Weighing Immunotherapy/Chemotherapy Options in NSCLC

As part of our coverage of the 2018 annual American Society of Clinical Oncology (ASCO) meeting, we spoke with Dr. Hossein Borghaei to discuss results of the CheckMate 227 trial in advanced lung cancer. Dr. Borghaei is chief of the division of thoracic medical oncology and specializes in the treatment of lung cancer at the Fox Chase Cancer Center in Philadelphia.

-Interviewed by Anna Azvolinsky

Cancer Network: Can you explain the design of this first-line CheckMate 227 trial in non–small-cell lung cancer?

Dr. Borghaei: This is a multicohort, multiarm study that was designed to investigate the role of nivolumab in addition to either chemotherapy or another immunotherapy antibody called ipilimumab vs chemotherapy alone in patients who are treatment-naive but have advanced non–small-cell lung cancer. The design [of the study] was such that all patients, regardless of their tumor histology, could enter the study-meaning, both squamous and nonsquamous histology was allowed.

The original design divided patients based on the level of PD-L1 tumor expression.[Patients with] expression of PD-L1 over 1% would go into one arm of the study, and the PD-L1–negative patients, with less than 1% PD-L1 expression, would go into another arm. For each treatment arm, there were three separate treatment options.

For the PD-L1–positive patients, the arms were ipilimumab plus nivolumab or chemotherapy or nivolumab alone. For the PD-L1-negative patient population the arms were ipilimumab plus nivolumab, chemotherapy alone, or nivolumab added to the chemotherapy to see if that combination would work better than either alone. The first part of the study was designed to have an answer to the co-primary endpoint of progression-free survival (PFS) in patients with a high tumor mutational burden. [This part of the study] was already reported and published in the New England Journal of Medicine by Dr. Mathew Hellman from Memorial Sloan Kettering in New York, indicating that regardless of the level of PD-L1 expression or histology, patients who had this biomarker of a high tumor mutational burden above a certain threshold had a better outcome compared to patients with a relatively low tumor mutational burden, in terms of PFS and response rate, with the combination of ipilimumab plus nivolumab compared to chemotherapy alone.

This trial had a complicated design with multiple cohorts. The study is still ongoing, to measure overall survival (OS) in certain subpopulations.

Cancer Network: As you mentioned, the trial sponsor had announced that this trial had met its co-primary endpoint of progression-free disease survival back in February, and some of the trial results were presented at the American Association for Cancer Research meeting in April. Could you highlight the new efficacy results, if any, that you presented at the ASCO meeting just recently?

Dr. Borghaei:  My presentation concentrated on the patients who were considered to be PD-L1–negative based on a definition in this study of having PD-L1 levels of less than 1% on their tumors. Again, in that arm of the study, the question was whether the addition of nivolumab to chemotherapy is better than chemotherapy alone, and then we have the analysis of nivolumab plus ipilimumab that was also added.

Now, I have to emphasize that my presentation was on the secondary endpoint, as the primary endpoint is still being analyzed. Most of what I presented did not have a statistical P value assigned to it because the primary analysis is still ongoing. My data presentation concentrated on the group of patients who were PD-L1–negative. In this group, the patients with squamous cell lung cancer received a different type of chemotherapy than the patients with nonsquamous histology. The bottom line is that even in this population of PD-L1–negative patients, a high tumor mutational burden was associated with better PFS and better duration of response with ipilimumab plus nivolumab than either chemotherapy alone or nivolumab plus chemotherapy.

More importantly, the study showed that if patients have PD-L1–negative tumors and a low tumor mutational burden, the addition of nivolumab to chemo or ipilimumab to nivolumab didn’t really provide additional benefit over chemotherapy alone.

In other words, I think that with this combination biomarker of PD-L1 expression and tumor mutational burden level, we can identify a patient subgroup that most likely won’t benefit from an immunotherapy combination in the frontline setting. Perhaps this is the population in which we want to start with chemotherapy and then consider second-line treatment with an immunotherapy agent, as is standard practice. That is the hypothesis generated by these data.

For this group [with] no or very low PD-L1 expression and low tumor mutational burden, we need to find a better treatment approach, and perhaps a better way to think about these tumors to find a good way to treat them.

Cancer Network: What is the safety profile of this chemotherapy plus checkpoint inhibitor combination in this patient population?

Dr. Borghaei: Clearly, when you add nivolumab to chemotherapy there are more side effects compared to chemotherapy alone. But interestingly, in this analysis, the group of patients that got ipilimumab plus nivolumab had a lower percentage of the grade 3 and 4 severe side effects.

