Pembrolizumab extends RFS in stage II melanoma

Pembrolizumab extended recurrence-free survival (RFS) in patients with high-risk stage II melanoma who had undergone complete resection, interim analysis results of the phase III KEYNOTE-716 trial showed.

“Patients with stage IIB and IIC melanoma are at high risk of disease recurrence and survival outcomes are similar to stage IIIA and IIIB melanoma,” said study author Dr Jason Luke, Director, Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, US, who presented the findings at ESMO 2021. “Current standard of care for patients after resection of high-risk stage II melanoma is observation.”

“These results are set to substantially change the population of melanoma patients who get treated in the adjuvant setting,” said Luke.

Study participants were 976 patients aged ≥12 years* (median age 60–61 years) with completely resected cutaneous stage IIB (64 percent) or IIC melanoma, ECOG performance status 0–1, and with negative sentinel lymph node biopsy. They were randomized 1:1 to receive intravenous pembrolizumab 200 mg (or 2 mg/kg for paediatric patients) or placebo Q3W for 17 cycles (up to 1 year) until disease recurrence or unacceptable toxicity.

Investigator-assessed RFS was significantly longer with pembrolizumab compared with placebo at a median follow-up of 14.4 months (median RFS not reached in either group; hazard ratio, 0.65, 95 percent confidence interval, 0.46–0.92; p=0.00658). [ESMO 2021, abstract LBA3]

Recurrence occurred in 11.1 and 16.8 percent of patients in the pembrolizumab and placebo groups, respectively, with 23 and 38 distant recurrence events (4.7 percent vs 7.8 percent), respectively. At 12 months, RFS rates were 90.5 and 83.1 percent, respectively.

Grade ≥3 any-cause adverse events (AEs) occurred in more pembrolizumab than placebo recipients (25.9 percent vs 17.1 percent). Grade ≥3 treatment-related AEs also occurred in more pembrolizumab than placebo recipients (16.1 percent vs 4.3 percent) and led to discontinuation in 15.3 and 2.5 percent, respectively. There were no deaths due to any-cause or treatment-related AEs in the pembrolizumab group compared with four due to any-cause AEs in the placebo group.

Immune-mediated AEs occurred in a greater proportion of pembrolizumab than placebo recipients (36.2 percent vs 8.4 percent). The most common immune-mediated AEs were thyroid abnormalities ie, hypothyroidism (15.7 percent vs 3.5 percent) and hyperthyroidism (10.4 percent vs 0.6 percent), though these were predominantly grade 1–2 in severity. About 20 percent of pembrolizumab recipients received long-term hormonal therapy to manage endocrine toxicities.

Real-world impact

“The US FDA is now examining this drug for the adjuvant treatment of stage IIB and IIC melanoma which, if approved, means we would be introducing immunotherapy earlier in the patient journey. This has the potential to spare patients recurrence and metastases,” commented Dr Omid Hamid, Chief of Research/Immuno-Oncology at The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles, California, US, who was not affiliated with the study.

“There has been a belief that early-stage melanoma doesn’t recur very fast and that these patients don’t develop metastatic disease,” added Luke. “These data clearly disprove that and show that patients with high-risk stage II melanoma recur quickly and distantly, just the same as patients with stage IIIA and IIIB. Treatment with pembrolizumab reduced that in a meaningful and statistically significant way, indicating that these stage II patients should be offered adjuvant therapy.”

Nonetheless, it remains to be seen which patients are best suited for adjuvant treatment, he said. “Historically we have defined high-risk patients after surgery as those with lymph node positive disease. In the future we will need to reconsider how we incorporate sentinel lymph node biopsy into our risk stratification,” he said.

Additionally, dose frequency and duration of adjuvant treatment need to be determined, noted Hamid. “[W]hile the incidence of grade 3 or 4 toxicity was minimal, side-effects could potentially have a significant impact on the lifestyle of these patients,” he continued. Luke also suggested that potential side effects of previous regimens may have been a deterrent to providing adjuvant treatment in patients with stage II disease.