A new phase III clinical trial has demonstrated promising efficacy and manageable safety for pembrolizumab as first-line treatment in patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). The single-arm, open-label KEYNOTE-913 study, conducted across 22 sites in 8 countries, provides further evidence supporting the use of PD-1 inhibitors in this rare but aggressive skin cancer.
The study, funded by Merck Sharp & Dohme LLC (a subsidiary of Merck & Co., Inc.), was published on October 8, 2024 in the American Journal of Clinical Dermatology. Its primary purpose was to evaluate the efficacy and safety of pembrolizumab monotherapy in treatment-naive patients with advanced MCC.
KEYNOTE-913 enrolled 55 patients with histologically confirmed MCC that was either locoregional and recurred following standard locoregional therapy (surgery and/or radiation) and not amenable to local therapy, or metastatic (stage IV). Key eligibility criteria included at least one measurable lesion per RECIST v1.1, ECOG performance status of 0-1, and adequate organ function. Patients could not have received previous systemic therapy for advanced/metastatic disease, with some exceptions for prior neoadjuvant/adjuvant chemotherapy. Those with active central nervous system metastases, active autoimmune disease, or active infection requiring systemic therapy were excluded.
The study population had a median age of 74 years (range 38-91), with 78% of patients aged 65 or older. Fifty-six percent were male and 71% were White. Most patients (82%) had stage IV disease at study entry. The median baseline sum of target lesions was 75 mm. Prior to enrollment, 69% had undergone surgery for MCC and 35% had received radiation therapy.
All patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles (approximately 2 years), or until disease progression, unacceptable toxicity, or investigator decision to discontinue. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
At the data cutoff (February 15, 2024), the median follow-up was 50.3 months. The study met its primary endpoint, with an ORR of 49% (95% CI 35-63). This included 12 complete responses and 15 partial responses. The median DOR was 39.8 months, with 69% of responders estimated to remain in response at 24 months.
Median PFS was 9.3 months (95% CI 3-26), with a 24-month PFS rate of 39%. Median OS was 24.3 months (95% CI 12.4 to not reached), and the 24-month OS rate was 51%. The treatment effect appeared generally consistent across patient subgroups.
Regarding safety, 69% of patients experienced treatment-related adverse events (TRAEs) of any grade, with 24% experiencing grade 3-5 TRAEs. The most common TRAEs were fatigue (22%), pruritus (22%), and increased lipase (18%). Eleven patients (20%) discontinued pembrolizumab due to TRAEs. One treatment-related death occurred due to Guillain-Barré syndrome.
Immune-mediated adverse events, a known class effect of checkpoint inhibitors, occurred in 25% of patients. Grade 3-5 immune-mediated events included one case each of grade 3 colitis, grade 3 encephalitis, and grade 5 Guillain-Barré syndrome.
The authors concluded that pembrolizumab demonstrated durable antitumor activity, promising survival outcomes, and a manageable safety profile in patients with recurrent locally advanced or metastatic MCC. They stated these results support the use of pembrolizumab in this patient population.
This study has several important strengths. As a phase III trial, it provides a higher level of evidence than previous phase II studies of PD-1/PD-L1 inhibitors in MCC. The long-term follow-up (median >4 years) allows for robust assessment of durability of response and survival outcomes. The multicenter, international design enhances generalizability of the results.
However, there are also some limitations to consider. As a single-arm study without a control group, it does not allow for direct comparison to other treatments. The open-label design could potentially introduce bias in adverse event reporting. Additionally, the sample size of 55 patients, while relatively large for a rare cancer like MCC, still limits the precision of efficacy estimates and power for subgroup analyses.
The results of KEYNOTE-913 are generally consistent with previous studies of PD-1/PD-L1 inhibitors in MCC, including the phase II CITN-09/KEYNOTE-017 trial of pembrolizumab and studies of avelumab, nivolumab, and retifanlimab. Collectively, these data have shifted the treatment paradigm for advanced MCC away from cytotoxic chemotherapy and toward immunotherapy as first-line treatment.
The potential clinical impact of this study is significant. It provides further evidence supporting the use of pembrolizumab as a first-line option for patients with recurrent locally advanced or metastatic MCC. The durable responses and promising survival outcomes observed are particularly noteworthy given the historically poor prognosis of advanced MCC.
For clinicians treating patients with MCC, these results reinforce the role of PD-1 inhibition as a standard first-line approach. The safety profile observed was consistent with the known effects of pembrolizumab in other tumor types, which may aid in counseling patients about potential risks and benefits of treatment.
From a regulatory perspective, this phase III data may help solidify the accelerated approval pembrolizumab previously received for MCC based on phase II results. It could potentially support full approval or inclusion in treatment guidelines as a preferred first-line option.
For researchers, this study provides a benchmark for future trials in advanced MCC. Areas for further investigation may include combination strategies to improve response rates, biomarker studies to identify patients most likely to benefit, and approaches to manage immune-related adverse events.
Several questions remain that warrant additional research. The optimal duration of PD-1 inhibitor therapy in responding patients is unclear - while this study treated for up to 2 years, the ideal treatment duration to balance efficacy and toxicity is unknown. Additionally, strategies for patients who progress on or after PD-1 inhibitor therapy need further study.
It's also important to note that while these results are encouraging, a significant proportion of patients still did not respond or had short-lived responses to pembrolizumab. Identifying predictive biomarkers beyond PD-L1 expression (which was not assessed in this study) could help better select patients for this approach.
In conclusion, the KEYNOTE-913 study provides robust phase III evidence supporting the efficacy and safety of pembrolizumab as first-line therapy for patients with recurrent locally advanced or metastatic Merkel cell carcinoma. These results further establish PD-1 inhibition as a standard of care in this patient population and set the stage for future research to build upon this treatment approach. As with any advance in a rare cancer, collaborative efforts between clinicians, researchers, and patients will be crucial to continue improving outcomes in this challenging disease.
References
Mortier L, Villabona L, Lawrence B, et al. Pembrolizumab for the First-Line Treatment of Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma: Results from the Single-Arm, Open-Label, Phase III KEYNOTE-913 Study. Am J Clin Dermatol. 2024;25(6):987-996. doi:10.1007/s40257-024-00885-w
