PD-1 Inhibitors Show Promise in Merkel Cell Carcinoma Treatment, Unmet Needs Persist
核心洞察
Retifanlimab received accelerated FDA approval in March 2023 for metastatic or recurrent locally advanced Merkel cell carcinoma (搜索) (MCC), demonstrating a 52% objective response rate in clinical trials.
Merkel cell carcinoma (搜索) incidence has been rising since 2000, with a global rate of 0.6 new diagnoses per 100,000 annually, highlighting the need for novel therapeutics.
The TRICK-MCC study is evaluating triplet therapy with retifanlimab, tuparstobart (anti-LAG-3 (搜索)), and verzistobart (anti-TIM-3 (搜索)) for advanced MCC after PD-1 (搜索) inhibitor failure.
Merkel cell carcinoma (搜索) (MCC) treatment has seen advancements with the FDA's accelerated approval of the PD-1 (搜索) inhibitor retifanlimab-dlwr (Zynyz) in March 2023. Despite these developments, the prognosis for patients with this rare skin cancer remains poor, underscoring the need for further therapeutic innovations. Retifanlimab's approval was based on the phase 2 POD1UM-201 trial, which demonstrated a 52% objective response rate (ORR) among patients who had not received prior systemic therapy for advanced disease.
Retifanlimab's Clinical Impact
The POD1UM-201 trial (NCT03599713) revealed that patients treated with retifanlimab (n = 65) achieved an ORR of 52% (95% CI, 40%-65%), including an 18% complete response (CR) rate. Furthermore, 76% of patients experienced a duration of response (DOR) of at least 6 months, and 62% had a DOR of at least 12 months. However, serious adverse effects (AEs) occurred in 22% of patients, with 11% discontinuing treatment due to AEs.
Shailender Bhatia, MD, from Fred Hutch Cancer Center, noted that retifanlimab offers another first-line treatment option that can result in durable responses for patients with metastatic MCC.
Epidemiology and Risk Factors
First described in 1972, MCC's incidence is approximately 40 times lower than malignant melanoma. However, since 2000, the occurrence of MCC has been steadily increasing, with a current global incidence rate of approximately 0.6 new diagnoses per 100,000 individuals annually. The 5-year overall survival (OS) rate ranges between 48% and 63%.
Older white males are disproportionately affected, being eight times more likely to be diagnosed with MCC compared to other individuals. Risk factors include intense exposure to ultraviolet rays, fair skin, and immunosuppression. The Merkel cell polyomavirus (MCPyV) is implicated in approximately 80% of MCC cases in Europe and North America.
Current Treatment Strategies and Unmet Needs
The primary therapeutic approach for localized MCC involves wide local excision followed by tumor bed radiotherapy. For advanced or metastatic disease, immunotherapy is recommended in the first- and second-line settings. However, there remains no cure for inoperable advanced or metastatic MCC, highlighting the need for novel therapeutic strategies.
PD-1 Inhibitors in Advanced MCC
Avelumab (Bavencio) was the first agent to receive FDA approval for MCC in March 2017, based on the phase 2 JAVELIN Merkel 200 trial (NCT02155647). The trial demonstrated an ORR of 33.0% (95% CI, 23.3%-43.8%) with avelumab in patients who had progressed on or after chemotherapy. Pembrolizumab (Keytruda) subsequently received accelerated approval in December 2018 for recurrent locally advanced or metastatic MCC, based on the KEYNOTE-017 trial (NCT02267603), which showed an ORR of 56% (95% CI, 41%-70%).
Novel Combination Therapies
Given that approximately 50% of patients with metastatic MCC experience disease progression despite anti-PD-(L)1 therapy, researchers are exploring combination therapies. The phase 2 TRICK-MCC study (NCT06056895) is evaluating retifanlimab in combination with tuparstobart (anti-LAG-3 (搜索)) and verzistobart (anti-TIM-3 (搜索)) for patients with advanced or metastatic MCC following PD-1 (搜索) inhibitor failure. The primary endpoint is ORR, with secondary endpoints including DOR, progression-free survival, and overall survival. As of November 8, 2023, the trial has recruited 8 of 20 planned patients, with an interim analysis planned after 10 patients are enrolled and followed sufficiently long enough to assess ORR.