9007...
What is the preferred second line, systemic therapy for NSCLC patients following first line chemoimmunotherapy?
This is as usual a quite complex question, and for a sophisticated audience such as theMednet readers, I always want to provide a nuanced answer; so here is what my preferred second line systemic therapy currently is:None.None.Still none…Indeed, now that chemo/immunotherapy has become the de facto s...