KEYNOTE-716: Primary melanoma, not lymph nodes, should ‘drive therapeutic decision-making’
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Key takeaways:
- Three-year results show durable distant metastasis-free survival and RFS benefits with adjuvant pembrolizumab.
- The regimen should be offered to all patients with stage II disease.
CHICAGO — Adjuvant pembrolizumab showed durable benefit vs. placebo among patients with resected stage IIB or IIC melanoma, according to randomized phase 3 study results presented at ASCO Annual Meeting.
After more than 3 years of follow-up, patients assigned the anti-PD-1 therapy achieved significantly longer distant metastasis-free survival (DMFS) and RFS, results of the KEYNOTE-716 trial showed.
“The curves continue to separate, and the magnitude of benefit is getting bigger over time,” Jason J. Luke, MD, associate professor of medicine in the division of hematology/oncology and director of the Immunotherapy and Drug Development Center within UPMC Hillman Cancer Center, told Healio. “The results emphasize that this should be the standard of care, and that it should be offered to all patients with stage IIB/C disease.”
Background
Historically, clinical observation had been standard for patients with resected stage IIB or IIC melanoma. Stage III melanoma — which usually involves nodal metastases — had been considered high-risk disease.
“That really drove the consideration of whether to give adjuvant therapy,” Luke said. “But historical registry data showed patients with stage IIB or IIC melanoma have similar melanoma-specific survival as those with stage IIIB. ... It’s actually the depth of the primary melanoma on the skin — not the lymph nodes — that drives risk for recurrence or death, and that was the impetus for this trial.”
Researchers launched KEYNOTE-716 to assess the efficacy of pembrolizumab (Keytruda, Merck) — already a standard adjuvant therapy across substages of completely resected stage III melanoma — for patients with resected stage IIB or IIC disease.
Researchers enrolled 976 patients aged 12 years and older.
Investigators randomly assigned 487 study participants to pembrolizumab dosed at 200 mg every 3 weeks for adults, or 2 mg/kg (up to 200 mg) every 3 weeks for pediatric patients. The other 489 received placebo.
Treatment continued for up to 17 cycles, or until disease recurrence or unacceptable toxicity.
RFS per investigator assessment served as the primary endpoint. Key secondary endpoints included DMFS and OS.
Prior results
Results presented at last year’s ASCO Annual Meeting, based on median follow-up of 27.4 months, showed significantly improved DMFS with pembrolizumab (HR = 0.64; 95% CI, 0.47-0.88), with higher rates of DMFS at 12 months (94.7% vs. 90.2%) and 24 months (88.1% vs. 82.2%).
Researchers observed the benefit across key subgroups stratified by T category, age, sex, ECOG performance status and race.
Pembrolizumab-treated patients also demonstrated a sustained RFS benefit (HR = 0.64; 95% CI, 0.5-0.84) and a higher likelihood of 24-month RFS (81.2% vs. 72.8%).
Updated findings
This year, Luke presented the final DMFS analysis, with median follow-up of 39.4 months.
Results showed sustained benefit in the pembrolizumab group with regard to DMFS (HR = 0.59; 95% CI, 0.44-0.79) and RFS (HR = 0.62; 95% CI, 0.49-0.79). Medians had not been reached for either outcome measure.
At 36 months, researchers reported higher rates of DMFS (84.4% vs. 74.7%) and RFS (76.2% vs. 63.4%) with pembrolizumab.
The DMFS benefit with pembrolizumab persisted regardless of disease stage at baseline (stage IIB, HR = 0.62; 95% CI, 0.42-0.92; stage IIC, HR = 0.57; 95% CI, 0.36-0.88).
The RFS benefit with pembrolizumab also appeared consistent regardless of stage (stage IIB, HR = 0.58; 95% CI, 0.43-0.79; stage IIC, HR = 0.65; 95% CI, 0.45-0.94).
Pembrolizumab exhibited a safety profile consistent with prior reports of the therapy, and researchers observed no new safety signals.
“One of the criticisms early on, with short follow-up, was it looked like there wasn’t as much benefit with adjuvant pembrolizumab for stage II as there was for stage III,” Luke told Healio. “Those of us involved with the trial knew that was wrong. It was just going to take a little longer to see it. Now, with 3 years of follow-up, the benefit looks very similar for stage II as it does for stage III.
“These results cement in stone the fact that all patients with stage II disease should be offered this treatment,” Luke added. “They may not take it as decision-making in the adjuvant setting is complicated. It requires multidisciplinary management and nuanced conversations about the risks of recurrence versus toxicities of treatment. But, ultimately, this speaks to the need to change the paradigm. The primary melanoma — not the lymph nodes — should drive our therapeutic decision-making.”
Next steps
Luke and colleagues will continue to follow patients for OS.
The trial includes a crossover design that allowed patients assigned placebo to receive pembrolizumab upon disease recurrence.
“The question of ‘treat now vs. treat later’ is a reasonable debate,” Luke said. “It’s very important to understand what happens to people who receive treatment at the time of recurrence — do they do worse or not?
“Although it is true that average or median outcomes may be similar, an individual won’t know if they will be the ‘average’ patient or not,” Luke added. “They might be the patient for whom recurrence is brain metastases that we can’t really treat. That’s ultimately the consideration for each patient about whether to proceed with adjuvant therapy.”
KEYNOTE-716 also provides “benchmark outcomes data” for the field at a time when the next generation of phase 3 clinical trials to assess adjuvant combination immunotherapies are getting underway, Luke said.
These include the KEYVIBE-010 trial — which will assess adjuvant pembrolizumab with vibostolimab (Merck), a humanized anti-TIGIT therapy — and another trial of pembrolizumab plus a personalized mRNA-based cancer vaccine developed by Moderna. Both of these studies include patients with stage II through stage IV disease.
“Data from these trials are essential to better understand what we should expect to happen to patients with stage II disease because, prior to KEYNOTE-716, they hadn’t been studied in randomized phase 3 trials,” Luke said.
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Luke JJ, et al. Abstract LBA9505. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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