Avelumab for the treatment of metastatic Merkel cell carcinoma

Summary

Avelumab is a promising new therapeutic agent for patients with metastatic Merkel cell carcinoma, a rare and aggressive type of neuroendocrine tumor of the skin. Until the recent approval of avelumab (Bavencio), no therapies were approved by the U.S. Food and Drug Administration for the treatment of metastatic Merkel cell carcinoma. In a recent trial, avelumab, an anti-programmed death ligand-1 antibody, demonstrated an objective response in 28 of 88 patients (31.8% [95.9% CI, 21.9-43.1]) with advanced, chemotherapy-refractory Merkel cell carcinoma. Overall, avelumab was well tolerated at a dose of 10 mg/kg administered intravenously every 2 weeks. Serious treatment-related adverse events were reported in 5 patients (6%), but no grade 4 adverse events or treatment-related deaths were reported. Preliminary data evaluating avelumab in chemotherapy-naive patients is also encouraging.

Background

Merkel cell carcinoma (MCC) is an aggressive type of neuroendocrine tumor of the skin that was first identified in 1972 (1). The annual incidence of MCC in the United States is increasing and is estimated to be 0.34 and 0.17 per 100,000 men and women, respectively (2). MCC tumors predominantly arise on sun-exposed skin of the head and neck and most patients with MCC are Caucasian (94.9%), male (61.5%) and immunosuppressed (3). Another cohort study found that chronic lymphocytic leukemia was over-represented in the MCC population (4). Tumor stage at diagnosis is the most significant predictor of survival (3, 5). The estimated 5-year survival rate is 75% for patients with primary tumors, 59% for patients with lymph node metastases and/or local recurrences, and 25% for patients with distant metastases (5).

Prior to the approval of avelumab in 2017, no Food and Drug Administration (FDA)-approved therapies were available for MCC. Cisplatin or carboplatin with or without etoposide are commonly used to treat metastatic MCC (6); however, literature on the use of chemotherapy in MCC is limited due to the disease’s rarity. Although some data suggest MCC is chemotherapy sensitive, responses appear to be short-lived and there is insufficient data to assess whether chemotherapy has a positive impact on survival. A recent retrospective study evaluated the objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) in patients with metastatic MCC receiving first- or second-line chemotherapy (7). Of 67 patients evaluated in the first-line setting, ORR was 29.4%, median DOR was 6.7 months and median PFS was 4.6 months. In the second-line setting, 20 patients were evaluated and demonstrated an ORR of 28.6%, median DOR of 1.7 months and median PFS of 2.2 months. Similar low response rates and durations were also suggested in a recent review: response rates ranged from 20% to 61% with a variety of cytotoxic regimens and the DOR among responders was ≤ 8 months (8). Undoubtedly, new treatment approaches are needed for this rare type of carcinoma. Brownell and colleagues are utilizing oncogenomic analysis to identify novel therapeutic targets for the treatment of MCC but these options are still being explored in preclinical models (9).

Data suggest that immune-suppressive conditions including organ transplantation and HIV are associated with an increased risk of developing MCC (10, 11). Published case reports provide additional evidence that MCC lesions improve once the underlying function of the immune system improves (12, 13). Furthermore, a polyoma virus has recently been linked to MCC and is now known as the Merkel cell polyomavirus (MCPyV) (2, 14). Overall, these data provide strong evidence linking MCC with immune suppression, as well as rationale for investigating immunotherapeutic agents such as checkpoint inhibitors for the treatment of this rare neoplasm.

Preclinical Pharmacology

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors have demonstrated improved survival and response rates in multiple types of solid tumors (15–17). The mechanism of action for PD-1/PD-L1 inhibitors is well established (18). PD-L1 plays a vital role in tumor immune evasion. The interaction of PD-L1 with its PD-1 and B7.1 receptors results in downregulation of a natural immune response in the tumor microenvironment. Blocking this interaction of the ligand on tumor cells with the receptor on T cells results in renewed activation of the immune system.

