Data show value of crossover, rechallenge treatment with pembrolizumab for melanoma
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Pembrolizumab induced an overall response rate among patients with high-risk melanoma who relapsed on placebo comparable to that expected among treatment-naive patients, according to results from the EORTC 1325/KEYNOTE-054 trial.
However, the findings, presented during the virtual ASCO Annual Meeting, showed lower efficacy among patients who were rechallenged with pembrolizumab (Keytruda, Merck) after experiencing recurrence 6 months or more after completing therapy.
By having a crossover design, the EORTC 1325/KEYNOTE-054 trial sought to address a “fundamental question” regarding the value of adjuvant pembrolizumab, Alexander M.M. Eggermont, MD, PhD, chief scientific officer at Princess Máxima Center for Pediatric Oncology and professor of clinical and translational immunotherapy at UMC Utrecht in the Netherlands, told Healio.
“The rationale is that by providing free treatment with pembrolizumab for up to 2 years at the time of diagnosis of a relapse in patients who were on the placebo arm of the trial, one may be able to formally address the question: Is the OS outcome in all patients with high-risk stage III melanoma (including all those who will never relapse) by [administering] adjuvant pembrolizumab treatment for 1 year better than treating only those patients who do relapse with pembrolizumab for up to 2 years?” he said.
“There was also an ethical component to the decision to guarantee all patients participating in the trial that if they were in the placebo arm and would relapse, they would be guaranteed free access to pembrolizumab as part of the clinical trial,” Eggermont added. “This was very important because in many countries when we launched the trial pembrolizumab was not yet accessible or reimbursed. Obviously, this aspect was very much appreciated by patients and doctors alike and, quite honestly, it was clearly the right thing to do.”
The EORTC 1325/KEYNOTE-054 trial included 1,019 adults with stage IIIA (15%), stage IIIB (46%) or stage IIIC (39%) melanoma who underwent complete resection of lymph nodes. Patients received adjuvant pembrolizumab dosed at 200 mg every 3 weeks (n = 514) or placebo (n = 505) for up to 1 year and a total of 18 doses.
As Healio previously reported, 3-year data from the trial showed pembrolizumab conferred a significant RFS benefit compared with placebo for patients with resected high-risk stage III melanoma (3-year RFS, 63.7% vs. 44.1%; HR = 0.56; 95% CI, 0.47-0.68).
During ASCO, Eggermont presented data from part 2 of the study’s protocol, for which 155 patients who were originally assigned placebo and recurred crossed over to the pembrolizumab group, and 20 patients originally assigned pembrolizumab but experienced recurrence 6 or more months after completing 1 year of therapy were rechallenged with pembrolizumab treatment at the same dose for up to 2 years.
Median follow-up from the start of part 2 was 41 months in the crossover group (median doses, 12) and 19 months in the rechallenge group (median doses, 5.5).
Of all 175 patients in part 2 of the trial, 24 completed therapy, 88 experienced disease progression, 20 discontinued due to toxicity, 28 discontinued due to investigator’s decision or another reason, and 15 remained on treatment.
In the crossover group, median PFS was 8.5 months (95% CI, 5.7-15.2), with a 3-year PFS rate of 32.2% (95% CI, 24.5-40.2). In this group, patients who recurred with resectable stage III disease had a 3-year PFS rate of 33.2% (95% CI, 19.8-47.2) and median PFS of 13.6 months, whereas those who recurred with unresectable stage III or stage IV disease showed a 3-year PFS rate of 32% (95% CI, 20.9-41.5) and median PFS of 8.2 months.
“One might think that patients who initially relapsed only as stage III resectable disease would have better [outcomes] than the patients who relapsed as an unresectable stage III/IV disease, but the curves are essentially the same and at 3 years they are both at 32% to 33%,” Eggermont said during his presentation. “The medians are different, but that is basically incidental as can happen with medians.”
In the rechallenge group, median PFS was 4.1 months (95% CI, 2.6-not estimable), with a 1-year PFS rate of approximately 40%.
ORR among patients with measurable advanced disease evaluable for response was 38.8% in the crossover group and 11.1% in the rechallenge group.
“Obviously, in the placebo-arm patients, we would expect a normal ORR of about 40% and a median PFS of about 8 months to 9 months, which is exactly what we saw,” Eggermont told Healio. “We did not know what to expect [in the rechallenge population]. But, the ORR was only 11% and the median PFS is [about 4] months. This [suggests] that these are patients who probably fall in the 25% of patients who were not sensitive the pembrolizumab in the first place (innate resistance) and would not have benefited either in the adjuvant or in the therapeutic setting.”
Although the analysis may be limited by a small number of patients in the rechallenge group, that group is “clearly a different patient population who relapse in spite of adjuvant pembrolizumab,” Eggermont added.
Grade 1 to grade 4 immune-related adverse events occurred among 30.3% of the crossover group and 20% of the rechallenge group. Most of these were endocrine disorders (crossover; 21.3%; rechallenge, 15%).
OS data are not yet mature, but it remains to be seen whether the crossover design will reduce the difference in final OS results, Eggermont said.
“Whether this would completely close the gap of 20% RFS rate (at 3 years) or 17% distant metastasis-free survival rate (at 3.5 years) remains to be seen,” he said. “My gut feeling is probably not, but it could close the gap by potentially half in my opinion. The impact of further rescue treatments in the advanced setting (BRAF plus MEK inhibitors in BRAF-mutant patients; anti-CTLA-4 plus anti-PD-1 in all patients; LAG-3, etc) remains to be seen, as well.”
Perspective
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Jeffrey M. Farma, MD, FACS
This abstract included a subset of patients in the EORTC 1325/KEYNOTE-054 trial with resected high-risk stage III melanoma who received either pembrolizumab or placebo after complete resection. KEYNOTE-054 demonstrated improved RFS and distant metastasis-free survival with adjuvant pembrolizumab for 1 year in high-risk stage III patients. For this analysis, researchers evaluated patients who had recurrence after this trial and either crossed over to pembrolizumab or were rechallenged with pembrolizumab after recurrence.
Overall, this is a unique group of patients. Those who were treated on the placebo arm and then recurred demonstrated a benefit with pembrolizumab, with an ORR of 39%. However, researchers observed less of a benefit for the 20 patients who were rechallenged with pembrolizumab after recurring.
Additional larger studies will need to be performed to further look at these groups; but, this study provides great insight, especially for patients with high-risk stage III melanoma who may not have been offered or treated with adjuvant therapy and who would then benefit from immunotherapy at the time of recurrence.
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Eggermont AM, et al. Abstract 9500. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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