Updates in Immunotherapy for Advanced Thoracic Malignancies - Episode 3

Treatment Options in PD-L1 Positive Non–Small Cell Lung Cancer

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Suresh Ramalingam, MD: Another regimen that enters the landscape, I want to hear, Martin, your overview of the CheckMate 9LA trial.

Martin Dietrich, MD, PhD: This is a 2-part study with PD-L1 positive, overlapping with the pembrolizumab approval for greater than 1% in the PD-L1 negatives. I want to start with the positive ones. This was a 3-arm study looking at chemotherapy as the comparator arm and then nivolumab, and then nivolumab plus ipilimumab, and there were incremental benefits. Both were better than chemotherapy, but particularly interesting for me in the overlap of the intent-to-treat population, but also in the individual subgroups, a benefit of the combination immunotherapy [I/O] over the nivolumab arm alone, which suggests to me that single-agent PD-1 is not covering exactly the entirety of our needs in our population, and that there is utilization and benefit to our original immunotherapy agent, which is ipilimumab. It’s been around for 9 years and finally is making its way into non–small cell lung cancer. This is interesting. If you will allow for the discussion from earlier that our PD-1 inhibitors are similar and are performing similarly, there is at least an absolute numerical benefit to using the combination if you choose to have a chemotherapy-free regimen for the PD-L1 positives.

What was even more exciting to me is the question of can you utilize immunotherapy alone in a population that has previously only produced negative results? CheckMate-026 was the hallmark trial that defined that we need at least some positivity of PD-L1 for benefit. There’s a bimodal distribution between the PD-L1 highs and the PD-L1 negatives, but ipilimumab serves as an immune sensitizer that further enhances and stimulates toward a PD-1 response. From a relative benefit standpoint, for a PD-L1 negative patient who is interested in immunotherapy, this is a suitable regimen. I was disappointed when the FDA didn’t approve the PD-L1 negative population. This would be a great option for this patient population where we typically see little benefit of the addition of single-agent immunotherapy. It would be interesting.

If you allow for that comparison again, chemoimmunotherapy, ipilimumab/nivolumab looked good in comparison. Those were 2 arms, and it was originally scolded for being a complex trial, but in the end it turned out to be one that carried a number of valuable lessons, which is ipilimumab/nivolumab can be competitive in the PD-L1 positive space as a combination, it can be competitive against chemoimmunotherapy in the PD-L1 negative space. This is going to be hard to argue that this wouldn’t be a strong consideration for every patient in the PD-L1 continuum.

Suresh Ramalingam, MD: When we talk about this combined PD-1 and CTLA-4 blockade approach, one of the concerns people typically have is about tolerability and safety of this combination. My view, looking at both the CheckMate-227 and 9LA data, is that the combinations are tolerable, and early recognition of adverse events related to autoimmune phenomena can be managed, and patients can go on to complete therapy. Martin, we saw some results of patient-reported outcomes for the CheckMate 9LA trial recently. Can you talk to us about that?

Martin Dietrich, MD, PhD: CheckMate-227 has been, at least for non–small cell lung cancer, in a new dosing regimen. This is ipilimumab, 1 mg/kg body weight. We started at 3 mg/kg body weight in the melanoma setting, and in the adjuvant setting, even 10 mg/kg, and now at 1 mg/kg in non–small cell lung cancer. This is a dosing sweet spot, where you maintain an immune response, but your adverse effect profiles look substantially better, especially the GI [gastrointestinal] toxicities are now in the single digits in the grade 3/4 events, which is substantially lower than what we’ve seen with higher doses before. The 1 mg/kg body weight makes this a completely new setup.

This also relates to the fact that we must reconsider the reputation of this agent. This is an immune-sensitizer. This relates to the patient-reported outcomes, which are substantially better in terms of general quality of life for patients compared to chemotherapy, which is not surprising that if you prevent the cytotoxic adverse effects that are not liked by patients as well as clinical deterioration, that you would have patients that are overall doing better. My impression of this is that this is a well-tolerated regimen both in the combination setting with chemotherapy, where you have a limited addition of chemotherapy, as well as in single agent, and should be given a second look based on the new dosing.

Suresh Ramalingam, MD: I would like to hear the opinions from some of our other participants on this panel about where they see a role for the I/O-I/O approach in non–small cell lung cancer in the frontline setting, given the data and the approvals we’ve seen with that. Steve, starting with you.

Stephen Liu, MD: It’s compelling. There are a lot of reasons why this is an appealing regimen. When I introduce this regimen or discuss it with my patients, while I will mention that this is a chemotherapy-free regimen, and there’s a lot of interest in that, I’m quick to follow that it’s not toxicity-free, and the grade 3 adverse event rate for CheckMate-227 is very similar to the chemotherapy arm. They’re just different toxicities. You won’t see necessarily the myelosuppression, the alopecia, the nausea that we may see with cytotoxic chemotherapy, but there are still a lot of other toxicities we need to be aware of. I need to find the right patients to use that.

There are a couple of reasons why I might go to a dual checkpoint blockade regimen up front. One would be, as Martin alluded to, that hazard ratio in the PD-L1 negative is compelling. You had mentioned earlier breaking things down by histology. If you look at PD-L1 negative squamous cell carcinoma, the outcomes with chemotherapy/I/O are not good. The CTLA-4 in PD-1, in that arena, arguably has better outcomes across trials. The hazard ratio was much better in the PD-L1 negative than we expected, and that was in part due to underperformance of the chemotherapy, but the chemotherapy arm did worse. The CTLA-4 in PD-1 arm really did the same for PD-L1 positive and negative with a very comparable survival. A very impressive duration of response, it’s compelling.

If all things are equal and you start with dual checkpoint blockade, and if it doesn’t work, if you’re not in that group where you get that long-term survival, now my second-line option is platinum doublet chemotherapy, which I would consider an upgrade over standard second-line docetaxel-based therapies.

Suresh Ramalingam, MD: It adds a line of therapy for you when you use the I/O-I/O combination.

Stephen Liu, MD: Yes.

Suresh Ramalingam, MD: Christine, I see you nodding. I take it that you share that viewpoint that Steve just mentioned.

Christine Bestvina, MD: I absolutely do. We also at the University of Chicago have had an investigator-initiated trial looking at combination ipilimumab/nivolumab and stereotactic body radiotherapy, or SBRT, and that was presented at ASCO [the American Society of Clinical Oncology annual meeting] this year in abstract form. Because of that, I’ve had a lot of comfort giving ipilimumab/nivolumab and managing the toxicities, and also have seen, exactly as Steve was just referring to, the benefits that that PD-L1 population with a 0% expression of PD-L1, seeing the benefits that they can obtain with this dual checkpoint blockade is quite impressive.

One of the other things that I love about this regimen is that time to chemotherapy gets pushed out. You get to save an amazing second-line option of carboplatin/pemetrexed, which has been the backbone of management for these patients for the prior 10 to 20 years. There are a lot of reasons to consider it as a frontline option.

Transcript Edited for Clarity