Positive Responses, PFS for Pembrolizumab-Naïve Patients Continue, But Lower Efficacy Reported in Rechallenged Population

Patients with melanoma who received placebo and who progressed after the first part of the phase 3 EORTC 1325/KEYNOTE-054 trial (NCT02362594) were allowed to crossover and receive pembrolizumab (Keytruda) post recurrence, per study protocol. This crossover subpopulation (n = 155) experienced a 38.8% overall response rate (ORR) and an overall 3-year progression-free survival (PFS) rate of 32%. Patients in the first part of the trial who received pembrolizumab and progressed were rechallenged with pembrolizumab in the second part of the trial (n = 20) and experienced a lower efficacy rate than the crossover subpopulation overall.¹

“Allowing crossover in a trial with adjuvant therapy [helps to determine] if it’s better to give treatment to all patients or only at relapse,” Alexander M. Eggermont, MD, PhD, professor of clinical and translational immunotherapy, UMCU, Utrecht University, and chief scientific officer, Princess Máxima Center, Utrecht, in the Netherlands, said during his presentation at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.²

At ASCO 2020, part 1 of EORTC 1325/KEYNOTE-054 showed that pembrolizumab had a 3-year prolonged relapse-free survival (RFS) of 63.7% compared to 41% for placebo (HR, 0.56; 95% CI, 047-0.68).³ Distant metastasis-free survival at 3.5 years was 66.7% (95% CI 61.8-71.2) in the pembrolizumab group and 51.6% (46.6-56.4) in the placebo group (HR 0.61; 95% CI, 0.49-0.76; P < .0001).⁴

At the clinical cutoff date of October 16, 2020, for part 2 of the study, median follow up for the crossover group was 41 months (range, 30-48) from the start of part 2 and 19 months (range, 14-26) for the rechallenge group.

Patient characteristics at baseline for part 2 showed that 50 patients in the crossover group had stage III disease; 7 patients in the rechallenge group had stage III disease. Median treatment exposure for the crossover group was 8 months (range, 0-25.5) and 3.2 months (range, 0-24.3) in the rechallenge group. Total number of doses in the crossover group was 12 (range, 1-36) and 5.5 (range, 1-36) in the rechallenge group.

In the crossover group, treatment discontinuation was due to normal completion of treatment (15%) and recurrence, progression, or death due to disease progression (49%). In the rechallenge group, discontinuation was due to normal completion of treatment (5%) and recurrence, progression, or death due to disease progression (55%).

In the crossover group, recurrence/PFS was 32.2% (95% CI, 24.5%-40.2%). When stage of disease was compared, patients with stage III disease recurrence/PFS was 33.2% (95% CI, 19.8%-47.2%) and those with stage III/IV was 32.0% (95% CI, 20.9%-41.5%).

“One might think that patients who initially relapse with stage 3 resectable disease would be better than the patients who immediately relapse with nonresectable, stage 3. But these rates are essentially the same at 3 years,” Eggermont said.

For patients with M1a, M1b, and M1c/M1d disease, the ORR was 71.5%, 26.6%, and 36.1%, respectively. “This is basically what we would expect, in a treatment-naive, advanced melanoma patient population,” Eggermont explained. For patients with an evaluable response, PFS from the start of treatment was 30.9% (95% CI, 20.9%-41.5%) and from the objective response (n = 31) was 68.7% (95% CI, 48%-82.5%).

Turning to the rechallenge group, Eggermont said the recurrence/PFS was worse compared with the crossover group with only 1 complete response (11%), 3 patients with stable disease (33.3%), and 5 patients with progressive disease (55.6%). “This is clearly a less favorable population,” he noted.

Regarding immune-related adverse events (irAEs), the 1-year incidence of grade 1-4 was 28% in the crossover group and 21% in the rechallenge group. Specifically, in the crossover group, grade 1-4 was 30.3% and 7.1% for grade 3-4. Endocrine-related disorders were reported in most of this group (21.3%). In the rechallenge group, grade 1-4 irAEs was 20.0%. There was no grade 3-4 irAEs reported.

“In summary, in the crossover group, the 3-year PFS rate was 32% at a median of 8.5 months,” Eggermont concluded. “The overall response rate was [similar to] the traditional monotherapy of anti-PD-1 rate of 40%,” he said. Eggermont added that the data about the impact on overall survival was not yet available.

_REFERENCES

_{1. Eggermont AM, Meshcheryakov A, Atkinson V, et al. 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. J Clin Oncol. 2021;39(suppl 15; abstr 9500):9500. doi: 10.1200/JCO.2021.39.15_suppl.9500}

_{2. Eggermont AM, Meshcheryakov A, Atkinson V, et al. 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. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 9500.}

_{3. Eggermont AMM, Blank CU, Mandala M, et al. Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III melanoma: updated results from the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020;38(33):3925-3936. doi:10.1200/JCO.20.02110}

_{4. Eggermont AMM, Blank CU, Mandalà M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(5):643-654. doi:10.1016/S1470-2045(21)00065-6}