PD-1 Inhibitors Make Impact in Merkel Cell Carcinoma, But Unmet Needs Persist

Merkel Cell Carcinoma

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Despite recent developments in the treatment landscape of Merkel cell carcinoma (MCC), including the 2023 FDA accelerated approval of the PD-1 inhibitor retifanlimab-dlwr (Zynyz), patients with the disease have a poor prognosis and have historically been underserved due to the rarity of the disease, underscoring the need for the development of additional novel therapeutics in the space.¹

Retifanlimab received accelerated approval from the FDA on March 22, 2023, for the treatment of adult patients with metastatic or recurrent locally advanced MCC. The regulatory decision was supported by findings from the phase 2 POD1UM-201 trial (NCT03599713), which enrolled patients who had not received prior systemic therapy for advanced disease. At the time of the approval, data from POD1UM-201 demonstrated that patients who received retifanlimab (n = 65) achieved an objective response rate (ORR) of 52% (95% CI, 40%-65%), including a complete response (CR) rate of 18%. Seventy-six percent of patients experienced a duration of response (DOR) of at least 6 months and 62% had a DOR of at least 12 months.^1,2

In the safety population (n = 105), serious adverse effects (AEs) occurred in 22% of patients;¹ 11% discontinued treatment due to an AE and dose interruptions due to AEs were reported in 25% of patients.² The most common any-grade AEs reported in at least 10% of patients included fatigue (28%), musculoskeletal pain (22%), pruritus (18%), and diarrhea (15%).

“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” Shailender Bhatia, MD, director of the Melanoma and Renal Cancer Team and a professor in the Clinical Research Division at Fred Hutch Cancer Center, stated in a news release.³ Bhatia is also a professor in the Division of Hematology and Oncology at the University of Washington School of Medicine in Seattle. "The approval of [retifanlimab] offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease, and I look forward to having [retifanlimab] in our treatment portfolio for these difficult-to-treat patients,” he added.

The Historical Incidence and Epidemiology of MCC

MCC was first described in 1972 and has an incidence rate approximately 40-times lower than that of malignant melanoma.^4,5 However, the occurrence of the disease has been steadily rising since 2000, with a current global incidence rate of approximately 0.6 new diagnoses per 100,000 individuals annually; this is approximately double the rate reported in the late 20th century.⁴ MCC is a rare primary neuroendocrine carcinoma of the skin and has an approximate 5-year overall survival (OS) rate ranging between 48% and 63%. Additionally, patients with regional lymph node involvement (stage III disease) have a 5-year OS rate of approximately 51%. The survival rate is between 17% to 29% in those with distant metastases (stage IV disease) whereas it is 64% in those without metastases (stage I to II disease).⁵

Older white males are 8-times more likely to be diagnosed with MCC compared with other individuals and twice as likely to be diagnosed compared with females. The median age of patients affected by the disease is 76 years, and as a result of treating an older patient population, clinicians often must use approaches that differ from standard treatment protocols.⁵

In 2008, Merkel cell polyomavirus (MCPyV) was first identified in MCC tissue;⁴ integration of MCPyV into the host genome is estimated to cause 80% of cases of MCC in Europe and North America.⁵ Other risk factors for MCC include intense exposure to ultraviolet rays, fair skin color, and immunosuppression.⁴ PD-L1 expression is also often present within MCC cells and the tumor microenvironment.⁵ Clinical factors that confer a poor prognosis include the presence of regional and distant metastases, a primary tumor diameter exceeding 2 cm and/or its extension beyond the dermis, a tumor location in the head/neck region, and an age above 75 years. Males and patients who have comorbidities such as immunosuppression also have a poor prognosis.

The primary therapeutic approach for patients with localized MCC is wide local excision followed by tumor bed radiotherapy and nodal basin management. However, there remains no cure for patients with inoperable advanced or metastatic stage III and IV disease and it is recommended that these patients receive immunotherapy in the first- and second-line settings in the absence of contraindications. Chemotherapy, radiotherapy, best supportive care, and clinical trial participation can also be considered for these patients depending on various factors.

PD-1 Inhibitors Shape Therapeutic Paradigm of Advanced/Metastatic MCC

The first agent to earn FDA approval in MCC was avelumab (Bavencio); it was granted accelerated approval in March 2017 for the treatment of adult and pediatric patients 12 years and older with metastatic MCC, including for those who had not received prior chemotherapy.⁶ The approval was supported by findings from the phase 2 JAVELIN Merkel 200 trial (NCT02155647), which examined avelumab in 88 patients with metastatic MCC who experienced disease progression during or after chemotherapy.⁷

At the time of the approval, data from JAVELIN Merkel demonstrated that patients who received avelumab achieved an ORR of 33.0% (95% CI, 23.3%-43.8%), including an 11.4% (95% CI, 6.6%-19.9%) CR rate.⁷ Most patients (86%) experienced a DOR of at least 6 months and 45% had a DOR lasting at least 12 months.