In the chemotherapy-plus-nivolumab group, the grade 3 and 4 toxicities were close to 50%-but only 25% and 35% of patients in the ipilimumab-plus-nivolumab group and chemotherapy-alone group experienced these toxicities. The ipilimumab-plus-nivolumab toxicities are consistent with the prior analysis from this trial that were previously published and presented at AACR. However, the rate of patients who could not go on with study treatment due to side effects was still low, in the 8% to 10% range.

Cancer Network: There is already a similar combination, that of pembrolizumab, (another anti-PD1 antibody), plus chemotherapy, pemetrexed, and carboplatin, which received an accelerated approval from the FDA for first-line treatment of non–small-cell lung cancer. Could you put these CheckMate 227 findings into context given the already approved, similar combination? Is there a slight difference in the patient populations that were tested in the two trials?

Dr. Borghaei: The addition of pembrolizumab to chemotherapy shown in the Keynote 189 trial was superior to chemotherapy alone for patients with nonsquamous non–small-cell lung cancer. And the survival benefit was apparent regardless of the level of PD-L1 expression on the patients’ tumors.

All of the patients, including those with PD-L1 expression of less than 1%, seemed to derive both response and survival benefit. PFS was better in the patients who had a greater than 1% PD-L1 expression, but PFS was not better with the combination compared to chemotherapy alone in the patients with low PD-L1–expressing tumors. The combination had been in use in the US based on a phase II Keynote 21 cohort G study, and this combination received regulatory FDA approval. The Keynote 189 study was a confirmatory trial that gave us more details on the way that PD-L1 expression might influence responses to these therapies.

Given the fact that this combination is already an FDA-approved regimen, clearly that is the treatment of choice for patients who are eligible for that combination of pembrolizumab plus chemotherapy. The ipilimumab-plus-nivolumab combination as it appears in this CheckMate 227 trial is not yet an FDA-approved regimen.

The results with the tumor mutational burden biomarker add to the complexity of this study, so as of now, we cannot yet use tumor mutational burden as a biomarker and ipilimumab plus nivolumab outside of a clinical trial. So the question is then, if we live in a hypothetical world in which both regimens are approved, is there a way to select patients for one or the other regimen?

First, I want to emphasize that having more options is always good. And there are a handful of patients [who] come in and say that they do not want to receive chemotherapy, and so having an ipilimumab-plus-nivolumab option for those patients is good. This [option] also reserves the ability to use a platinum chemotherapy doublet down the road if a combination like ipilimumab plus nivolumab does not work.

From a biological point of view, if a patient has a high tumor mutational burden and low PD-L1 expression, based on the CheckMate 227 trial, you could argue that those patients could have a better PFS response with ipilimumab plus nivolumab compared to nivolumab plus chemotherapy. Perhaps if we select patients for high tumor mutational burden and low PD-L1 expression, ipilimumab plus nivolumab would be an option.

We don’t have a head-to-head comparison of ipilimumab plus nivolumab to pembrolizumab plus chemotherapy, the Keynote 189 regimen-but I think I can envision being able to look at the PD-L1 expression and tumor mutational burden level and select specific patients that could be treated with the immunotherapy-only combination or an immunotherapy plus chemotherapy.

On the other hand, Keynote 189 showed us that every patient benefited from the addition of chemo plus pembrolizumab, but we have a prior study, Keynote 024, in which patients with higher PD-L1 expression of greater than 50% had a much better outcome with pembrolizumab alone compared to chemotherapy alone. So, the next question is, in that patient population, are we gaining more response rates and [improved] survival with the addition of chemotherapy to a checkpoint inhibitor antibody?

In other words, if the patients that have tumors with more than 50% PD-L1 expression are benefiting for single-agent pembrolizumab, is there a need to add chemotherapy? The answer to that question is not so obvious, because again, we don't have a direct comparison and we tend not to compare one study directly to another. But if you look at the OS, it is roughly 70% in both studies for patients who have 50% or greater PD-L1 expression.

So, again, perhaps the chemotherapy plus checkpoint inhibitor antibody would be the treatment of choice for patients in the moderate range of greater than 1% and less than 50% PD-L1 expression. On the other hand, [if my] patient in the clinic has a huge disease burden and is very symptomatic, [where] clinically it looks like I need to use my best option upfront to shrink the tumors and make the patient better, then I think chemo plus pembrolizumab is the treatment of choice because of the high response rate and because the PFS rate was better in most patients who had PD-L1 expression greater than 1%.

This combination gives me an option in someone who I am worried would not have a second chance at controlling their tumors. Then I will go in with the pembrolizumab plus chemotherapy combination and hope that they have a good response and get their disease under control. These trials are providing us with multiple scenarios to provide the best option for our patients.