Checkmate 9LA: Nivolumab, ipilimumab and chemotherapy for stage IV NSCLC

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Published: 30 Jun 2020
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Prof Martin Reck - Lung Clinic Grosshansdorf, Grosshansdorf, Germany

Prof Martin Reck speaks to ecancer in an online interview for the virtual ASCO 2020 meeting.

He discusses the CheckMate 9LA trial which looks at nivolumab ipilimumab 2 cycles of platinum-doublet chemotherapy versus 4 cycles chemo as first-line treatment for stage IV/recurrent non-small cell lung cancer (NSCLC).

Prof Reck outlines the background and reasoning for trialling the combination of checkpoint inhibitors, with the addition of 2 cycles of chemo.

He gives a detailed description of the positive response for the combination arm, and outlines the toxicities which were expected, and manageable, with these particular drugs.

This programme has been supported by an unrestricted educational grant from Bristol Myers Squibb.


Hello everyone, my name is Martin Reck. I’m working at the Lungenklinik in northern Germany, I’m specialised in thoracic oncology. It’s my pleasure to talk to you about the results and the background of the CheckMate 9LA, a new treatment opportunity for patients with metastatic non-small cell lung cancer.

The background has been the observation that the immunotherapy combination of two different checkpoint inhibitors, the anti-PD1 inhibitor nivolumab and the anti-CTLA-4 inhibitor ipilimumab, has the ability to generate a long-term overall survival benefit in several tumours. We also have seen in the CheckMate-227 trial that this combination was associated with a survival benefit, in particular a long-term survival benefit, compared to chemotherapy independent from our biomarkers, PD-L1 expression status and tumour mutational burden.

The idea of the CheckMate 9LA was the control of the fast tumour progression by adding two cycles of chemotherapy to the immunotherapy combination and to build on the survival benefit which has been generated by the use of nivolumab and ipilimumab. So the concept was the comparison between short chemotherapy, two cycles of chemotherapy, in combination with the immunotherapy combination of nivolumab and ipilimumab, compared to standard chemotherapy. The primary endpoint was overall survival and secondary endpoints which were tested hierarchically were response, progression free survival and efficacy correlated to the PD-L1 expression status.

The data monitoring committee confirmed superiority for the primary endpoint of overall survival in a pre-specified interim analysis corresponding to a hazard ratio of 0.69. With four months of further follow-up consolidation and improvement of overall survival was seen now corresponding to a hazard ratio of 0.65. We observed a very early separation of the Kaplan-Meier curves and, as mentioned before, we did observe a consistent benefit in overall survival. Still we do have a lot of patients in censoring so we do expect a further improvement of the outcomes with the follow-ups in the next years.

As laid out in the statistical plan, progression free survival and response were tested hierarchically also a significant improvement in response and progression free survival was observed in favour of the combination arm. When we look at response, interestingly the rate of primary progressions was reduced in the combination arm, underlining the concept of the control of the early progression of the disease.

When we talk about the benefit related to the different patient characteristics, the benefit in survival and progression free survival was seen dominantly in most investigated subgroups. In particular when we look on the stratification factors, these were histology and PD-L1 expression status, the benefit and efficacy was seen in both major histologies, non-squamous and squamous histology, and it was seen independent from the PD-L1 expression status in patients with PD-L1 negative as well as PD-L1 positive tumours.

One important question was the question of tolerability because we have a very intensive treatment for our patients. We did observe a higher number of adverse events leading to discontinuation of one of the agents and we also did observe a higher frequency of grade 3 and 4 treatment related adverse events in the combination arm. On the other hand, also treatment duration was longer in the combination arm because the patients received a maintenance therapy with the immunotherapy combination. The rate of fatal toxicities was very low, in both arms it was 2%.

Interestingly, the frequency of typical chemotherapy-associated adverse events like anaemia, neutropenia and thrombocytopenia was reduced in the combination arm, probably due to the fact that the patients only had received two cycles of chemotherapy. The picture and the severity of the immunotherapy-associated adverse events was very similar to the picture that we have seen in the CheckMate-227. So there were no new immunotherapy-associated adverse events in the combination arm with the chemotherapy.

So, in conclusion, the CheckMate 9LA met its primary endpoint of a significant improvement in overall survival in the pre-specified interim analysis. The confirmation in all endpoints was seen with a four month further follow-up. The tolerability profile was as expected, there were no new safety signals observed in this trial, and the efficacy was independent from certain patient characteristics like histology or PD-L1 expression status.

So currently this combination has been already approved by the FDA and I think it represents a very attractive new therapy opportunity for untreated patients with advanced non-small cell lung cancer without oncogenic alterations.

Thank you.