Overcoming Resistance to ICI Therapy With Ramucirumab and Pembrolizumab in Advanced NSCLC

Karen L. Reckamp, MD

Most patients with advanced non–small cell lung cancer (NSCLC) develop resistance to immune checkpoint inhibitors (ICIs). Available therapies for patients with advanced NSCLC who become resistant to ICIs remains an unmet need that investigators are actively trying to improve.

In the phase 2 Lung-MAP substudy S1800A (NCT03971474) for patients with stage IV, previously-treated NSCLC, the combination of pembrolizumab (Keytruda) and ramucirumab (Cyramza) was evaluated in patients with acquired resistance to ICI. Acquired resistance in the study was defined as previous ICI therapy for at least 84 days with progressive disease on or after therapy.

A total of 137 eligible patients were treated in the study. The primary end point assessed was overall survival (OS), and the secondary end points were response, duration of response, investigator assessed-progression free survival and toxicity. To assess outcomes, patients were stratified by PD-L1 expression, histology, and intent to receive ramucirumab in the standard of care (SOC) arm. The SOC combination was ramucirumab and docetaxel.

After demonstrating an improvement OS compared with SOC, S1800A became the second study without a chemotherapy backbone to show a potential survival benefit compared with standard treatment regimens using the Lung-MAP platform. The median OS observed with ramucirumab/pembrolizumab was 15.0 (95% CI, 13.2-17) compared with 11.6 months (95% CI, 8.5-13.8) with SOC (HR, 0.61; 95% CI, 0.38-0.97; 1-sided P =0.019).

There was no difference in PFS between the treatment arms (HR, 0.86; 95% CI, 0.57-1.31], 1-sided P =0.25. The median PFS in the ramucirumab/pembrolizumab arm was 4.5 months (95% CI, 4.0-6.9) vs 5.2 months (95% CI, 4.0-6.6) in the SOC arm. There was also no difference in overall response rate between the treatment arms (P =0.28).

In an interview with Targeted Oncology™, Karen L. Reckamp, MD, director, Medical Oncology, associate director, Clinical Research, and Medical Oncology director, Lung Institute at Samuel Oschin Cancer Center, discussed that limited options for patients with advanced NSCLC who are resistant to ICI therapy. Reckamp also discusses how Lung-MAP research might play a hand in bringing new therapies in the future.

TARGETED ONCOLOGY: What should oncologists know about approaching treatment of a patient with advanced non–small cell lung cancer, who is previously treated with immunotherapy?

Reckamp: Most of our patients now receive either a combination of immunotherapy and chemotherapy or immunotherapy alone as part of their frontline treatment for advanced non–small cell lung cancer. We're also starting to use immunotherapy in the treatment of earlier stage non–small cell lung cancer. So, most patients do get exposed to immune checkpoint inhibitors at some point during their therapy. Although there are great benefits that patients experience, most will have tumor progression and develop some tumor resistance to immune checkpoint inhibitors.

At this moment in time, we don't have the best therapies. We don't know the best therapies to provide patients once a tumor has grown on immune checkpoint inhibition and chemotherapy. So, we conducted a study to evaluate what might be better therapies than our standard of care which generally include chemotherapy as a single agent or the combination of docetaxel and ramucirumab.

Can you provide specifics on the current limitations with standard of care? Ahat makes the combination of ramucirumab and pembrolizumab a promising option for this patient population?

The limitations are standard or care are really that the combination of ramucirumab and docetaxel was approved in about 2014. And this has been the only standard in addition to single-agent chemotherapy for patients who have had tumor growth on chemotherapy and immune checkpoint inhibitor therapy. So, we really are at a point where we need some novel therapies, novel combinations, and uniquely ramucirumab/pembrolizumab is a non-chemotherapy option for patients. So that's one way that makes this combination exciting.

How did you and your co-investigators approach the assessemnet of ramucirumab and pembrolizumab vs standard of care in the Lung-MAP nonmatched substudy S1800A?

So, Lung-MAP is a Precision Medicine Platform trial, and it allows patients to have genomic testing through Foundation One. From there, patients go on to either a matched trial if there's a genomic alteration, or down to the unmatched arm. Our research presented at ASCO was from the unmatched arm S1800A. And so, the combination of ramucirumab and pembrolizumab was for patients who did not meet criteria for the matched arms that we had available at that time. And when we were thinking of this study, this was a randomized phase 2 trial and we wanted to see if there was an indication of efficacy.

We knew that overall survival, in general, has been a better indication of efficacy, especially with immunotherapy in the second-line setting. So, we chose to use overall survival as our primary endpoint. We often do see discordance of overall survival and other outcomes such as progression-free survival and objective response.

What were the key findings in this subgroup?

In this study, again, the primary endpoint was overall survival. We had 136 patients randomized, and we found an improved overall survival in the ramucirumab and pembrolizumab arm, with a median overall survival of 14.5 months versus 11.6 months in those who receive standard of care. I think importantly, in the standard of care arm, 2/3 of the patients did receive docetaxel/ramucirumab as the most potent combination that we have at this time and as a standard of care for patients who have had tumor growth on both immunotherapy and chemotherapy in the past.

We evaluated the outcomes of overall survival by PD-L1 status, and there was no difference based on PD-L1 status, there was benefit for all patients receiving ramucirumab/pembrolizumab. By performance status, we did see a trend toward increased benefit in those patients who had squamous cell or mixed histology. But again, there was a benefit across all subgroups.

What did these findings mean about the future use of ramucirumab/pembrolizumab in this patient population?

I think importantly, this was a patient population that had received at least 84 days of prior immune checkpoint inhibitor therapy before experiencing tumor progression. And so, this is an acquired resistance population. And in this population, we now see overall survival benefit with the combination of ramucirumab and pembrolizumab as a non-chemotherapy option, and against the most potent regimen that we had in the second-line docetaxel/ramucirumab. We are hoping to move this forward into a phase 3 trial to better understand the magnitude of benefit of this combination.

_REFERENCE:

_{Reckmap KL, Redman MW, Dragnev KH, et al. Overall survival from a phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for advanced non–small cell lung cancer previously treated with immunotherapy: Lung-MAP nonmatched substudy S1800A. J Clin Oncol. 2022;40 (16): 9004-9004. doi: 10.1200/JCO.2022.40.16_suppl.9004}