Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

Abstract

9500 Background: The phase 3 double-blind EORTC 1325/KEYNOTE-054 trial evaluated pembrolizumab (pembro) vs placebo in stage III cutaneous melanoma patients (pts) with complete resection of lymph nodes. Pembro improved RFS (hazard ratio [HR] 0.57) and DMFS (HR 0.60) (Eggermont, NEJM 2018, TLO 2021). In the pembro group, the incidence of immune related AE (irAE) grade 1-5 was 37%, and of grade 3-5 was 7%. We present the safety profile, response rate and PFS for the subset of pts who had a recurrence and crossed over or were rechallenged with pembrolizumab, within protocol. Methods: Pts were randomized to receive iv. pembro 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year). Upon recurrence with no brain metastases, pts with an ECOG PS 0-2 were eligible to enter part 2 of the study, i.e. to receive pembro 200 mg iv. every 3 weeks for a maximum of 2 years, for crossover (those who received placebo) or rechallenge (those who recurred ≥6 months after completing one year of pembro therapy). Treatment was stopped in case of disease progression (RECIST 1.1) or unacceptable toxicity. Results: At the clinical cut-off (16-Oct-2020), 298 (59%) pts had a disease recurrence in the placebo group; 155 pts participated in the crossover part 2 of the trial. A total of 297 (58%) pts completed the 1-yr pembro adjuvant treatment, of whom 47 had a recurrence ≥6 mths from the stop of treatment and 20 entered in the rechallenge part of the trial. Among 175 pts who started pembro in Part 2, 160 discontinued due to completion of therapy (N=24), disease progression (N=88), toxicity (N=20), investigator's decision (N=21), or other reason (N=7); 15 pts were still on-treatment. Results for the 2 groups are provided in the table. The median number of doses was 12 and 5.5, respectively (resp), and the median follow-up was 41 and 19 mts, resp. Among the 175 pts, 51 (29%) had a grade 1-4 irAE (by group: 47 [30%] and 4 [20%] resp) and 11 (6%) a grade 3-4 irAE. Conclusions: Pembrolizumab treatment after crossover yielded a 39% ORR in evaluable pts and an overall 3-yr PFS of ̃32%, but after rechallenge the efficacy was lower. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA The median PFS (95% CI) from start of Part 2 was 14 (5-27) and 8 (5-15) mts for stage III-resected and III/IV various, resp. Among the 80 stage IV crossover pts with evaluable disease, 31 (39%) had an objective response: 14 (18%) CR, 17 (21%) PR. The 2-yr PFS rate from response was 69% (95% CI 48-83%). For these 80 pts, the median PFS was 6.1 mts and the 3-yr PFS rate was 31% (95% CI 21-41%). Among 9 stage IV rechallenged pts with an evaluable disease, 1 (11%) reached CR, 3 had SD and 5 PD. Clinical trial information: NCT02362594. [Table: see text]

The concepts of rechallenge and retreatment with immune checkpoint blockade in melanoma patients

“…Nine of these patients had unresectable stage IV disease and were evaluable for response. The activity was low with only one complete response (CR) (CR 1/9; SD 3/9; PD 5/ 9) and a median PFS of 4.1 months [14].…”

European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2022

“…Key parameters of adjuvant trials with immune checkpoint inhibitors or BRAF/MEK inhibitors that led to approvals. PD-1 in those who never received it[101]. The real measure of this crossover would be a comparison of the OS in those who were treated early in adjuvant compared to those treated later at relapse.…”

Real-world relapse-free survival data on adjuvant anti-PD-1 therapy for patients with newly diagnosed and recurrent stage III melanoma

“…These patients started with adjuvant pembrolizumab after developing a recurrence during or after treatment with a placebo. This group has a 1-year RFS of ± 35% and it is remarkable that the patients with resectable stage III disease only barely seem to profit more from the treatment than the patients with unresectable stage III/IV disease [11]. The median follow-up time was 53 months in cohort B (interquartile range [IQR], 34–95 months) and 37 months (IQR, 35–40 months) in the EORTC1325/KEYNOTE-054 trial.…”

“…The first outcomes of this group, which consists of a combination of patients with un- and resected stage III and IV disease, were presented on the ASCO annual meeting 2021: 32% of patients were relapse-free at 3 years after crossover treatment. Although stage III resected melanoma and stage III and IV unresected melanoma had a similar 3-year progression-free survival (PFS, 33% vs. 32%, respectively), the first did have a better median PFS (14 months vs. 8 months, respectively) [11]. Moreover, these results would seem to indicate a worse outcome than compared to the RFS of patients who were immediately randomized to pembrolizumab with a 3-year RFS of 64%.…”