Chemoimmunotherapy in Advanced NSCLC Treatment

Experts in lung cancer discuss recent updates from ESMO 2021 and IASLC 2021 WCLC on combination immunotherapy plus chemotherapy for the treatment of advanced NSCLC.

John V. Heymach, MD, PhD: We’ve spoken about immunotherapy or combination immunotherapy but without chemotherapy. We did get additional data about chemotherapy-immunotherapy combinations with a few studies as well.

Sandip, tell us about the KEYNOTE-407 study update in squamous patients.

Sandip P. Patel, MD: The KEYNOTE-407 trial was a study in the frontline space, metastatic squamous histology for KEYNOTE-407 that looked at carboplatin-taxane, which could be paclitaxel or nab-paclitaxel in this study for 2 years. We saw similar results and durability of responses. One of the paradoxes with immunotherapy is that squamous is almost universally associated with smoking. Also, we associate immunologic responses with smoking-related neoantigens. But if you look at any study—not just KEYNOTE-407, but any of the squamous studies, any of the subgroups—the squamous arm tends not to do as well as nonsquamous. Initially, I thought, “Maybe it’s because they have comorbidities.” But even if you look at PFS [progression-free survival], it’s not quite the same.

That said, overall survival [OS] benefits broadly in all comers, regardless of PD-L1 status. That’s 1 of the key aspects for the chemotherapy–I/O [immuno-oncology] studies: we’re seeing benefit. With KEYNOTE-407 though, we didn’t see the same level of benefit in PD-L1–negative patients as we saw in KEYNOTE-189, which had a phenomenal hazard ratio, I think 0.56, 0.58 for PD-L1 negative. We didn’t see that with KEYNOTE-407. This is 1 scenario in which you can absolutely use chemotherapy-pembrolizumab. That’s 1 of the most commonly used regimens in frontline metastatic squamous non–small cell lung cancer, but there are others as well.

John V. Heymach, MD, PhD: You’re right. It’s surprising. I wonder if it has to do with tumor bulk, why squamous patients aren’t getting as much benefit there.

Stephen, we brought up cemiplimab before as a single agent in the high PD-L1s, but they’ve also conducted a study with chemotherapy. Do you want to tell us about that?

Stephen Liu, MD: This was the EMPOWER-Lung 3 study, very similar to the IMpower study, the atezolizumab studies. EMPOWER-Lung 3 was a randomized phase 3 trial where patients were randomized 2:1 to cemiplimab plus chemotherapy vs chemotherapy alone. This merged both histologies. What they showed, no surprise, was that there was a survival benefit. Overall the hazard ratio was 0.71, and the 1-year OS rate improved from 56% to 66%. It was a better PFS, better response rate, better duration of response.

When we look at some of the subsets there, we see that there was quite a bit of benefit for squamous with a hazard ratio of 0.56. On the other hand, when we look at the PD-L1 negative, maybe the area where we need this the most, the benefit wasn’t as large. In fact, the hazard ratio was right at 1. The challenge with a study like this is when you merge the histologic subtypes, you can do your study quickly but you’re a little less well powered to look at each subtype. That’s the problem with the stats here. Overall, this reinforces the paradigm. When you add an active PD-1 or PD-L1 inhibitor to platinum doublet chemotherapy, you improve outcomes across the board. Thus, there are no real surprises here and maybe another option in the future.

John V. Heymach, MD, PhD: That’s another possible option. You mentioned the squamous subset had a little better hazard ratio there than we saw in the KEYNOTE-407. What are your thoughts? Is that a criterion that may push you, or do you think that small subgroups are not powered appropriately?

Stephen Liu, MD: Ideally, when we look at a study like KEYNOTE-407, it’s just in squamous. We break it down by a PD-L1 subtype. Now it’s a 2x2 matrix histology and PD-L1 expression in some of the other cohorts. My subsets get smaller and smaller. Just as I won’t read too much into the squamous, in a positive sense, I won’t read too much into the PD-L1 negative in a negative sense in overall. When we add these together, my expectation is that we improve outcomes. I don’t expect this to be any different—no worse, maybe no better. As you mentioned, I’m hoping we can build on this backbone to improve outcomes.

John V. Heymach, MD, PhD: Yes, that’s right.

Transcript Edited for Clarity

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