Ramucirumab plus pembrolizumab improves OS in advanced NSCLC

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Published: 4 Jun 2022
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Dr Roy Herbst - Yale Cancer Center, New Haven, USA

Dr Roy Herbst speaks to ecancer about the results of a phase II clinical trial, known as S1800A, which indicated that an immunotherapy drug combination could extend the lives of those diagnosed with advanced non-small cell lung cancer. 

They team evaluated pembrolizumab and ramucirumab in advanced, ICI-exposed NSCLC, under the aegis of Lung-MAP, a master protocol for patients with stage IV, previously treated NSCLC.

Dr Herbst explains that in the trial, half of the patients received standard of care or chemotherapy plus ramucirumab. The other half received an immunotherapy combination of an immune checkpoint inhibitor plus ramucirumab.

A 40% improvement in survival was found in patients that received the immunotherapy combination vs those who had standard chemotherapy, with less toxicity.

He concludes by discussing the next steps in the investigation and noting that a phase III trial is planned.

Read the news story here.

The study that our group presented today was called Lung-MAP 1800A. Lung-MAP is called the Lung Cancer Master Protocol; it’s a large private-public partnership that brings together academic institutions, cooperative groups, industry, the NCI, the NIH, to study drugs throughout the country. So we have over 700 sites open around the country and we put over 4,000 patients on this trial. The trial assigns patients to the sub-study that’s best for them. In this case, we presented today the sub-study 1800A, in fact Dr Reckamp presented it, that was for patients who had already failed immunotherapy. As many advances as we’ve had here, at ASCO and elsewhere, we still know that immunotherapy really only truly helps about 15-20% of patients with lung cancer, and many others either don’t respond or become refractory.

So we set out to look for a new regimen that could help those patients. So the trial presented here is a combination of pembrolizumab, an agent that targets PD-1, and ramucirumab, an antibody that targets vascular endothelial growth factor. There has been some pre-clinical work and some phase I work, which I conducted and led, that showed that this combination was more active than either drug alone. But of course you never know that until you study it in a randomised setting so we assigned patients based on the Lung Master Protocol, patients came in, they all had sequencing done using a foundation medicine platform. If these patients had driver mutations they went on the right sub-study for that – EGFR, RET, RAS – but if they didn’t and they had already failed immunotherapy, which of course is quite common in this country, they then went on to receive ramucirumab and pembrolizumab compared to a control of standard chemotherapy. That was a real world control – most of the patients got docetaxel or ramucirumab, some of them got docetaxel alone.

The results really exceeded our expectations. The trial was powered for survival and in fact we saw a 40% improvement in overall survival in the patients that got the immunotherapy combination versus those that got standard chemotherapy with less toxicity, so patients lived longer. It’s only a phase II study, it's only about 140 or so patients, but still, the results were quite compelling, they were just presented here with a great deal of excitement. The discussant was quite positive, both about the trial design and also that this could probably be used, pending review by the NCCN and other compendia groups. So very exciting data, and it shows progress in lung cancer with new therapies. I’ll tell you, I’ve been in this field for quite some time, I don’t know of any other combinations yet that have shown efficacy in patients who have failed immunotherapy so this is really something that we’re very excited about.

Could you give some examples of the immunotherapy regimens that patients were failing on?

Most patients who get immunotherapy get chemotherapy and immunotherapy together these days. In this trial, since it is being presented today and it started three or four years ago, some patients might have had chemotherapy first, followed by immunotherapy sequentially, and actually some might have had immunotherapy first followed by chemotherapy, since chemoimmunotherapy has only really been the standard for the last two or three years. But it’s any one of those three combinations. That’s why we need a bigger trial to confirm this because there are some differences in how patients were treated, but they all had to have either not responded or to have failed the immunotherapy to go on this study. It’s a step forward, the hazard ratio is 0.6 or so which is a 40% improvement, which translated to a median improvement in survival of four or so months. Again, we’re constantly trying to ratchet it up and do better for these patients with lung cancer and this is, I hope, a next step.

What did you see in terms of adverse events?

The adverse events are much more significant with chemotherapy where you have neutropenia, low blood counts, you have neurotoxicity. With immunotherapies you tend to get rash, you tend to get inflammation of different areas whether it would be the lungs, pneumonitis, or the colon. We saw very little if any of that in a severe state, in was really extremely well tolerated. That’s the beauty of this, it’s less toxic than the standard chemotherapy but produced a longer survival.

What’s next for this study?

Next is to take it to the phase III setting. As much as I’d love to see it used based on this, and I think it can be in certain situations, ultimately it’s going to have to be compared in a much larger study two or three or four times the size. We’re not working on this, this study was part of the Lung Cancer Master Protocol; we’re working with different cooperative groups now to design the study that will be used in (inaudible) setting and hopefully we’ll have something by the end of the summer. This is team science at its very best, this is helping patients – number one goal – bringing people together from all over the United States as investigators and local community physicians to treat the patients. I’m at Yale Cancer Center, I'm very proud of that, we’re a big academic centre, people come to us, we treat a good part of Connecticut, but many people can’t come to the big cancer centre, they need to be treated at their point of care, and this trial brought those drugs there, so a real team effort.

I’ve been working in this field for quite some time and I’ve seen lung cancer progress, and it really is science that’s driving that improvement. So this is really science, some of it that comes from Yale - checkpoint inhibitors, Weiping Zou, and others at our team were very involved in that. Now we’re taking this to the next level, developing the right combinations. These combinations have to be rational and based on science; we still have much we can learn from this Lung-MAP study as we continue to analyse the samples for correlative science and hopefully that’ll be an ASCO presentation next year.