Frontline I-O Monotherapy Versus Combination Therapy for PD-L1+ Stage IV NSCLC

Drs Roy S. Herbst and Sandip P. Patel comment on patient candidacy for immunotherapy as monotherapy to treat PD-L1+ metastatic non–small cell lung cancer versus chemoimmunotherapy.

Mark A. Socinski, MD: Before I transition to Sandip, as we move from monotherapy to the combinations, give me a sense, Roy: In your practice, do all patients over 50% get monotherapy? Or are there those patients you think are better served with chemotherapy–I/O [immuno-oncology]? Do you see a difference in these—say, 50% to 60% PD-L1–positive versus 90% to 100% PD-L1–positive populations?

Roy S. Herbst, MD, PhD: That’s a loaded question. Even in the 50%, the response rate is, what, 43%? Even a high PD-L1, over 50%, have a primary resistance. Yes, we have to start thinking about combinations. In the clinical setting, without a protocol, I’m at a place where the protocols are flying back and forth every minute. But without a protocol, I still try to give the immunotherapy alone to the 50% of patients unless they’re having significant symptoms, and I’m worried they need an immediate response. Then I might add the chemotherapy to the immunotherapy. I will then add chemotherapy later on if they’re having a less-than-robust response. But of course, there are so many protocols looking at what to do in that 50% group, the No. 1 being the SKYSCRAPER-01 trial, looking at TIGIT, another checkpoint [inhibitor], perhaps you can do that. There’s been some thought that antiangiogenic, or VEGF inhibitors, might have an effect on the immune microenvironment, so there are some trials. But in most cases, if we can avoid chemotherapy, especially during this last year with COVID-19, it’s nice to be able to avoid making someone neutropenic.

Mark A. Socinski, MD: Sandip, give us your thoughts on the chemo–I/O. Obviously, if you’re committed to using chemo–I/O, perhaps the PD-L1 status is a little less meaningful. But what are your thoughts on the major trials—KEYNOTE-189, KEYNOTE-407, IMpower—and how they’ve changed the landscape.

Sandip P. Patel, MD: To follow up on Dr. Herbst’s excellent discussion, previously we were talking about single-agent I/O for patients with PD-L1 high, typically greater than 50%. It depends on the assay for a given agent. The question is, for patients who are PD-L1 low, or even PD-L1 high, greater than 50% but have highly symptomatic burden, they’re admitted to the hospital with very large, painful lesions. They need an immediate response. The question then becomes, could you combine chemotherapy with the newest immunotherapy? Though we’re a decade into this immunotherapy era, we try to maximize response. One point about the Kaplan-Meier survival curves we’ve seen for I/O versus even chemotherapy alone is that in a biomarker-selected population for PD-L1 greater than 50%, some patients don’t benefit. As mentioned earlier, it’s hard to salvage, especially if they have highly symptomatic tumors.

The thought behind combining chemotherapy with immunotherapy is the basis of multiple frontline studies that allow for utilization of immunotherapy independent of PD-L1 status. As Dr. Herbst mentioned, there are opportunities for I/O monotherapy for patients who are PD-L1 high. The first two involve pembrolizumab: carboplatin-pemetrexed-pembrolizumab, for the KEYNOTE-189 status for patients with nonsquamous. It’s important to mention that these are patients without EGFR and ALK mutations across all these studies. For the majority of patients with targeted mutations, such as BRAF and MET, who should undergo appropriate molecular sequencing, their best treatment is targeted therapy up front. In these studies, EGFR and ALK were tested for. If positive, the patients went on appropriate targeted therapy. But if negative, they were allowed to be randomized to chemotherapy versus chemotherapy-immunotherapy. The point to make about KEYNOTE-189, which is in non-squamous histology, is that we have a tail of the survival curve. It’s really impressive to see responses, even in PD-L1–negative patients. For PD-L1 zero, there’s an overall survival advantage when you combine chemotherapy with immunotherapy in this setting.

For the majority of the frontline studies, the duration of therapy was two years. There is some controversy around what to do at the two-year mark, and this is an ongoing question. That’s part of the personalization of medicine, is that discussion of what to do. But the idea that we’re seeing durable responses, both in squamous, which is the KEYNOTE-407 study with carboplatin-taxane, or in the KEYNOTE-189 study, these really represent the backbone of the treatment of non–small cell lung cancer. We’ve also seen benefit from the integration of immunotherapy with angiogenesis inhibitors, so the IMpower150 study looked at carboplatin, paclitaxel, bevacizumab, and atezolizumab in combination. One aspect of this study is that it allowed patients who had prior EGFR-ALK treatment. Essentially, they finished their targeted therapy but were going on to this chemotherapy-immunotherapy combination.

Though the analysis was complicated, there were some interesting analyses that suggested benefit in these populations. This has represented a backbone, especially for driver mutation patients, and there were some provocative data related to liver and CNS [central nervous system] metastasis as well. The other study in the frontline space that integrates immunotherapy—Dr Herbst was mentioning some of the TIGIT-based combinations—is our original immune checkpoint blockade agent, ipilimumab, an anti-CTLA4 agent, in combination with a PD-1 agent, nivolumab, in combination with chemotherapy. This is the CheckMate 9LA study, in which two cycles of chemotherapy are given, and patients go on to immunotherapy alone.

We saw some updated results recently at ASCO [American Society of Clinical Oncology Annual Meeting] suggesting a durability of a benefit, and some provocative data in certain cohorts. For example, the PD-L1 negative cohort, the less than 1%, squamous histology, and then patients with CNS metastasis, seemed to confirm preferential benefit. But this is comparison with chemotherapy, not chemotherapy-immunotherapy.

Finally, we’ve seen some really tantalizing data with another CTLA4 agent, tremelimumab, which hasn’t found a home in combination with durvalumab and chemotherapy. This was teased as a press release about a month ago for which we don’t yet have the full data. The frontline space has become complicated, in addition to personalized medicine, above and beyond just looking for the appropriate driver mutations and making sure patients get appropriate driver mutation-directed therapy if they lack those driver mutations. Their optimal immunotherapeutic strategy will likely become less clear before it becomes more clear as we’re starting to integrate some of these novel therapeutics into the frontline space.

What’s the best role of CTLA4-based combinations, and how can we best understand the role of chemotherapy, especially if a patient is PD-L1 high? These are some of the outstanding questions in the field. We’re seeing five-year survival data, meaning three years after their last dose with a durability of response, so it’s a really phenomenal time for patients, and we just want to raise that bar further.

Mark A. Socinski, MD: Something we never saw with chemotherapy by itself.


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