Is Adjuvant Atezolizumab a New Standard in Stage II/IIIA Lung Cancer?

This transcript has been edited for clarity.

It's Mark Kris from Memorial Sloan Kettering Cancer Center. I'm speaking today about a recent publication in The Lancet in the September 20, 2021, issue.

This paper details a worldwide randomized phase 3 trial comparing atezolizumab, the anti–PD-L1 drug, with no additional therapy in patients with completely resected stage II and stage IIIA lung cancers who have received postoperative chemotherapy with cisplatin and another agent.

Cisplatin-based chemotherapy after surgery in these patients is our current standard of care. This trial is a fairly clean one to address this very pertinent issue. What I like about this trial and this approach, particularly from a medical oncologist standpoint, is that the goal is to improve the cure rate.

We have the potential here to take one of our systemic agents and use it in a situation that could enhance the chance of cure. I know there is some controversy here, but to me, what's more important is the disease-free survival curve. Only those patients who get on that curve and stay on that curve can be cured. The disease-free survival curve is indeed the most important one because, to me, that's the cure curve.

This trial was designed to compare no additional treatment with 16 doses of atezolizumab at the standard dose given every 3 weeks. They hoped to have an improvement in disease-free survival, with a hazard ratio of 0.73. As the basis of comparison, they used a standard where the no additional treatment would yield a median survival of 35.34 months. In the trial, with no additional treatment, the median survival was 35.3 months, which was right on target.

What makes sense here, in terms of the expected result, would be that those patients who have some sign of susceptibility to an immune checkpoint inhibitor — high PD-L1 is probably the best one we have — would do better. And conversely, in patients who had very low PD-L1 and patients who had driver mutations where immunotherapeutic drugs are nowhere near as effective — some would say they're ineffective — we would not expect a good result.

Lo and behold, that's exactly what we saw. For stages II to IIIA, the hazard ratio for disease-free survival was 0.66. The 2-year disease-free survival was improved by 14%, from 61% to 75%, and the 3-year disease-free survival, from 48% to 60%. The goals of the trial, as proposed, were met. There were no unexpected or unanticipated findings.

One inconvenient truth of the trial: All patients received cisplatin but they did not specify which agent was to be given with the cisplatin. The regimen that gave the best result, and in the forest plot the only one that resulted in a significant improvement, was the regimen that had vinorelbine added.

What's the take-home message from this study? I think it's very clear that patients who have a complete resection, stage II to IIIA disease, a PD-L1 status of 1% or greater — that is, some evidence of PD-L1 expression — have a clear benefit in terms of disease-free survival with 16 post-adjuvant chemotherapy doses of atezolizumab. In my mind, that should be a clear standard.

When you look at the results in patients who had ALK fusions or EGFR mutations, they benefited far less. For those people, we should look for other avenues. Particularly for the patients with EGFR mutations, we have another agent that is guideline-approved and available, which is osimertinib. Their improvement in 2-year survival was 46%. Clearly, if you have an EGFR mutation, you should receive osimertinib following chemotherapy. I think the point there is that you should test for EGFR mutations because they can point you to a better treatment.

What about other drivers? Well, the jury's still out on that. I think the data would say that giving a matched drug to the driver makes the most sense. We have good data for that for EGFR. My guess is that, as time goes on, we're going to have that for other drugs as well. I know there's a trial going on now with selpercatinib as an adjuvant treatment for patients with RET-positive tumors.

For people who have no PD-L1 expression, where we really don't have data that giving a checkpoint inhibitor is helpful, we have to look for a new strategy beyond chemotherapy. Chemotherapy remains the standard of care for those people. Radiation for selected patients with stage IIIA disease is a bit of a longer discussion.

This trial by Felip and coauthors clearly gives us a new standard of care for people who have PD-L1 expression, complete resections, and in my mind, don't have driver oncogene present: atezolizumab for 16 doses.

There are other trials coming up. There are adjuvant trials of pembrolizumab, durvalumab, and nivolumab in the hopper. My expectation is we're going to see very comparable results and we're going to be giving checkpoint inhibitors after chemotherapy in patients with completely resected disease.

Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. His research interests include targeted therapies for lung cancer, multimodality therapy, the development of new anticancer drugs, and symptom management with a focus on preventing emesis.

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