Transcript - KEYNOTE-716 New Facts You Need To Know - Article
Question – Please Tell Us About The KEYNOTE-716 Study.
At ASCO 2022 I presented the first analysis of the distant metastasis free survival in the keynote 716 study so this is a study of patients with resected stage 2b and 2c melanoma this is a patient group who actually have a very high risk of recurrence by 24 months many patients have recurred and their prognosis at five years is very poor with a poor overall survival so seven uh 976 patients were randomized one to one with resected stage 2b or 2c melanoma to either to receive pembrolizumab at 200 milligrams every three weeks or placebo for 17 cycles that's 12 months of treatment so the primary analysis was the relapse free survival which was published in the lancet last year which showed a significant improvement in the relapse free survival a second subsequent analysis showed a sustained benefit in that relapse free survival with a hazard ratio of 0.61 and that this third analysis presented at ASCO we presented for the first
time the distant metastasis free survival pembrolizumab significantly improved the distant metastasis free survival over placebo with a hazard ratio of 0.64 that's a 36 reduction in the risk of distant metastases and the p-value was 0.0029 the 12-month and 24-month distant metastasis-free survival rate were higher in the pembrolizumab arm and every key subgroup predefined at the trial although not powered showed a benefit towards pembrolizumab map over placebo and that includes the t subcategory staging from the AJC’s 8th edition of t3b t4a and t4b tumors
In terms of the relapse free survival we looked at it again a third time and we saw that again a sustained benefit with a hazard ratio of 0.64 showing that pembrolizumab improves risk relapse free survival with time when we look at the types of recurrences we saw that the pattern of first recurrence we saw much reduced numbers in the pembrolizumab arm for example distant metastasis as a first recurrence occurred in 45 patients with 487 for the pembrolizumab arm but 79 patients in the placebo arm two of those patients had a recurrence at screening in the placebo arm so in summary this trial has demonstrated a sustained benefit of Pembrolizumab versus placebo in resected stage 2b and 2c melanoma in terms of adverse events treatment-related adverse events occurred in 83 percent of patients on the Pembrolizumab arm but 64 in the placebo arm and there were no treatment related deaths grade 3 adverse events 17 in Pembro and 5 in placebo importantly this study showed that pembrolizumab can prevent distant metastases in patients with resected stage 2b and 2c melanoma
Question - Common Questions From Your Colleagues?
So some of the common questions I hear from my colleagues first of all Georgina the stage 2 population is a large population in melanoma this means that if we consider pembrolizumab we are treating a lot of patients with drug therapy to prevent recurrence in the proportion that are at risk what how can we select patients better now this is a great question because indeed the stage 2 population is a large population however the benefit is very significant we're talking about a 36 reduction in the risk of distant metastasis what we need to do now in the field is look for biomarkers that can select the beneficiaries so when we looked at the subgroups however uh every subgroup benefited from pembrolizumab uh including patients um with various different sub categories including the older patients greater than 65 versus the younger patients males females so at this point we don't have any good biomarkers to select out the beneficiaries but we have to remember that the reduction in the risk of recurrence and distant metastasis is significant at 30 at 36 percent the second common question I get um from clinicians around the world is will this uh be something that we should be using in all stage two patients and uh what are the factors that you consider and one thing about the keynote 716 trial is that there is a second part to the trial which has not matured yet and that's the three challenge crossover truck part of the trial where patients who recur on the placebo arm or who recur after six months of their last pembrolizumab dose have the ability to cross over to receive pembrolizumab and that part of the trial answers the question whether we can still have the same long-term benefit and overall survival if we treat at recurrence but at this point in time we don't have that data and it is a discussion with the patient about the risk that is the toxicities and the Pembrolizumab was well tolerated although there are some concerns of this very small percentage of irreversible endocrinopathies patients can get versus the potential benefit for that patient and that is the reduction in the risk of recurrence so this is a discussion between patient and physician in terms of the risk and the benefit ratio for that specific patient
Question - How Will This Data Impact Clinical Practice?
So this data is very important this is the first trial to demonstrate a benefit of adjuvant therapy in stage 2 resected stage 2b and c melanoma in terms of reducing the relapse free survival and distant metastasis free survival this is the first data ever a stage 2 is a highly represented patient population it is common but it is also a great unmet need and an under recognized risk of recurrence and an under recognized risk of a distant metastasis basically in that first 24 months and we will see with further maturing of this data beyond so this data can can impact a clinical practice today the drug is not available in every country around the world but where it is it will be a discussion between patient and physician regarding the risk and this toxicities potential toxicities and the potential benefit which is a 36 reduction in the risk of distant metastases
Question – What Are The Next Steps?
Uh the next step for this research is to identify patients who stand to benefit from these treatments at the moment every subgroup benefits that was explored in this study keynote 716 but it would be very important to be able to identify a more narrow subgroup the beneficiaries for this drug therapy and so that's what we are working on now whether we can identify patients who will benefit the most from this adjuvant therapy the other next step is to wait for the maturity of this trial to see the overall survival and where the treatment later at recurrence can preserve or give us the same long-term overall survival benefit for patients with stage two melanoma
Question – Final Thoughts
The KEYNOTE-716 study was is a very important study for the field it is the first study to demonstrate that we can change the outcome of patients with stage 2b and stage 2c resected melanoma a high risk population you