CheckMate 227: Combining CTLA-4 and PD-L1 in NSCLC


Suresh S. Ramalingam, MD, FASCO: This has been a very exciting discussion on targeted therapies. We want to switch gears and move on to talk about immune checkpoint inhibitors in lung cancer landscape as the next part.

When immune checkpoint inhibitors entered the lung cancer arena, we were initially using them as monotherapy in the salvage setting. Then it moved to the frontline setting. In the last 2 years, we’ve been learning a lot about combining chemotherapy with immune checkpoint inhibition. At this ESMO [European Society for Medical Oncology] Congress, we’re learning more data about combining a CTLA-4 antibody with a PD-1 [programmed cell death protein 1] antibody. Johan, can you briefly talk about the rationale for combining a PD-L1 [programmed death-ligand 1] or a PD-1 inhibitor with a CTLA-4 inhibitor?

Johan F. Vansteenkiste, MD, PhD: Yes. Well, the rationale is that if you give anti—CTLA-4 and anti–PD-1 or PD-L1, you tackle 2 points in the cancer immunity cycle, which makes it quite acceptable that you may have a more pronounced effect than with single-agent immunotherapy alone. What we have seen here at ESMO is another report of the CheckMate 227 study, because it’s a never-ending story. It’s a very complex trial with a lot of strata, with a lot of endpoints. But I think what we have seen here at ESMO is perhaps the most important presentation, until now, of CheckMate 227. This is because we previously learned that the progression-free survival was better with nivolumab-ipilimumab than with chemotherapy if you give it in patients with high tumor mutation. But this did not translate into overall survival data.

What we have here now are overall survival data, and we have overall survival data of the patients who do have PD-L1 expression. They have at least 1% expression of PD-L1 on the tumor cells. In that cohort that is reported now, the ones without PD-L1 expressions will be reported later, I suppose. There was a very important effect in the way that the combination of nivolumab and ipilimumab, in terms of overall survival in that group, did significantly better than the ones who were given doublet chemotherapy alone.

Strange enough, this was the case both in patients with a high and a low tumor mutational burden. This was now irrespective of tumor mutational burden. But what was of particular interest in this study is that the effect of superiority in terms of overall survival of nivolumab-ipilimumab versus chemotherapy was quite sustained. In the overall survival curves, there was a plateau at 1 year and at 2 years where the patients who received NIVO [nivolumab]—IPI [ipilimumab] were clearly above the ones with chemotherapy. This can be perhaps related to the fact that this is combination immunotherapy with anti–CTLA-4 and anti-PD-1, which means that it may perhaps be more induction of memory cell effects. This could explain the curves later onward and that’s mainly what we want to see. We want to see plateaus with immunotherapy, and plateaus are clearly above the ones that we know historically. I think this is the case in this part of the presentation of the CheckMate 227, so I feel it’s a very important presentation.

Suresh S. Ramalingam, MD, FASCO: As you point out, Johan, the tail of the curve elevating that, which means patients were benefiting, stay on that therapeutic benefit for a longer duration of time, which is an important factor. That’s 1 of the key points in the CheckMate 227 trial that the duration of response with immune checkpoint inhibition plus CTLA-4 combination is clearly much better than chemotherapy. Pasi, what are your thoughts on the durability of benefit with the combination of IPI and NIVO?

Pasi A. Jänne, MD, PhD: Well, I think it’s impressive. I don’t think we see that with chemotherapy, even with maintenance chemotherapy. I think it’s a fundamentally different type of treatment approach. It’s gratifying to see that, and it clearly opens up an option for patients to start with combination immunotherapy in the frontline setting as opposed to systemic combination chemotherapy. It’s an exciting finding and really a welcome addition to our sort of immunotherapy armamentarium, especially in the frontline setting.

Transcript Edited for Clarity

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