Immune-Based Combination Regimens Play a Growing Role in MCC

Merkel cell carcinoma (MCC) is a rare, highly aggressive skin tumor associated with the Merkel cell polyomavirus (MCPyV) infection, which has been detected in nearly 80% of MCC diagnoses.¹ The cell of origin is still unknown, but recent findings suggest that MCPyV-positive MCC can derive from epithelial cells.²

A 2019 analysis of data from the United States Cancer Statistics Public Use Database collected from 2006 to 2015 showed that incidence of MCC is growing. In the study, MaryBeth B. Freeman, MPH, and colleagues found an overall incidence of 2.1 per 100,000 people for MCC and an annual percent change of 2.3%. Incidence growth was highest among patients aged 70 to 74 years (4.1%) and those of the non-Hispanic Black race (2.7%).³

The 5-year relative survival rates are 55.1% among men and 67.7% among women. Survival rates decrease with later stage and older age at diagnosis, and are found to be lowest among non-Hispanic Black patients, who have the poorest survival rate at 54.1%.

Findings from the Surveillance, Epidemiology, and End Results (SEER) Program showed a 95% increase in the number of reported MCC cases from 2000 to 2013 compared with 57% for melanoma and 15% for all solid cancers. Improve detection techniques account for some of that growth, but MCC incidence increases exponentially with age, from 0.1 per 100,000 person-years for those aged 40 to 49 years to 9.8 per 100,000 person-years for those 85 years and older. As the US population ages, MCC incidence is expected to further grow from an estimated 2835 cases in 2020 to 3284 cases in 2025.⁴

Radiation Improves OS in MCC

Regarding treatments, surgical resection will always be the preferred treatment option for MCC, said Brian C. Baumann, MD, chief of the genitourinary service and an assistant professor of radiation oncology at Washington University School of Medicine in St. Louis. “Generally speaking, [surgery] should be followed with postoperative radiation therapy. For the very small, well-resected lesions with no other adverse features, you could omit radiation. But this is a unique cancer and even for something small and seemingly unimpressive clinically, radiation still has benefit.”

Baumann served as co-principal investigator for a retrospective study of localized MCC that showed a survival benefit associated with radiation therapy. Investigators analyzed data from 6156 patients who underwent local excision (LE) of T1 to T4 cancers with or without adjuvant radiotherapy from August 2020 to January 2021.

In multivariate regression analysis, LE margins greater than 1.0 cm (HR, 0.8; 95% CI, 0.81-0.95; P <.001) and adjuvant radiotherapy (HR, 0.78; 95% CI, 0.72-0.84; P <.001) were associated with improved overall survival (OS). OS was comparable between patients who received adjuvant radiotherapy and had LE margins of 1.0 cm or smaller (HR, 0.81; 95% CI, 0.74-0.89; P < .001) and in those who did not receive adjuvant radiotherapy and had LE margins larger than 1.0 cm (HR, 0.80; 95% CI, 0.71-0.89; P = .87).⁵

“It appears as though radiation can compensate for a smaller margin, but the best outcomes occurred with a margin larger than 1 cm and when the patient got postoperative radiation. Postoperative radiation was associated with a survival benefit in this in this cohort,” Baumann said “We think a 1 cm or larger clinical margin should be something that the surgeons aim for. [These results] provide more data that, certainly for the smaller clinical margin patients but also for the larger clinical margin patients, physicians should probably strongly consider adjuvant radiation therapy.”

Immunotherapy Adds a New Option

For metastatic disease, the standard treatment options include complete lymph node dissection and/or definitive nodal radiation. MCC will respond to chemotherapy, but such treatment has limited efficacy because the disease has high rates of relapse and resistance.

“If you have metastatic disease, the treatment recommendations are evolving,” Baumann said. “This is not a disease that has traditionally been particularly responsive to chemotherapy. But there’s more and more evidence showing that immunotherapy can work well for this disease.”

