Scratching Beneath the Surface in Merkel Cell Carcinoma

Due to its rarity, there will likely never be a television advertisement for Merkel cell carcinoma (MCC), according to James DeCaprio, MD. Nonetheless, he said, there are several opportunities to build on to help raise awareness and conduct an array of clinical trials, due to the disease’s “spectacular” response to checkpoint blockade.

“In Australia, actually, Merkel cell carcinoma is a household word. It’s actually well understood because of [the area’s] great increased risk for skin cancers of all kinds,” said DeCaprio, a professor of medicine at Harvard Medical School, and physician at Brigham and Women's Hospital, Dana-Farber Cancer Institute. “But actually, Merkel cell carcinoma is of a higher incidence. Now, because of certain therapies, even metastatic patients live long, and they get to tell their story. [The disease] is so aggressive that patients don’t often live to tell the story.”

That being said, the work is far from done.

MCC is described as an aggressive neuroendocrine cancer that arises in the dermoepidermal junction and is known to be the second most common cause of death from skin cancer following melanoma.¹ While its exact origin is unknown, MCC is known to have features of both epithelial and neuroendocrine origin and arise in cells with mechanoreceptors.

The annual incidence of MCC is 0.7 per 100,000 in the United States, according to data from 2013, with a significant increase between 2000 and 2013. However, the increase is likely related to improved diagnostic pathology tools, improved clinical awareness of MCC, an aging population, increased sun exposure in suspectable subgroups, and improved registry tools.

“It is rising as a theme that we're seeing a lot of skin malignancies,” said Sandra P. D’Angelo, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center. “But this is one of the extra rare ones that we encounter in the clinics.”

MCC also has an improved incidence in patients with HIV, hematologic malignancies, and those with autoimmune diseases or who are taking immunosuppressive medications; additional increased cases are in those with psoriasis heavily treated with methoxsalen and ultraviolet A.

“Merkel cell carcinoma tends to be more common in Caucasian older males, and some risk factors that we’re aware of is sun exposure; the other important one is immunosuppression,” D’Angelo explained. “Therefore, either having a weakened immune system because you're on some treatment for other medical problems—such as receiving a transplant, or having HIV—[puts you at risk]. The other important one is having a concurrent hematological malignancy; we find that those patients actually have a worse prognosis. Most of our patients still don't actually present with a concurrent immunosuppressive comorbid condition, though having that condition increases the risk of Merkel cell carcinoma 10- to 15-fold.”

The most common sites of disease are seen on the skin/face (26.9%), skin of upper limb and shoulder (22.0%), skin of lower limb and hip (14.9%), skin of trunk (10.6%), skin of scalp and neck (9.0%), skin not otherwise specified (6.0%), external ear (3.1%), eyelid (2.5%), skin of lip (2.4%), and unknown primary site (0.8%).

While the simplest approach for managing MCC is surgical resection, patients will often experience disease recurrence, D’Angelo said, adding that systemic therapies are not often recommended for patients for those with stage I to III disease.

“It's really in that setting where there's been a lot of breakthroughs—in the treatment of patients with metastatic Merkel cell carcinoma over the last few years,” D’Angelo added.

Therapeutic Advances

While therapeutic options overall for MCC are limited, immunotherapy has been a significant area of development and led to the first approved treatments for this patient population.

“Prior to the introduction of these agents in our clinics, most patients with Merkel cell carcinoma received chemotherapy, and chemotherapy was really good at shrinking the Merkel cell carcinoma, but the duration of benefit was quite dismal at only about 3 months,” reflected D’Angelo. “By the time patients finished chemotherapy, their cancer began to grow. Over the last few years, there has been a lot of work done with checkpoint inhibitors, and drugs such as avelumab and pembrolizumab are now the standard of care.”

In March 2017, the FDA granted an accelerated approval to the PD-L1 inhibitor avelumab (Bavencio) for the treatment of adults and pediatric patients 12 years and older with metastatic MCC, including those who have not received previous chemotherapy.²

The decision was based on results from the open-label, phase 2 JAVELIN Merkel 200 study, in which the PD-L1 inhibitor demonstrated a 33% objective response rate (ORR; 95% CI, 23.3-43.8), which included an 11.4% (95% CI, 6.6-19.9) complete response (CR) rate and a 21.6% (95% CI, 13.5-31.7) partial response rate. In 86% of patients, the duration of response (DOR) was at least 6 months, with 45% of patients having a DOR of at least 1 year.

