CheckMate 9LA: ‘Doing better’ for stage IV/recurrent NSCLC

Challenges to overcome

In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.

Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.

With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).

Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
 

Better by design

In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.

Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.

Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.

Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.

Longer follow-up needed

In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.

As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.

It would be ideal to know whether the tail of the OS curve will flatten out.
 

Do the best you can

Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.

In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.

Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Reck M et al. ASCO 2020, Abstract 9501.