CheckMate-9LA: Histology and Frontline Impact

Stephen Liu, MD: When we look at CheckMate 9LA, this trial did include both squamous and nonsquamous histology. It’s important to look at those ratios. About 30% of patients were squamous, which is a bit higher than some of the other studies. We know from multiple randomized trials, including some cross-trial comparisons, that our outcomes in the squamous histology are a bit worse. Factoring in those numbers, the outcomes are really impressive. When we break it down by histology, we did see a consistent benefit, a survival benefit in both the squamous and nonsquamous histologies with fairly comparable outcomes and comparable improvements. This is a regimen where histology will dictate which chemotherapy you deliver with those first 2 cycles. But the overall approach of giving 2 cycles, a limited course of histology-specific chemotherapy with dual-checkpoint blockade, should apply across histologies.

Neal E. Ready, MD: It’s natural for us to compare trials. The CheckMate 227 trial and the CheckMate 9LA trial were for all histologies, whereas the other randomized trials in this setting—for instance, KEYNOTE-189, KEYNOTE-407, IMpower150, IMpower130—were histology specific. We have data for chemotherapy–I/O [immuno-oncology] in nonsquamous lung cancer and chemotherapy–I/O in squamous cell lung cancer, and overall survival tends to be better in the nonsquamous setting compared with the squamous setting.

Keep in mind that for CheckMate 227 and 9LA, what we see is a composite. If we look at histology-based outcomes like 227 and 9LA, we see better survivals in the nonsquamous group. In the CheckMate 227 study, nivo-ipi [nivolumab-ipilimumab] had a median survival of over 19 months for the nonsquamous group, and in CheckMate 9LA survival was over 17 months. A better outcome for the nonsquamous compared with the squamous.

We shouldn’t be carefully comparing the different trials because they’re not exactly in the same population or in the same countries. They have slightly different eligibility criteria, but it’s only natural that when we’re choosing treatment for patients we’re trying to get the most effective treatment. It is useful for the different studies to make sure you’re looking at the outcome for the specific histologies, because that can be helpful in guiding appropriate choice of treatment.

Stephen Liu, MD: The CheckMate 9LA regimen giving 2 cycles of histology-specific chemotherapy with dual-checkpoint blockade is another option, and we have to tailor the treatment options to the specific patients we see. In someone with aggressive disease, a high burden of disease, that initial use of chemotherapy is appealing to prevent that early drop-off, that early progressive event. When you think you may only have 1 opportunity to deliver treatment for those patients, I think including cytotoxic chemotherapy is of value. It’s an interesting strategy limiting chemotherapy to those first 2 cycles. By preventing continued chemotherapy, will we avoid more cumulative toxicity? Will we enable more development of memory T cells by preventing the potentially detrimental effect of cytotoxic chemotherapy over time?

When we’re adding chemotherapy to dual-checkpoint blockade, there will be a cost. There is certainly more toxicity when we’re adding treatments to it. The rates of grade 3/4 adverse events and the discontinuation rates were higher certainly with the CheckMate 9LA regimen compared with chemotherapy alone, but some of the toxicity rates were better. The rates of anemia and neutropenia were a bit lower with the 9LA regimen, reflecting less cumulative toxicity from chemotherapy, perhaps less long-term neuropathy. It has to be for the right patient in the right clinical circumstance. There will be a role for it. Defining a specific role for all patients is challenging, and in the right clinical context it certainly can provide value.

The true measure for all these regimens will really be long-term survival and which approach leads to more durable survival at landmark rates. But we simply don’t have those data yet.

Neal E. Ready, MD: It will make a big impact. Many patients want to avoid chemotherapy when they can or minimize exposure to chemotherapy. This will give clinicians an option when the patient has a significant tumor volume and they’re symptomatic from their cancer, and the clinician is concerned that if the initial treatment doesn’t control the cancer, the patient will get into trouble and then we won’t be able to get additional treatment. Have that option of giving the 2 cycles of chemotherapy first with the immunotherapy to make sure there isn’t early progression. But have the double immunotherapy onboard to try to get a high level of durable-immunotherapy responses, so the clinician can feel confident they’re minimizing the likelihood the cancer is going to progress early. Then maximizing the chance that they’ll get a durable immune response to therapy. This will help clinicians have an option where they’re trying to avoid or minimize toxicity from chemotherapy, maximize response to immunotherapy, and do it safely and effectively.

Another thing I’ll just point out is that when we initially had the results of CheckMate 227, we had anticipated that the best outcome might be in the PD-L1–positive lung cancers, which is evidenced by the fact that that was the primary end point of the study. But then we found that perhaps the most promising result was in the PD-L1–negative population, where it really looked there was a marked benefit compared with chemotherapy. CheckMate 9LA confirmed that, because when you look at the outcome for the experimental therapy in the PD-L1–negative lung cancer population, it does look quite positive and promising and really confirms the result in the PD-L1–negative patients from CheckMate 227, at least in my mind when I look and say, “Are these in agreement, or was the CheckMate 227 result just an outlier to me?” The 9LA regimen results confirm that and make me feel more confident about that result.

Personally and as an institution, we have a lot of experience with that combination. We were involved with the phase 1 study, CheckMate 012, which went back to 2013 and 2014. We have put a lot of patients on this treatment over many years. We’ve really learned how to use this regimen. The low-dosage ipilimumab 1 mg/kg every 6 weeks is very different from the regimen used in melanoma, where you might give 3 mg/kg of ipilimumab every 3 weeks.

Even in the lung cancer population, we all feel very confident using this kind of therapy. I have extensive experience using this regimen on patients in their 70s, and I have had a significant number of patients receive a full 2 years of treatment and come off therapy because they finished their 2 years but did not develop any substantial toxicity.

Transcript Edited for Clarity