Treatment Efficacy in Non–Small Cell Lung Cancer

Suresh Ramalingam, MD: We learned about another interesting study in the frontline setting that looked at a newer checkpoint inhibitor, cemiplimab. Steve, what did that study report and what were the implications?

Stephen Liu, MD: You’re referring to the EMPOWER-Lung 1 study. This is looking at a PD-1 inhibitor, cemiplimab, vs standard chemotherapy as the frontline treatment for PD-L1 positive non–small cell lung cancer. A randomization to a PD-1 inhibitor vs chemotherapy may sound familiar to the KEYNOTE studies we’ve seen, like KEYNOTE-024. What we saw were in line with those results, that PD-1 blockade with cemiplimab improves survival compared to chemotherapy. We saw an improvement in PFS, [progression-free survival] but most importantly, an improvement in survival, the hazard ratio there in the PD-L1 high subset at 0.57. Cemiplimab had a better response rate, a better PFS, better overall survival, and a better toxicity profile, a winner across the board. This was despite having a high crossover rate, in fact, higher than what we saw in KEYNOTE-024. The crossover rate in this study was 74%, reflective of the time where the drug is more widely available. What we’re seeing with EMPOWER-Lung 1 reaffirms what we’ve seen with other PD-1 inhibitors in this space.

Suresh Ramalingam, MD: Another PD-1 inhibitor, it’s probably the third drug. We have PEMBRO [pembrolizumab] and ATEZO [atezolizumab] already approved in this space, and cemiplimab shows data. Having seen these data, Christine, do you notice any remarkable differences between one drug vs the other?

Christine Bestvina, MD: There aren’t dramatic differences that I’m appreciating between the 3 drugs and what we’ve seen in the trials. I have a tough time moving away from what has become standard as pembrolizumab in the frontline setting to seeing a large advantage of cemiplimab over what we already have.

Suresh Ramalingam, MD: One interesting feature about this study was there was a high number of patients with squamous cell carcinoma in the EMPOWER study, about 45%. Is there a difference in efficacy of I/O [immunotherapy] agents between squamous and nonsquamous histology? Martin and Firas, I would be curious to hear your thoughts on this.

Martin Dietrich, MD, PhD: Squamous cell carcinoma is a more immunotherapy-sensitive disease. The correlation with smoking, higher TMB [tumor mutational burden], and inflammatory markers is probably more stringent than for adenocarcinomas. They all exclude EGFR and ALK, but I’m not certain that they all have a full biomarker assessment. Are all PD-1s made the same? I know that we have questions about the PD-L1s. But I have to say that the data, despite the crossover rate, the hazard ratios are better, the absolute numbers are better, so I don’t want to put the topic to rest. I’ve looked back at other disease spaces where cemiplimab was performing quite well, but there may be differences between the individual PD-1 inhibitors. Cemiplimab was designed following nivolumab, it’s a second-generation PD-1, and there may be a difference. But squamous cell carcinoma is more set up to provide a meaningful benefit for immunotherapy, especially when you don’t properly select out all the oncogenic driver adenocarcinomas that may be involved in the study.

Firas Badin, MD: I agree with Martin. If you practice where I practice in the tobacco belt, we see a lot of squamous cell carcinoma. There is a difference in responses between adenocarcinomas and the squamous cell carcinomas, regardless of the difference between PD-1 inhibitors. When you combine immune checkpoint inhibitors, PD-L1 status plays a lesser role, as well as histology plays a lesser role. We’ll be talking about some of the combination checkpoint inhibitors. When you’re doing more than 1 immune checkpoint inhibitor, you tend to overcome some of those differences based on PD-L1 status or histology. To me with this study, as Stephen alluded to, the crossover rate was high, and despite that, the survival advantage was still seen. It might argue that if you delayed initiation of immunotherapy, then patients may not do as well. You can add a checkpoint inhibitor down the road after they’re done with chemotherapy, but we’re seeing more evidence that the earlier you adopt immunotherapy, the better the outcomes are.

Stephen Liu, MD: I agree with that. If this trial had read out in 2017, it would have changed the world. In 2020, the world has already changed, and to me that lessens the impact. I would absolutely be in favor of an approval here. I don’t know if there’s a lot for me to change my practice. We tend to be creatures of habit, and inertia is a little difficult to overcome. I’ve got my work pathways set up, I’ve got prior authorization routes set up, my EMR [electronic medical record] is set up. I don’t know if I see data that are compelling enough to make me change my practice, but I’d absolutely support combinations building on this or using this as a control in a randomized trial.

Suresh Ramalingam, MD: Steve, when you said the world has changed in 2020, I thought that was the most understated statement of the year. But we will take that. One thing I found interesting, when you look at these trials, and going back to Christine’s point, what’s different from one another, what’s fascinating is these are trials done with different drugs, in different settings, albeit they’re all patients with first-line non–small cell lung cancer. What you end up seeing is the hazard ratios for PFS and survival almost come together across these drugs, even though we know that there are intrinsic differences from one drug to the other. The consistency of the results is something that gives us confidence that giving frontline therapy for a high PD-L1 patient with a single-agent checkpoint approach is very strong.

Let’s segue into talking about the I/O-I/O combination approach, where we have seen some results in the past few months that are interesting. I can talk about the CheckMate-227 trial, and then I’ll turn it to Martin to talk about the 9LA trial, which are both strategies that combine ipilimumab with nivolumab. I had the pleasure of presenting the CheckMate-227 data at ASCO [the American Society of Clinical Oncology 2020 annual meeting]. This was a trial that enrolled patients with frontline non–small cell lung cancer and randomized them to various treatments based on the PD-L1 expression level. Patients who had PD-L1 expression greater than 1% were randomized to chemotherapy alone vs NIVO [nivolumab] alone vs IPI [ipilimumab] plus nivolumab, and the PD-L1 less than 1% group, the randomization was to chemotherapy alone versus chemotherapy plus nivolumab versus ipilimumab plus nivolumab.

When we look at the comparison of ipilimumab plus nivolumab versus chemotherapy, there was a statistically significant improvement in overall survival, both in the PD-L1 high group and the PD-L1 negative group. The survival hazard ratio was even more favorable in the PD-L1 negative group at 0.62.

We presented longer-term follow-up data from the trial, and the number that comes to my mind is the 3-year survival rate for patients treated with ipilimumab and nivolumab was 33%, both in the PD-L1 high and low group, which is remarkable considering that not too long ago, we were not talking about 3-year survival rates for patients with lung cancer. The combination of ipilimumab and nivolumab is now an FDA-approved regimen. It’s approved for PD-L1 positive patients in the US; NCCN [National Comprehensive Cancer Network] guidelines recommend it for both positive and negative patients.

Durability of response with ipilimumab and nivolumab in that trial was almost 3- to 4-fold higher compared to chemotherapy. If patients had a response with chemotherapy, the duration of response was 6-and-a-half months. With ipilimumab and nivolumab, the response duration was almost 23 months. This suggests that patients who derive response with this combined immunotherapy approach have the ability to maintain that benefit for a lot longer.

Transcript Edited for Clarity