CheckMate 816 trial: Nivolumab and platinum-doublet chemotherapy vs chemo as neoadjuvant treatment for resectable NSCLC

Dr Patrick M. Forde - Johns Hopkins University, Baltimore, USA

Back in 2018 we published a study which looked at giving immunotherapy to patients prior to surgery for stage I-III non-small cell lung cancer. Non-small cell lung cancer is the most common type of lung cancer and for many patients who have surgery for earlier stage lung cancer they will still experience relapse of the cancer after surgery. So the idea of giving immunotherapy prior to surgery was with the goal of exploring whether it was active in that setting and also in the longer term whether it can benefit patients in terms of preventing relapse. In that study back in 2018 we showed that about half the patients had a major pathologic response where 90% of their tumour regressed after two doses of treatment.

So then we designed the current study which is called CheckMate 816. This was a randomised phase III trial conducted across the world, it enrolled over 350 patients who were randomised to receive either a control arm of standard chemotherapy, platinum doublet for three cycles, prior to surgery or the investigational arm which was giving nivolumab, which is an anti-PD-1 immunotherapy, concurrently with the chemo and comparing those two arms and trying to show a clinical benefit.

The primary endpoints of the study were pathological complete response and the second primary endpoint was event free survival. This past weekend we reported the results for pathological complete response.

What was the methodology used in your study?

This was a randomised phase III trial, fairly pragmatically designed. It enrolled patients with stage IB cancers measuring 4cm or greater, stage II and stage IIIA. Those patients were all rigorously staged and then enrolled in the trial and randomised to one of the two arms. They had the three cycles of chemotherapy plus or minus nivolumab, went to standard surgery and then post-operatively they could receive the investigator’s choice of further therapy in the post-operative setting. As I said, we evaluated the surgical specimens for pathological response. That was done by a blinded independent committee of pathologists who did not know which arm of the trial their specimens came from. In the longer term we’re still following those patients for event free survival and for overall survival.

What were your findings?

We saw that when the study was evaluated for the pathological complete response endpoint, which we made the final report of just this last weekend at the AACR meeting, there was an improvement in pathological complete response from 2.2% with chemotherapy alone to 24% with chemotherapy combined with nivolumab. This was a significant improvement, as you can imagine, a greater than tenfold increase in pathological complete response.

We also saw that there was no impact on the feasibility of surgery by the addition of nivolumab to chemotherapy and there were the same or lower rates of toxicity when you added nivolumab to chemotherapy. So, both of those two findings were also important because we showed that there was no negative impact from adding nivolumab to chemo.

There’s potentially a very significant improvement in pathological complete response from the addition of nivolumab. We’re continuing to follow these patients for longer term survival outcomes but I think these are very promising results at this point.

We also did some correlative analysis and looked in particular at circulating tumour DNA levels in the blood, a technique called liquid biopsies. In a subset analysis we were able to show that there were higher rates of clearance of circulating tumour DNA from the blood in patients who received nivolumab with chemotherapy. Those patients who did clear circulating tumour DNA prior to surgery were more likely to have a pathological complete response. So I think that’s an interesting subset analysis and we hope to explore it further.

What is next for this trial?

We’ll be continuing to follow these patients. The timing of follow-up for event free survival is event driven so it depends on how quickly events occur for patients who were enrolled in the trial. But we’ll be following them closely and we hope to report the results for longer term survival outcomes in the near future.

Is there anything else important that you’d like to mention?

This is potentially a very important advance for patients with early stage lung cancer. We haven’t seen any advances in terms of immunotherapy for early stage lung cancer so far, at least reported. This neoadjuvant study also highlights the potential for neoadjuvant clinical trials to drive progress for cancer in general where you get an early endpoint in terms of pathological complete response and then the patients can be followed up for longer term clinical endpoints as well.