At the 2023 ASCO Annual Meeting, Jason Luke, MD, shares results from the protocol-specified final distant metastasis-free survival analysis of KEYNOTE-716, evaluating adjuvant pembrolizumab among patients with stage IIIB and IIIC resected melanoma.

In this analysis, with a median follow-up of 39.4 months, adjuvant pembrolizumab continued to show a benefit in both distant metastasis-free survival and recurrence-free survival, vs placebo. While patients must weigh the benefit of improved survival outcomes against the risk of adverse events, Dr Luke concludes, "the KEYNOTE-716 now establishes a standard of care that all patients with stage IIB and IIC [melanoma] should at least be offered adjuvant immunotherapy for their care."

Transcript:

I'm Jason Luke from UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania, and updating the results of the KEYNOTE-716 clinical trial. The audience will remember that KEYNOTE-716 is the global, randomized, placebo-controlled, phase 3 clinical trial investigating pembrolizumab in stage IIB and IIC melanoma. The rationale for this clinical trial was, whereas patients with stage III disease have had adjuvant therapy options with anti PD-1 immunotherapy and pembrolizumab for about 7 years now, it's been the case that patients with stage IIB and IIC have not had access to that treatment, despite the fact that the melanoma specific survival for stage IIB and IIC is roughly the same as for stage IIIA and IIIB. So, to rectify that, we launched KEYNOTE-716 with the study design being a 1-to-1 randomization of patients to receive either pembrolizumab at the standard dosing of 200 mg every 3 weeks for a year versus placebo, with key eligibility criteria being age greater than 12 years, fully resected stage IIB and IIC with negative sentinel lymph node biopsy, no prior therapy, and ECOG performance status of 0 or 1.

The primary endpoint of the study was recurrence-free survival (RFS) with the key secondary endpoint at distant metastasis free survival. And the audience may remember that approximately 2 years ago now, I presented the first analysis of 12-month landmark recurrence-free survival, where pembrolizumab met the primary end point for the clinical trial showing a statistically significant reduction in relapse. And the study has been updated a few times over the past couple of years with that benefit enhancing over time. And the study also met the key end point of distant metastasis free survival (DMFS). At ASCO 2023, we present the final protocol specified analysis of distant metastasis-free survival at interim analysis 4 with a median follow-up of 39.4 months and landmark at 36 months of followup, where we observe that pembrolizumab reduced distant metastasis-free survival versus placebo with a hazard ratio at 0.59, or a 41% improvement in DMFS.

And these are very important data as they emphasize 2 obvious points, one being that patients with stage IIB and IIC melanoma in fact are at very high risk for recurrence, and that pembrolizumab reduces that recurrence in a very meaningful way. Now, of course, we can't discount the fact that there are side effects associated with the use of anti-PD-1, with pembrolizumab. However, with long-term follow-up on our clinical trial, we saw no new safety signals relevant to what we already know about pembrolizumab. But certainly approximately 15% to 20% of patients can have thyroid dysfunction that may require thyroid hormone supplementation, and less than 5% can have those very severe immune-related adverse events that may not be reversible, such as hypophysitis and pancreatitis leading to diabetes. For an individual patient, it is the standard of care to offer pembrolizumab to patients in the adjuvant setting for stage IIB and IIC. Though, it is a nuanced consideration for an individual patient, how they perceive that benefit in terms of RFS and DMFS versus the side effect profile.

And these data will be very important and lay in a framework for future studies as 4 adjuvant phase 3 clinical trials are already ongoing for combination immunotherapy at this time. Two are combinations with LAG-3 antibodies, 1 with a TIGIT antibody and 1 with an individualized neoantigen therapy all on a PD-1 backbone. But based on the results of KEYNOTE-716, all of these studies now include an eligibility population from stage IIB all the way through to stage IV resected. And I think this has changed the framework of how we think about risk stratification in melanoma such that the KEYNOTE-716 now establishes a standard of care that all patients with stage IIB and IIC should at least be offered adjuvant immunotherapy for their care.

Source:

Luke JJ, Ascierto PA, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: Final analysis of distant metastasis-free survival in the phase 3 KEYNOTE-716 study. Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract LBA9505