New Long-Term KEYNOTE-716 Data Presented at ASCO 2023

“I'd really just emphasize that [pembrolizumab] is the standard of care and patients with stage 2 disease should be offered pembrolizumab as adjuvant therapy. Understandably, some patients may not take it, but it should be offered to all patients in that scenario,” said Jason Luke, MD, FACP, in an exclusive interview with Dermatology Times®.

Luke, an associate professor of medicine in the division of hematology/oncology and the director of the Cancer Immunotherapeutics Center of the UPMC Hillman Cancer Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center, as well as the principal investigator of the KEYNOTE-716 pembrolizumab (Keytrdua; Merck) clinical trial, recently presented new long-term data of distant-metastasis-free survival from the trial at the 2023 American Society of Clinical Oncology (ASCO) meeting.

Pembrolizumab is FDA-approved as adjuvant therapy for the treatment of stage IIB/C melanoma in adult and pediatric patients.

Transcript

Luke: Hi, I'm Jason Luke from the UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania, where I was the principal investigator for the KEYNOTE-716 clinical trial.

Dermatology Times: How were you involved in the KEYNOTE-716 trial as the principal investigator?

Luke: So I had the good fortune of being the overall principal investigator for the KEYNOTE-716 clinical trial. And in fact, this was a clinical trial that was about 5 years in development, dating back actually to the original approvals of pembrolizumab for stage 3, adjuvant therapy in melanoma. We started working diligently at that time to try to address the unmet need in stage 2 melanoma. And we're very gratified now to see that pembrolizumab has been approved as a standard therapy by the FDA for stage IIB/C melanoma. And at ASCO, 2023, we're updating with long-term follow-up at 36 months, the distant metastasis free survival outcomes for patients, which I think set a new standard of care in the field.

Dermatology Times: Can you please provide an overview of the study background, methods, and key results?

Luke: So KEYNOTE-716 was a global randomized, placebo-controlled, phase 3 clinical trial, testing pembrolizumab versus placebo in high-risk stage IIB and IIC melanoma. And of course, for context, it's important to point out that while adjuvant immunotherapy has been a standard of care for most of the last decade in stage 3 disease, options for stage 2 were limited, despite the fact that the melanoma-specific survival for stage IIB and IIC melanoma is essentially the same as for stage IIIB. So to try to address this lack of treatment options in stage 2, KEYNOTE-716 was launched, where 976 patients were randomized, basically 1:1 to either receive pembrolizumab or placebo. And patients who received pembrolizumab received the standard dose that we give at 200 milligrams every 3 weeks for up to a year. Patients were then followed with the opportunity to cross over from placebo to pembrolizumab at the time of metastatic recurrence. So we reported the initial results from KEYNOTE-716 now about 2 years ago, where at the first interim analysis of 12 months, the trial hit its primary endpoint for a statistically significant difference in recurrence-free survival. Subsequent that at 2 years, we saw the updated data for the secondary endpoint of distant metastasis-free survival, which was also significant. And now with 3 years of follow-up, these data have matured even further, where we see an increase in robust and consistent impact on distant metastasis-free survival, with patients receiving pembrolizumab having approximately a 41% improvement in distant metastasis-free survival relative to the placebo control arm. So these are very important data that helps to inform patients as they choose what treatment would be best for them after surgery for melanoma. And we think that they set a new standard of care for the field moving into the future.

Dermatology Times: What results from the trial were you most pleased with?

Luke: Well, the results of KEYNOTE-716 were gratifying, in that they reinforced what we already knew and yet changed the standard of care at the same time. And that may seem odd, but in melanoma oncology dating back, you know, 10 to 20 years ago, there really were no treatments, frankly speaking. And so it was a surgical-based disease. And the algorithms for managing patients were that patients were deemed to be at higher risk if they had regional lymph node involvement at the time of surgery. But what we know from database analysis from say the AJCC is that patients with Stage IIB and IIC disease, meaning deep primary lesions on the skin, in fact have similar outcomes to those with stage IIIB.So it isn't actually the lymph node that drives the risk, it's the primary lesion itself. So it was gratifying to see in KEYNOTE-716, that there was such a robust and durable benefit to giving pembrolizumab because we already knew that pembrolizumab would impact on recurrence in DMFS in stage 3, so by logic, it should work in stage 2. And in fact, that's exactly what we've seen. And so to me, it's been very gratifying to observe that which we expected but to document it, but also to challenge sort of that classic dogma in the field because I think patients were underserved previously being deemed to be low risk, when in fact, they had the same risk as stage 3, but they didn't have options for treatments and KEYNOTE-716 change that now with the FDA approval of pembrolizumab in the stage 2 setting, and I'd really just emphasize that it is the standard of care and patients with stage 2 disease should be offered pembrolizumab as adjuvant therapy. Understandably, some patients may not take it, but it should be offered to all patients in that scenario.

Dermatology Times: Were there any notable challenges from KEYNOTE-716?

Luke: Well, a notable challenge to the pursuit of KEYNOTE-716 was exactly the inertia that went into this study. Because for decades, surgeons, meaning, well had educated patients that they were cured when they had had a negative sentinel lymph node biopsy. But for all the reasons I just said that wasn't true. And in fact, with a deep primary lesion, their risk of recurrence was similar to stage 3. So accrual to the study actually, initially was not as robust as one had hoped for. And it was because of bias in the field, that patients were being educated that they were fine, when in reality, they weren't necessarily fine. So it took a period of time to ramp up the accrual. But now it's very obviously the case that there's a benefit there. So for the next generation of clinical trials that will investigate combination immunotherapy strategies, I think that you know, will be less of a problem because we've documented that there's such a benefit to giving immunotherapy in this setting.

Dermatology Times: How do you hope the long-term data from KEYNOTE-716 helps physicians treat their patients with stage IIB/C melanoma moving forward?

Luke: The importance of these long-term update data for distant metastasis-free survival from KEYNOTE-716 are important on multiple levels. I think one, they really drive home the point that adjuvant pembrolizumab has a durable and meaningful impact on relapse and DMFS. And number 2 is they set a new benchmark in the field for stating what adjuvant therapy can do. It's been actually multiple decades since a clinical trial investigated stage 2 melanoma. So we now have a better setting of the modern natural history of the disease with no treatment, but also what an intervention like pembrolizumab can do. And that sets us up for the next generation of clinical trials which will look at combinations of next checkpoints and neoantigen approaches and other things. And so these data really are essential for the field as we move into the future. And again, I think really emphasizes that the standard of care is to offer adjuvant pembrolizumab to patients and there should not be any other layer of patient selection other than to say, if patients have deep primary lesions, they should be offered this treatment, whether they choose it or not. Of course, it's a complicated decision. But that is the standard of care.

[Transcript edited for clarity]