Expert: KEYNOTE-716 Could be a "Game-Changer" for Patients with Stage 2 Melanoma At High Risk of Recurrence


Until this study, adjuvant immunotherapy was standard of care for stage 3B melanoma but not stage 2, which has relatively similar survival rates and risk of recurrence.

Jason J. Luke, MD, FACP, Associate Professor of Medicine at UPMC Hillman Cancer Center, Pittsburg, Pennsylvania, discusses standard use of adjuvant immunotherapy for earlier stage melanoma to reduce risk of recurrence and distant metastasis with Pharmacy Times at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, from June 2 to 6.

PT Staff: What are primary roadblocks affecting current melanoma treatment options?

Jason J. Luke, MD, FACP: Well, in melanoma, we had an explosion of treatment options in the past 10 years. But unfortunately, despite that great success, many patients unfortunately do still relapse after surgery and have inadequate options in that setting. So really, in thinking about where the field needs to go, there's sort of a 2-pronged attack. One would be moving therapies that we know are more effective into the perioperative setting with the hopes that that would reduce the number of patients who ever actually develop relapse; as well as obviously developing new treatments for patients with truly refractory metastatic disease.

PT Staff: Could you describe the KEYNOTE-716 trial? How well did pembrolizumab achieve study outcomes, including distant metastasis-free survival?

Jason J. Luke, MD, FACP: So at ASCO 2023, we update the final protocol specified analysis of distant metastasis free survival (MFS) from KEYNOTE-716, which of course was the global randomized placebo controlled phase 3 clinical trial of pembrolizumab (KEYTRUDA®; Merck) versus placebo. And when we started this clinical trial, now dating back almost 5 years, there was a difference of opinion in the field about the relative risk of stage 2 patients. So even though we had long term data showing that patients with stage 2B and 2C melanoma have actually, in fact, very similar melanoma of specific survival relative to stage 3B, it wasn't standard to use adjuvant immunotherapy. So this study has been a game changer. And new benchmarks that are in the field emphasize the point that those patients with stage 2B and 2C disease do, in fact, have high-risk features that lead to recurrence, and that the application of pembrolizumab as an adjuvant therapy clearly reduces that risk very substantially. So in our abstract, we show a maintained durable and increasing benefit for distant MFS on the order of a hazard ratio of .59, or a 41% reduction in distant metastasis, for patients who are treated with pembrolizumab. And so certainly that's a very large benefit that should be offered to patients as standard of care (SoC) moving forward.

PT Staff: What could a patient management protocol using pembrolizumab look like for patients with stage 2B or 2C melanoma?

Jason J. Luke, MD, FACP: These data from KEYNOTE-716—which have been released to the public for 2 years now and emphasizes the benefit for pembrolizumab in this setting— have changed practice in melanoma oncology. So whereas the standard algorithm was a patient would see a dermatologist have a biopsy, and then go to a surgeon for perhaps wide local excision and sentinel lymph node evaluation and then see a medical oncologist for consideration of adjuvant therapy, that paradigm needs to change because now that we have these data. Patients with only deep primary lesions also should be offered adjuvant therapy. So a better workflow would be for patients to perhaps seed or dermatologist or family practitioner, and then be referred in parallel to see the surgeon and the medical oncologist for that multidisciplinary evaluation of whether what kind of surgery should be pursued and whether or not adjuvant therapy wouldn't be appropriate for them. Of course, not all patients necessarily need adjuvant therapy or want to pursue it. And there's a tradeoff between side effects and reduction in risk of recurrence and distant metastasis. However, that's a nuanced conversation needs all the providers involved at the time of engagement with the patient.

PT Staff: What are the most important toxicities to know about pembrolizumab?

Jason J. Luke, MD, FACP: The side effect profile of pembrolizumab is well-characterized across all of oncology. And in KEYNOTE-716 we saw no new safety signals. And with long-term follow up, we also saw no increase in adverse events (AEs). Now that being said, of course, it's well known that immune-related AEs can be associated with immunotherapies like pembrolizumab and in our study, we did see there was approximately a 15% incidence of thyroiditis, which can lead to a long-term need for supplementation of thyroid hormone, as is very common in many people in the population. You know, more than that, though, there is approximately a 5% risk of an irreversible side effect, such as hypothesis or pancreatitis, which can also lead to the need for long term hormonal supplementation. And so, for certain treatment populations, of course, that would be a potential concern. But you know, we consider these to be well known side effects because pembrolizumab is active and used in many different oncology indications. So again, to emphasize in this clinical trial, the side effect profile looked very similar to what we already know about pembrolizumab. So really, it's thinking about “does the patient value more the reduction in risk of recurrence and distant metastasis versus that concern about any potential long-term toxicity, albeit that those are quite rare?”

PT Staff: What would be the significance of expanding this indication to include use as an adjuvant therapy?

Jason J. Luke, MD, FACP: So in melanoma, we've known for roughly 5 to 7 years already that anti-programmed death 1 (PD1) immunotherapy would reduce the risk of recurrence and distant metastasis in stage 3 melanoma. But the odd thing in our field was that patients with stage 2 melanoma did not have access to the treatment, despite the fact they had the same level of recurrence risk that we saw on stage 3. So these data were very, very important in sort of level setting, you might say, or bringing things back to the even keel; because now patients with similar levels of risk across stages all have an FDA-approved therapeutic option that can be offered to them in the perioperative setting. Now we also know that pembrolizumab can reduce recurrence or event free survival (EFS) in patients treated with it in the neoadjuvant setting, or prior to surgery even. And whether that's a paradigm that will extend beyond the highest risk bulky presentations is unknown at this time. It is possible in the future that we may extend the use of anti-PD1s, just pembrolizumab, even earlier into the disease setting, but for right now we know that for people who have deep primary lesions that are restricted by surgery, offering them pembrolizumab is the standard of care (SoC), albeit that it's a nuanced conversation about which patients want to pursue it, first pursue observations.

PT Staff: If patients with stage 2 disease were observed to have a similar rate of recurrence, why would there be such a different treatment protocol?

Jason J. Luke, MD, FACP: Well, these historical legacy issues really drive out of what our paradigms were. So if you go back in melanoma oncology, [say] 15 years, there basically was no treatment for advanced melanoma and there was no real treatment that truly reduced the risk of recurrence. And so for that reason, it was primarily a surgically-based management of the disease. And there were certain paradigms that went along with that. Now, of course, in the past 15 years, melanoma has been the step tip of the spear in terms of molecular and immuno-oncology approaches, with new drugs being developed. And it's just taken time for standard medical practice to catch up with the impact that that has had now going into earlier stages of disease. And so none of this is really good, bad, ugly, beautiful, etc. It's just that things need to change over time. And we need to make sure that education is out there so that people are aware of the newest treatment options that can be available for their patients.

PT Staff: Do you have any parting words?

Jason J. Luke, MD, FACP: Only to emphasize again that patients with stage 2B and 2C melanoma are at high risk of recurrence. And classically, we've thought about this as being patients with melanoma who had lymph nodes were those who needed the most intervention. But these data really emphasize that that's not the case. And rather, it's the patient's primary melanoma, and how deep that is on the skin, that really drives most of the risk. And so we need to get this message out to our oncology community, but also to the surgical community. Because commonly when they engage with the patient, they'll say, “Well, we did your lymph node evaluation, and there's nothing involved. So you're in good shape. “But in fact, that's not exactly correct. It's really the primary lesion that drives a risk. And this is where we need multidisciplinary evaluation of patients so we can communicate with them clearly and helps them to make the best decision for them.

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