Is Disease-Free Survival a Meaningful Endpoint in NSCLC?

Adjuvant atezolizumab (Tecentriq) significantly improved disease-free survival compared with best supportive care after chemotherapy in patients with resected stage II-IIIA non-small cell lung cancer (NSCLC), according to the results of the IMpower010 study presented at the 2021 virtual American Society of Clinical Oncology (ASCO) annual meeting.

In this exclusive MedPage Today video, Nicholas Rohs, MD, of the Icahn School of Medicine at Mount Sinai in New York City, discusses his issues with the study design, but why he still believes the results are meaningful.

Following is a transcript of his remarks:

My name is Nick Rohs, I’m an assistant professor at Mount Sinai Hospital in New York City. I’m a thoracic oncology specialist, which is why I’m here today to talk about the IMpower010 trial. This trial is a really exciting trial, I think it was one of the most impactful trials that came out of ASCO this year, and it is focusing on adjuvant immunotherapy.

So the IMpower010 trial was a large trial, it had over 1,200 patients who are entered and over 1,000 who were randomized in a 1:1 fashion. And these were patients with non-small cell lung cancer who were going through curative intent surgery. These were earlier-stage patients. I believe it was IB through IIIA, and these were patients who went through surgery, and then received an appropriate platinum doublet after their surgery. This was a cisplatin-based doublet. So cisplatin plus pemetrexed, Taxotere, gemcitabine or [vinorelbine] Navelbine, I believe. And then they were randomized 1:1 to either atezolizumab, 1200 mg IV every 3 weeks versus best supportive care.

So I think that’s probably where my first point of discussion is, is that they were randomized to best supportive care, which I think is a little bit of a miss there. I would’ve liked to see this randomized to a placebo, but I understand it’s difficult to get somebody to agree to 16 infusions of placebo. So these patients went through this and what we saw at ASCO this year was a preplanned, interim analysis of their primary goal, which was disease-free survival.

So they have a hierarchical statistical method where they did disease-free survival. I believe they originally did it with the PD-L1 greater than 1%. And then they go down to the intent-to-treat population, and then eventually they trigger over to overall survival. So I think that’s also where a lot of the debate is coming here.

But these were really intriguing results. In the greater than 1% PD-L1 expressors there was a hazard ratio of 0.66. So another point of discussion that we’ve been having is that a lot of these benefits were probably driven by the high PD-L1 expressors. So, the ones who had the [tumor cells] greater than 50%, the hazard ratio is actually 0.43. And then when they looked at the less than 1%, it was 0.97. So, there’s definitely a lot of this benefit that’s being driven from the high expressors, but we do see a benefit for all PD-L1 expressing tumors.

This data is very early, this was a preplanned interim analysis. We’re still looking for this data to mature. I think everybody’s really excited about hearing the overall survival data, but I think that this is definitely an impactful study. And I think that this will be speaking to the future of non-small cell lung cancer in the curative-intent surgical setting.

We’ve been seeing a lot of exciting data about the neoadjuvant and now the adjuvant space. We’ve seen the NADIM trial, the KEYNOTE-816 trial showing really intriguing chemo-IO [immunotherapy] and IO neoadjuvant data. So seeing that paired with some really good adjuvant IO data, I think that this is the advent of the at least perioperative therapy with IO for these patients. So I think it’s really good to see some separation of the overall survival curve early. We got a little sneak peek at that, but definitely still immature.

I think being able to see [circulating tumor] DNA data for minimal residual disease and how that may be affecting these results is going to be really interesting. But I’m pretty confident that immunotherapy is here to stay in the perioperative setting. So these are really exciting results. I think we’re all looking forward to seeing more of them.

I think really one of the biggest debates that we’ve been having in this space, as well as in other solid tumors that have been having some of this neoadjuvant data is if disease-free survival really our meaningful endpoint. I think overall survival has always been our gold standard. I don’t think we’ve really ever defined this except for maybe recently in the ADAURA trial, which used EGFR TKIs. And I think that hazard ratio was so striking that more people were really willing to adopt that, but there’s still a lot of debate. So I’m looking forward to seeing this data set mature, and where we go from here I think can only be up and onwards.