Regarding safety, 7% of patients had to permanently discontinue avelumab due to AEs and 24% temporarily discontinued treatment due to AEs. Common any-grade AEs reported in at least 10% of patients included fatigue (50%), musculoskeletal pain (32%), and diarrhea (23%).

Subsequently, in December 2018, the FDA granted accelerated approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC.⁸ The regulatory decision was based on findings from the phase 2 KEYNOTE-017 trial (NCT02267603), which enrolled patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for advanced disease.

Patients who received pembrolizumab (n = 50) achieved an ORR of 56% (95% CI, 41%-70%), comprised of a 24% (95% CI, 13%-38%) CR rate.⁹ A majority of patients (96%) experienced a DOR of at least 6 months and 54% achieved a DOR of at least 12 months.

Beyond PD-1 inhibitor monotherapy, there has been interest from investigators in combining these agents with other therapies to improve outcomes for patients with advanced or metastatic MCC. Although anti–PD-(L)1 inhibitors lead to durable responses in approximately 50% of patients with metastatic disease, approximately 50% of patients treated with them will experience primary or secondary disease progression.¹⁰

For example, during the 2024 ASCO Annual Meeting investigators presented the study design of the phase 2 TRICK-MCC study (NCT06056895) that is examining triplet therapy blocking several checkpoints. As other T cell exhaustion pathways are active in MCC aside from PD-(L)1, the proof-of-concept study will evaluate retifanlimab in combination with the anti–LAG-3 agent tuparstobart (INCAGN02385) and the anti–TIM-3 agent verzistobart (INCAGN02390) for the treatment of patients with advanced or metastatic MCC following disease progression after treatment with a PD-1 inhibitor. Patients need to have an ECOG performance status of 2 or less in order to be eligible for the study.

In the induction phase of the trial, eligible patients will receive retifanlimab every 4 weeks in combination with tuparstobart and verzistobart every 2 weeks for up to 169 days in the absence of disease progression or unacceptable toxicity.¹¹ Patients will receive the agents every 6 weeks in the maintenance phase for up to 715 days in the absence of disease progression or unacceptable toxicity.

The primary end point is ORR. Secondary end points include DOR, disease control rate, progression-free survival, OS, disease-specific survival, and safety.¹¹ As of November 8, 2023, TRICK-MCC has recruited 8 of 20 planned patients, and an interim analysis is planned to occur after 10 patients are enrolled and followed sufficiently long enough to assess ORR.¹⁰

References

1. FDA grants accelerated approval to retifanlimab-dlwr for metastatic or recurrent locally advanced Merkel cell carcinoma. FDA. March 22, 2023. Accessed November 27, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-retifanlimab-dlwr-metastatic-or-recurrent-locally-advanced-merkel
2. Zynyz. Prescribing information. Incyte; 2023. Accessed November 27, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761334s000lbl.pdf
3. Incyte announces FDA approval of zynyz™ (retifanlimab-dlwr) for the treatment of metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). News release. Incyte. March 22, 2023. Accessed November 27, 2024. https://investor.incyte.com/news-releases/news-release-details/incyte-announces-fda-approval-zynyztm-retifanlimab-dlwr
4. Li Z, Ji W, Hu Q, Zhu P, Jin Y, Duan G. Current status of Merkel cell carcinoma: Epidemiology, pathogenesis and prognostic factors. Virology. 2024;599:110186. doi:10.1016/j.virol.2024.110186
5. Lugowska I, Becker JC, Ascierto PA, et al; ESMO Guidelines Committee. Merkel-cell carcinoma: ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up. ESMO Open. 2024;9(5):102977. doi:10.1016/j.esmoop.2024.102977
6. FDA approves first treatment for rare form of skin cancer. FDA. March 23, 2017. Accessed November 27, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-rare-form-skin-cancer#:~:text=In%20addition%2C%20there%20is%20a,and%20for%20regulating%20tobacco%20products.
7. Bavencio. Prescribing information. EMD Serono, Inc; 2017. Accessed November 27, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf
8. FDA approves pembrolizumab for Merkel cell carcinoma. FDA. December 19, 2018. Accessed November 27, 2024. https://www.fda.gov/drugs/fda-approves-pembrolizumab-merkel-cell-carcinoma
9. Keytruda. Prescribing information. Merck; 2018. Accessed November 27, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s045lbl.pdf
10. Miller NJ, Ambrazeviciute G, Chen W, et al. TRICK-MCC: a proof-of-concept, investigator-initiated study of combination therapy with anti–PD-1, anti–LAG-3, and anti–TIM-3 in participants with advanced or metastatic PD-(L)1 refractory Merkel cell carcinoma. J Clin Oncol. 2024;42(suppl 16):TPS9618. doi:10.1200/JCO.2024.42.16_suppl.TPS9618
11. Triple immune checkpoint inhibition for advanced or metastatic PD-(L)1 refractory Merkel cell carcinoma (TRICK-MCC). ClinicalTrials.gov. Updated September 20, 2024. Accessed December 3, 2024. https://clinicaltrials.gov/study/NCT0605689