Roy S. Herbst, MD, PhD, Examines the Use of Ramucirumab Plus Pembrolizumab in ICI-Resistant Advanced NSCLC

Roy S. Herbst, MD, PhD, Ensign Professor of Medicine and Professor of Pharmacology at Yale School of Medicine and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut

In a nonmatched substudy of the phase 2 Lung-MAP trial (S1800A; NCT03971474), patients with advanced non–small cell lung cancer who have resistance to immunotherapy were treated with ramucirumab (Cyramza) plus pembrolizumab (Keytruda) vs standard of care. Investigators analyzed 130 eligible patients, with a primary end point of overall survival, and the study was implemented across nearly 600 sites around the country.

Roy S. Herbst, MD, PhD, Ensign Professor of Medicine and Professor of Pharmacology at Yale School of Medicine and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut, as well as principal investigator of the Lung-MAP Protocol, discussed results of the phase 2 trial presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

In an interview with CancerNetwork^®, Herbst discussed the results from the trial, new safety signals observed, and the major takeaways for practice.

CancerNetwork^®: Can you review the Lung-MAP S1800A substudy of ramucirumab plus pembrolizumab vs standard of care in patients with advanced non–small cell lung cancer who are resistance to immunotherapy?

Herbst: Immunotherapy has changed the face of lung cancer. As a clinician and a scientist, I’ve seen it work in patients. It’s truly remarkable, but it only works well in 15% to 20% of patients. Many patients become resistant or never even respond [to immunotherapy] at all. We’re constantly searching for mechanisms of primary and acquired resistance. One lead that we’ve had over the last few years is that targeting vascular endothelial growth factor [VEGF] and blocking it can improve the results that have been seen in other tumor types like renal cancer. We did some phase 1 work in lung cancer as well. You target both PD-1 or PD-L1—in this case, we targeted PD-1 with pembrolizumab—and you then target the VEGF with an antibody against the receptor of the vector for the R2 receptor with ramucirumab. That combination will have synergy and will help patients who are already refractory to pembrolizumab alone.

This trial [was undertaken as part of] the Lung-MAP protocol. I’m the founding chair of Lung-MAP, and the current principal investigator. The Lung-MAP protocol is a public-private partnership. We have groups from around the country, the National Cancer Institute, the foundation for the NIH [National Institutes of Health], Friends of Cancer Research, and all the cooperative groups through the National Clinical Trials Network working on this. Then the private part, [is made up of pharmaceutical] companies. We come together to run trials using a master protocol mechanism where the patients get profiled on day 1—that’s paid for, by the way, at no cost to the patient. The trial are open at hundreds of sites around the country, over 700 sites, bringing drugs to patients with a need for the most personalized care. Based on the profile, patients are either assigned to a specific substudy based on that biomarker or if they don’t have a match, they get immunotherapy.

The immunotherapy is for patients who have failed [prior lines of treatment], were eligible for the ramucirumab plus pembrolizumab trial, S1800A, that Karen L. Reckamp, MD, presented on behalf of our team today. The results [of this trial] were quite extraordinary. We designed this as a survival trial because we had some prior data to suggest that you don’t always see an improvement in response or progression-free survival with immunotherapy combinations. In fact, that was the case here. If the trial had been designed for progression-free survival, it would have been negative. However, building it as a survival trial, that was a phase 2, not a phase 3 [trial enrolling between] 140 to 160 patients, so a moderate size trial. This trial could quite quickly, because of the Master Protocol Network, allow patients to be enrolled throughout the country.

We put 6 or 7 patients on [treatment] at the Yale Cancer Center in New Haven, Connecticut, where I work, and the results presented at ASCO today showed an improvement in survival by 40%. The survival curve separated almost immediately. The median survival improved by 4 or 5 months with a hazard ratio of .61 to a 40% improvement in survival, with fewer toxicities with the experimental arm than the standard of care chemotherapy that it was compared with, that being a docetaxel-based regimen in most cases. [Patients received] either docetaxel alone or most patients, docetaxel with ramucirumab. This is exciting because if you look through this ASCO and you know what’s available in the literature, they are very few if, in fact, any combinations that work in this setting. This seems to be a unique setting, one of the great unmet needs, where we’re seeing some benefits. We’re all excited about it.

Were there any new safety concerns with ramucirumab plus pembrolizumab that weren’t previously observed?

You do need to watch for toxicity in previously treated patients. Frankly, chemotherapy is much more toxic than immunotherapy. That might be one of the reasons why this works well because patients can tolerate it quite well. We saw some rashes and some other low-grade toxicity in the lungs, colon, and liver, but very low grade. For the most part, there were no new signals. In fact, we were pleasantly surprised that it was so well tolerated, which is one of the advantages of this combination. When you use an antibody to target the VEGF receptor, it’s much better tolerated than [what we see with other drugs in] some of the other trials that are ongoing in this space for people using oral small molecules or tyrosine kinase inhibitors which tend to be a bit more toxic.

How will this research impact the treatment paradigm, especially for those who have previously been treated with immunotherapy?

The independent discussant here today felt that this could be used in clinical practice. I’m a little biased, but I would certainly agree. It still needs a larger trial to confirm it for full approval. This is a reasonable-sized trial that could go into the NCCN [National Comprehensive Cancer Network] compendia or other areas. We’ll have to see how independent evaluators look at it, but I think that there’s a use for it. There are many patients in this situation, but we’re in the process of designing a follow-up trial. That will be phase 3 study and will include all the cooperative groups to answer that question.

What do you hope your colleagues took away from the presentation?

I hope that they were inspired [and they know that] we’re making progress. There was a big step in the last decade with PD-1 and PD-L1 agents. That was a huge benefit, but only for some patients, and we’re making significant incremental progress. This is clearly a positive trial and you see it the minute those curves go up on the wall. People are inspired to do more research, more trials, enroll their patients to trials, and focus on the efficacy and safety of drugs for patients with this disease. Patients and the advocates here are seeing that we’re continuing to make progress. These are patients who do not normally have the standard drivers like EGFR, ALK, RAS, RET, MET, and so forth and we’re working on therapies for them.

Reference

Reckamp 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(suppl 16):9004. doi: 10.1200/JCO.2022.40.16_suppl.9004