The FDA approved the PD-L1 inhibitor avelumab (Bavencio) in 2017 for the treatment of patients 12 years and older with metastatic MCC. In December 2018, the agency approved pembrolizumab (Keytruda) for patients with locally advanced or metastatic MCC.

More recently, investigators published findings from a long-term analysis of a cohort of the single-arm, phase 2 JAVELIN Merkel 200 trial (NCT02155647) in May 2020. These data formed the basis for the avelumab’s initial approval.

Patients in the trial with metastatic MCC and disease progression after prior chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks. As of September 2018, investigators followed 88 patients for median of 40.8 months (range, 36.4-49.7 months).⁶

The overall response rate (ORR) was 33.0% (95% CI, 23.3%-43.8%), including a complete response rate of 11.4% (n = 10). The median duration of response was 40.5 months (95% CI, 18.0 months to not estimable).

As of May 2019, the median OS was 12.6 months (95% CI, 7.5-17.1 months). The 42-month OS rate was 31% (95% CI 22%-41%).

“Some of the trials generating the most excitement for me are the ones combining radiation with immune therapy to see if we can trigger what we call an abscopal effect where radiation kills the Merkel cell cancer, releases pieces of the cancer into the bloodstream, and essentially helps to generate a more vigorous immune response that is then potentiated by the immune therapy,” Baumann said. “We’ve seen this in a number of different cancers and there's some evidence to suggest that this happens in Merkel [cell carcinoma]. There have been some trials where we’re applying targeted radiation to 1 or more lesions in metastatic patients and combining it with immune therapy to see if radiation can actually improve the overall response.”

Investigators are currently assessing adjuvant PD-1 or PD-L1 inhibitors in 3 prospective randomized trials. In the ongoing, phase III STAMP trial (NCT03712605), patients with completely resected stage I to IIIB disease are randomly assigned to either pembrolizumab or observation following surgery, with a primary end point of recurrence-free survival. In the ongoing, phase 3 ADAM trial (NCT03271372), investigators are comparing adjuvant avelumab versus placebo in 100 patients. The primary objective is relapse-free survival.

Finally, investigators are assessing nivolumab (Opdivo) plus either concurrent radiation therapy or ipilimumab (Yervoy) as adjuvant therapy in a phase 1 trial (NCT03798639); 1-year treatment completion rate is the primary outcome measure. The small study (N = 7) is expected to be completed by December 31, 2021.

“Certainly, in the patients with potentially curable disease, combination therapy is very important and often that combination therapy is surgery and radiation,” Baumann said. “But I think that immune therapy will likely have a growing and more important role in the future for this disease.”

References

1. Villani A, Fabbrocini G, Costa C, Carmela Annunziata M, Scalvenzi M. Merkel Cell Carcinoma: therapeutic Update and Emerging Therapies. Dermatol Ther (Heidelb). 2019;9(2):209-222. doi:10.1007/s13555-019-0288-z
2. Kervarrec T, Aljundi M, Appenzeller S, et al. Polyomavirus-positive Merkel cell carcinoma derived from a trichoblastoma suggests an epithelial origin of this Merkel cell carcinoma. J Invest Dermatol. 2020;140(5):976-985. doi: 10.1016/j.jid.2019.09.026
3. Freeman MB, Holman DM, Qin J, Lunsford NB. Merkel cell carcinoma incidence, trends, and survival rates among adults aged ≥50 years from United States Cancer Statistics. J Am Acad Dermatol. 2019;80(4):1154-1156. doi:10.1016/j.jaad.2018.10.045
4. Paulson KG, Park SY, Vandeven NA, et al. Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics. J Am Acad Dermatol. 2018;78(3):457-463.e2. doi:10.1016/j.jaad.2017.10.028
5. Andruska N, Fischer-Valuck BW, Mahapatra L, et al. Association between surgical margins larger than 1 cm and overall survival in patients with Merkel cell carcinoma. JAMA Dermatol. 2021;157(5):540–548. doi:10.1001/jamadermatol.2021.0247
6. D'Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J Immunother Cancer. 2020 May;8(1):e000674. doi: 10.1136/jitc-2020-000674