The following year, in December 2018, the FDA had granted an accelerated approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC.³

The approval was based on findings from the phase 2 CITN-09/KEYNOTE-017 trial (NCT02267603), in which pembrolizumab elicited an ORR of 56% (95% CI, 41%-70%) per independent review, as well as a 24% CR rate and a 32% partial response rate, in those who did not previously receive systemic therapy for their advanced disease.

In the multicenter, single-arm, open-label study, 50 treatment-naïve patients with recurrent locally advanced or metastatic MCC, who did not receive prior therapy, were treated with 2 mg/kg of pembrolizumab every 3 weeks. At a median follow-up of 14.9 months (range, 0.4-36), data showed that the median DOR was not reached (range, 5.9 to 4.5+). Among the 28 patients who responded, 96% had a DOR of at least 6 months and 54% had a DOR of more than 1 year; 5 patients (10%) had stable disease. Sixteen patients (32%) had progressive disease and 1 patient was not assessed for response.

Additional findings showed that the median PFS was 16.8 months with pembrolizumab, which was higher than historical data for chemotherapy controls; here, the median PFS ranges from 3.1 to 4.6 months. This was also true for median OS, which had not been reached for pembrolizumab compared with historical data ranging from 9.5 to 10.2 months with frontline chemotherapy in MCC.

The median time to response was 2.8 months (range, 1.5-9.7). Most responses had occurred by 12 weeks and most were also ongoing at the time of the data cutoff of February 6, 2018. Responses were observed regardless of MCPyV status; the ORR was 59% in MCPyV-positive patients and 53% for those who were MCPyV negative.

“The sobering part of this whole endeavor is that only about 50% of patients with metastatic Merkel cell carcinoma will respond and benefit from immunotherapy,” said D’Angelo. “So, that is just 1 in 2 patients, right? That highlights the need to do more.”

Immunotherapy is also being explored earlier on in the disease course.

For example, in the phase 1/2 CheckMate-358 study, neoadjuvant nivolumab (Opdivo), when given 4 weeks prior to surgery in patients with MCC, led to a 47.2% pathologic complete response (pCR) rate; among 33 patients who had surgery and were radiographically evaluable, 54.5% had tumor reductions of 30% or greater. The median relapse-free and overall survival had not yet been reached at a median follow-up of 20.3 months.⁴

Other ongoing studies in the localized setting include the phase 3 STAMP study (NCT03712605), evaluating pembrolizumab vs standard observation in patients with completely resected stage I to III MCC, and the phase 3 ADAM trial (NCT03271372) of avelumab compared with placebo in the adjuvant setting for patients whose disease has spread to the lymph nodes and have undergone surgery and/or radiation.

On the Horizon in Merkel Cell Carcinoma

Additional efforts are looking to improve the 50% benchmark through trials that are combining checkpoint inhibitors with other agents, such as MDM2 inhibitors. An ongoing phase 2 study (NCT03787602) is evaluating the oral small molecule MDM2 inhibitor KRT-232 plus avelumab in patients with p53 wild-type MCC who have failed treatment with a PD-1/PD-L1 inhibitor.

“It has very promising activity, so we’re very excited about that,” said DeCaprio of KRT-232. “Hopefully, you’ll be hearing more about that in the coming months from the big meetings coming up.”

Another phase 2 trial, MERKELIN2 (NCT04393753), is looking at avelumab in combination with the investigational HDAC inhibitor domatinostat (4SC-202) in advanced unresectable and/or MCC, also who have progressed on a prior checkpoint inhibitor.

Beyond these novel combinations, avelumab is also being explored in combination with comprehensive ablation radiation therapy in a randomized, phase 2 study in those who have progressed on therapy and have unresectable disease (NCT04792073).

“A lot of these agents are designed to potentially make the immune microenvironment more friendly to allow these checkpoint inhibitors to be more effective. These are just some of the trials that are ongoing, and we hope they will offer more than that 50% response rate—which is great, but obviously not good enough for those patients who aren't benefiting.”

