Frontline Treatment in Non–Small Cell Lung Cancer

Suresh Ramalingam, MD: Hello and welcome to this OncLive® Peer Exchange, “Updates in Immunotherapy for Thoracic Malignancies.” I’m Dr Suresh Ramalingam from Winship Cancer Institute of Emory University in Atlanta, Georgia. Joining me today for this discussion are my colleagues, Dr Firas Badin from Baptist Health in Lexington, Kentucky; Dr Christine Bestvina from the University of Chicago in Illinois; Dr Martin Dietrich from the University of Central Florida in Orlando; and Dr Stephen Liu from Georgetown University School of Medicine in Washington, DC. Welcome everyone to this program.

Today we’re going to discuss a number of topics, including immunotherapy-based treatments in the up-front treatment of non–small cell lung cancer, recent developments in small cell lung cancer, and finally we will finish up with mesothelioma, a disease where there has not been a lot of progress in 2 decades.

We’ve had a number of recent meetings that have provided us with key insights into how we use this exciting group of drugs for treatment of our patients. We’ve had conclusion of ASCO 2020 [the American Society of Clinical Oncology annual meeting], the World Conference on Lung Cancer presidential virtual session, and more recently, the ESMO [European Society for Medical Oncology] 2020 conference. Now because these were all virtual conferences, we have not had a chance to talk face to face, but certainly all of us have been interacting through various platforms to bring to our clinics the exciting advances from these practices.

Let’s begin with frontline treatment of non–small cell lung cancer. This is the setting where we know molecular testing is done for every patient with non–small cell lung cancer, specifically the patients with nonsquamous non–small cell lung cancer. We want to ensure that every patient with a targetable driver mutation is treated with targeted therapy, and there are at least 7 driver mutations with the FDA-approved targeted approaches. Assuming that those patients are not going to be candidates for frontline chemotherapy, we’re going to focus this discussion on patients who don’t have a driver mutation to start with. With that in mind, I’m going to invite Dr Stephen Liu to talk about a study that was reported at ESMO recently, which was the combination of nivolumab with chemotherapy and bevacizumab.

Stephen Liu, MD: This was a randomized trial for patients who didn’t have EGFR/ALK alterations, and there are a lot of parallels between this and the approved IMpower150 regimen. That regimen builds on the backbone of carboplatin/paclitaxel/bevacizumab, showing that when you add atezolizumab, we improved outcomes. This was a similar approach, except instead of the PD-L1 antibody atezolizumab, this used the PD-1 inhibitor nivolumab. Patients all received standard carboplatin, paclitaxel, and bevacizumab, with a simple 1:1 randomization to concurrent nivolumab or placebo. After induction therapy, they then received maintenance bevacizumab and continued the nivolumab or placebo maintenance therapy.

We saw at ESMO 2020, that the addition of nivolumab to the carboplatin/paclitaxel/bevacizumab backbone did improve progression-free survival [PFS], a notable improvement there. We had a hazard ratio for PFS of 0.56, clearly improving outcomes. It’s immature yet for survival. We did not yet see a survival benefit—a hazard ratio of 0.85 with a pretty wide confidence interval—but showing some signal that when you add nivolumab to the carboplatin/paclitaxel/bevacizumab backbone, we do improve outcomes.

Suresh Ramalingam, MD: This whole concept of combining antiangiogenic or anti-VEGF targeted therapies with immune checkpoint inhibition is something that’s widely pursued not just in lung cancer, but in many other cancers as well. We saw another abstract in the same lines, which was the combination of atezolizumab and bevacizumab. What did you learn from that study?

Stephen Liu, MD: This one fell under the radar, a smaller study presented by Takashi Seto, MD, PhD, but an impressive end point. This was a single-arm phase 2 study, a modest trial, only 40 patients. This trial enrolled patients with PD-L1 high expression non–small cell lung cancer. No randomization, single arm, all patients receiving atezolizumab, the standard PD-L1 inhibitor, but given concurrent bevacizumab. What we saw in these early end points was a high response rate, over 60%. For reference, when we look at PD-1 inhibitors alone in some of our best studies for PD-L1 high, we’re looking at response rates in the upper 30% range. Seeing a response rate of 64% I thought was quite compelling. The PFS, again, immature, a modest study, but we have a 1-year PFS rate of 55%, which is quite impressive. It’s unfortunate this was a single-arm study. I would have loved to have seen a second arm with atezolizumab monotherapy to really see how this stands up. But those high response rates suggest that there may be synergy between these 2 pathways.

Suresh Ramalingam, MD: Interesting. Christine, when you look at these 2 studies and think about what these data mean to our current landscape in lung cancer, how do you see this? Is this exciting for you? Is this something that tells you there’s more work to be done?

Christine Bestvina, MD:I do think there’s more work to be done as Stephen alluded to, particularly the trialed atezolizumab and bevacizumab was not a randomized trial. I would like to see that confirmed with randomization against atezolizumab, which as the authors pointed out, is something that’s planned. But the response rate demonstrated in that study is extremely exciting to me. When we talk about triplet therapy, chemotherapy plus immunotherapy in the patients with high PD-L1 expression, one of the arguments that providers will make for using the triplet over monotherapy is if there’s a high response rate that’s needed, you may choose the triplet. But with seeing this high response rate with the addition of bevacizumab to atezolizumab, I wonder if we’ll be able to use angiogenesis inhibitors in a similar fashion, while still sparing more traditional chemotherapy agents.

Suresh Ramalingam, MD: When you talk about 4-drug combinations, Martin, I would be curious to hear about your thoughts. What can you tell us about the safety profile of these regimens?

Martin Dietrich, MD, PhD: There are several considerations. I still have difficulties finding the role for bevacizumab in the first-line setting, and I personally haven’t used it much. There’s a cumulative toxicity profile, they stay within their lane in terms of additional adverse effects, and I’m concerned about cost. But I would like to understand in the first-line setting what’s the contribution to efficacy. The trial atezolizumab plus bevacizumab was interesting, and there’s a lot of thought even from other disease spaces, that the antiangiogenesis may be contributing to an anti–PD-1 effect. But this was a small study with a very PD-L1 enriched population. There was a tremendous contribution from patients who had 75%-plus PD-L1 expression. It’s hard to interpret that information in the context. I would consider the thought that Stephen brought up, that this is a study that is thought-provoking but it needs confirmation in a more controlled fashion. I don’t have a big role for either the nivolumab- or the atezolizumab-based bevacizumab trials at this point.

Suresh Ramalingam, MD: Thank you. Firas, anything to add there with regard to this strategy from your standpoint?

Firas Badin, MD: I agree with my colleagues. They are interesting data. In our thoracic clinic, we’re moving away from single-agent PD-1 inhibitors into combination treatments, but we haven’t found the best dancing partner yet with PD-1 inhibitors. Is it anti-VEGF treatment? Is it anti–CTLA-4? Is it chemotherapy? I think it’s exciting. Nobody knows the data yet. One of the questions that came to my mind is, is there a particular subgroup of patients that might need a quadruplet, because as Martin reviewed, it’s not only the adverse effects, but also the financial toxicity about giving 4 drugs all at once for those patients. We know from previous studies that patients with liver metastases might do better with quadruplet regimens, with anti-VEGF plus anti–PD-1. We need to wait and see and have more data. But it’s exciting to see these kinds of combinations.

Transcript Edited for Clarity