Data show value of cross-treatment and novel challenge with pembrolizumab for melanoma
Source / Disclosures
Eggermont AM, et al. Abstract 9500. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
Disclosures: Eggermont reports share ownership in RiverD and Skyline Diagnostics and speaker bureau fees and consultant / advisory board roles with BIOCAD, BioInvent, BioNTech, CatalYm, Ellipses Pharma, GlaxoSmithKline, IO Biotech, ISA Pharmaceuticals, Merck, Nektar , Novartis, Pfizer, Sellas Life Sciences and Skyline Diagnostics. Please see the summary for all relevant financial information from other researchers.
Pembrolizumab induced an overall response rate in high-risk melanoma patients who relapsed on placebo, comparable to that expected in treatment-naïve patients, according to the results of the EORTC 1325 / KEYNOTE-054 trial.
However, the results, presented at the ASCO Virtual Annual Meeting, showed less efficacy in patients who were reintroduced with pembrolizumab (Keytruda, Merck) after experiencing a relapse 6 months or more after completing the drug. treatment.
By having a crossover design, the EORTC 1325 / KEYNOTE-054 trial sought to answer a “fundamental question” regarding the value of adjuvant pembrolizumab, Alexander MM Eggermont, MD, PhD, the scientific director of the Princess Máxima Center for Pediatric Oncology and professor of clinical and translational immunotherapy at UMC Utrecht in the Netherlands told Healio.
Alexandre MM Eggermont
“The reason is that by providing free treatment with pembrolizumab for up to 2 years at the time of diagnosis of relapse in patients who were in the placebo arm of the trial, one may be able to formally respond to the question: is the OS outcome in all high-risk stage III melanoma patients (including all those who will never relapse) by [administering] adjuvant treatment with pembrolizumab for 1 year better than treating only patients who relapse with pembrolizumab for up to 2 years? ” he said.
“There was also an ethical element in the decision to assure all patients in the trial that if they were in the placebo arm and relapsed, they would have free access to pembrolizumab as part of the clinical trial.” , added Eggermont. “It was very important because in many countries, when we started the trial, pembrolizumab was not yet available or reimbursed. Obviously, this aspect was highly valued by patients and doctors alike, and quite frankly, 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 lymph node resection. Patients received 200 mg adjuvanted pembrolizumab every 3 weeks (n = 514) or placebo (n = 505) for up to 1 year and a total of 18 doses.
As Healio previously reported, the 3-year data from the trial showed that pembrolizumab conferred a significant benefit on SSR compared to placebo in patients with high-risk stage III resected melanoma (LFS at 3 years, 63.7% vs. 44.1%; HR = 0.56; 95% CI, 0.47-0.68).
During the ASCO, Eggermont presented data from part 2 of the study protocol, in which 155 patients initially assigned to placebo and who relapsed were transferred to the pembrolizumab group, and 20 patients initially assigned to pembrolizumab but had experienced a recurrence 6 months or more after completing 1 year of were reintroduced with treatment with pembrolizumab at the same dose for up to 2 years.
The median follow-up from the start of part 2 was 41 months in the crossover group (median doses, 12) and 19 months in the rechalenge group (median doses, 5.5).
Of all 175 patients in Part 2 of the trial, 24 completed treatment, 88 experienced disease progression, 20 discontinued due to toxicity, 28 discontinued due to a decision from the investigator or for some other reason, and 15 remained on treatment.
In the crossover group, the 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 relapsed with resectable stage III disease had a 3-year PFS rate of 33.2% (95% CI: 19.8-47.2) and a median PFS of 13, 6 months, while those who recurred with unresectable stage III or stage IV disease showed a rate of 3-year PFS of 32% (95% CI, 20.9 to 41.5) and PFS median of 8.2 months.
“One would think that patients who initially relapsed only as resectable stage III disease would have a better [outcomes] than patients who have relapsed as unresectable stage III / IV disease, but the curves are essentially the same and at 3 years they are both 32% to 33%, ”Eggermont said during his presentation . “The medians are different, but it’s mostly incidental as it can happen with the medians.”
In the retest group, the median PFS was 4.1 months (95% CI, 2.6 – not estimable), with a 1-year PFS rate of approximately 40%.
The ORR in patients with measurable and evaluable advanced disease for response was 38.8% in the crossover group and 11.1% in the retest group.
“Obviously, in patients on the placebo arm, we would expect a normal ORR of around 40% and a median PFS of around 8-9 months, which is exactly what we saw,” said Eggermont in Healio. “We didn’t know what to expect [in the rechallenge population]. But the ORR was only 11% and the median PFS is [about 4] month. This [suggests] that these are patients who probably fall into the 25% of patients who were not sensitive to pembrolizumab in the first place (innate resistance) and would not have benefited either as an adjuvant or as a therapeutic setting.
Although the analysis may be limited by a small number of patients in the rechallenge group, this group is “clearly a different patient population who relapse despite adjuvant pembrolizumab,” Eggermont added.
Grade 1 to 4 immune adverse events occurred in 30.3% of the crossover group and 20% of the retest group. Most of them were endocrine disorders (crossover; 21.3%; reintroduction, 15%).
The operating system data is not yet mature, but it remains to be seen whether the cross-design will reduce the difference in the operating system’s end results, Eggermont said.
“It remains to be seen whether this would completely close the 20% gap in RFS rate (at 3 years) or 17% in distant metastasis-free survival rate (at 3.5 years),” he said. declared. “My hunch probably isn’t, but it could potentially cut the gap in half in my opinion. The impact of other rescue therapies 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.) also remains to be seen.