Other novel agents are moving through the MCC pipeline. In March 2021, the FDA granted an orphan drug designation to the spherical acid toll-line receptor 9 agonist cavrotolimod (AST-008) for the treatment of patients with MCC.⁵ The agent previously was granted fast track designations in January 2021 for use in combination with a PD-1 inhibitor in those with locally advanced or metastatic MCC who were refractory to prior PD-1–directing therapy, as well as for use in combination with a PD-1/PD-L1 inhibitor in those with advanced or metastatic cutaneous squamous cell carcinoma who are refractory to prior PD-1/PD-L1 blockade.

In a phase 1b trial, cavrotolimod was tested in combination with pembrolizumab (Keytruda) or cemiplimab-rwlc (Libtayo) in 20 patients with cancer, including melanoma (n = 10), MCC (n = 5), cutaneous squamous cell carcinoma (CSCC; n = 2), head and neck squamous cell carcinoma (n = 2), and leiomyosarcoma (n = 1). Investigators explored safety, tolerability, pharmacokinetics, and pharmacodynamics of the agent as a monotherapy and in combination for the dose-escalation portion of the study. The primary end point was identifying the recommended phase 2 dose (RP2D).

Data showed that cavrotolimod elicited an ORR of 21%, and in those who received cavrotolimod at the highest dose of 32 mg, the ORR was 33%, and this was determined to be the RP2D.⁶

Responses were seen in 2 patients with advanced MCC, 1 of whom had a CR, and 2 with melanoma. The median duration of response had not yet been reached in these responders, and no responders experienced progressive disease at a median follow-up of 11 months.

Regarding safety, cavrotolimod was found to be well tolerated and no serious toxicities associated were observed. The most commonly adverse effects included flu-like symptoms and injection-site reactions. This phase 2 portion of this trial with cavrotolimod (NCT03684785) is ongoing.

LSD1 inhibition is another area of heavy investigation in DeCaprio’s lab at Dana-Farber Cancer Institute.

“Because it's a rare cancer, it makes it challenging to put together a drug study, or to really come up with a plan to go after this, but I think the Merkel cell carcinomas that we've studied have been very, very sensitive to LSD1 inhibition, so I think there's an opportunity,” he said. “We're just getting started.”

Getting to Work

Identification of predictive biomarkers beyond the existing potential with PD-L1 and tumor mutational burden, improved recognition of clinical features, and an improved understanding of when to use immunotherapy are all on the list of goals to achieve in MCC management.

DeCaprio also cited MCC’s “fascinating” biology and his drive to continue unraveling the malignancy’s true driver mutations and predictive markers of immunotherapy.

“Because it's a rare cancer, there's not so much experience in treatment, but it's very, very clear that you need a very skilled team of physicians that can take care of this disease and the patient,” he concluded. “Often, a lot of morbidity related to surgery, or even chemotherapy, could be spared in a patient if the team is experienced and know how to best take care of [them] and how to how to put that treatment plan together.”

References

1. Merkel cell carcinoma treatment (PDQ)–health professional version. National Cancer Institute. Updated March 23, 2019. Accessed May 13, 2021. https://bit.ly/2RgR3af
2. Kaufman H, Russell JS, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374-1385. doi:10.1016/S1470-2045(16)30364-3
3. Nghiem P, Bhatia S, Lipson EJ, et al. Durable tumor regression and overall survival (OS) in patients with advanced Merkel cell carcinoma (aMCC) receiving pembrolizumab as first-line therapy. J Clin Oncol. 2018;36 (suppl; abstr 9506). doi:10.1200/JCO.18.01896
4. Topalian SL, Bhatia S, Amin A, et al. Neoadjuvant nivolumab for patients with resectable Merkel cell carcinoma in the CheckMate 358 trial. J Clin Oncol. 2020;38(22):2476-2487. doi:10.1200/JCO.20.00201
5. Exicure granted orphan drug designation by the US Food and Drug Administration for cavrotolimod. News release. March 3, 2021. Accessed March 5, 2021. http://bit.ly/38fEukL
6. Pipeline: Cavrotolimod (AST-008). Exicure, Inc. Accessed March 5, 2021. http://bit.ly/3oNKCqV.