Avelumab (MSB-0010718C) is a fully human IgG1 anti-PD-L1 monoclonal antibody that contains a native Fc region (19, 20). Unlike other FDA-approved PD-1/PD-L1 inhibitors, avelumab has an intact Fc region that allows for antibody-dependent cell-mediated cytotoxicity (ADCC) (20). The Fc portion plays a vital role in the immune-mediated antitumor responses of monoclonal antibodies by engaging Fcγ receptors on natural killer (NK) cells (21). Boyerinas et al. performed in vitro studies to evaluate the ability of avelumab to mediate ADCC tumor lysis (20). These studies demonstrate the ability of avelumab to lyse a variety of human tumor cells in the presence of peripheral blood mononuclear cells (PBMCs) or NK cells and provide a rationale for combining avelumab with cytokines or anticancer vaccines to enhance the tumor microenvironment, potentially resulting in increased avelumab-mediated ADCC. Another study analyzing the effect of avelumab on 123 immune cell subsets in the peripheral blood of cancer patients found no statistically significant changes including on PD-L1-positive subsets (22).

Pharmacokinetics and Metabolism

The pharmacokinetics of avelumab were evaluated in 1,629 patients receiving 1-20 mg/kg intravenously every 2 weeks (23). The steady state mean volume of distribution for the 10 mg/kg dose was 4.72 L. Avelumab is eliminated primarily through proteolytic degradation. In patients receiving 10 mg/kg, systemic clearance was 0.59 L/day and the terminal half-life was 6.1 days. No clinically significant differences in clearance were noted based on age, sex, race, PD-L1 status, tumor burden, severe renal impairment or moderate hepatic impairment.

In patients with solid tumors, avelumab demonstrated a dose-proportionate increase in both area under the curve and maximum serum concentration (C_max) at 3-20 mg/kg (19). The mean time to C_max was within 1 hour after the infusion ended and was consistent across all dose levels. The half-life of avelumab in this population was 2.5 days (1 mg/kg), 3.4 days (3 mg/kg), 3.9 days (10 mg/kg) and 4.1 days (20 mg/kg), respectively, suggesting that target-mediated clearance was saturated at the two highest dose levels.

Anti-drug antibodies to avelumab were detected using an electrochemiluminescent immunoassay and was based on binding to labeled avelumab (19). Avelumab anti-drug antibodies were detected in 2 of 53 patients (4%). One patient tested positive at a single time point; the other tested positive at several time points and received a total of nine doses until disease progression.

Avelumab target occupancy of PD-L1 on CD39 T cells was assessed using flow cytometry, based on the difference in mean fluorescence intensity between samples taken at baseline and day 15 following 1 dose of avelumab. The reported mean PD-L1 target occupancy was 76% (1 mg/kg), 90% (3 mg/kg), 93% (10 mg/kg) and 87% (20 mg/kg), respectively.

Pharmacokinetic analysis of avelumab in patients with MCC is ongoing (24).

Clinical Studies

In addition to avelumab, both pembrolizumab and nivolumab (PD-1 inhibitors) have been studied in MCC and provide further evidence to support inhibition of the PD-1/PD-L1 pathway as an effective treatment strategy (25, 26). In a multicenter phase II trial, 26 patients with advanced MCC and no prior systemic therapy received pembrolizumab 2 mg/kg intravenously every 3 weeks (25). The ORR was 56% (95% confidence interval [CI], 35 to 76) and the response duration ranged from 2.2 months to 9.7 months with a 6-month PFS of 67% (95% CI, 49 to 86). Responses were observed in patients with MCPyV-positive and -negative tumors: 62% versus 44%, respectively. Another noncomparative open-label trial evaluated the safety and efficacy of nivolumab in 25 patients with MCC who had received ≤ 2 prior therapies (26). In 22 evaluable patients the ORR was 68% and the 3-month PFS and OS was 82% and 92%, respectively. Similar to the pembrolizumab trial, responses were observed in both MCPyV-positive and -negative tumors.

Avelumab was first evaluated in JAVELIN Solid Tumor (19). This phase Ia, multicohort, dose-escalation trial followed a standard 3+3 cohort design to assess four doses of avelumab (1, 3, 10 and 20 mg/kg) administered intravenously every 2 weeks. Eligible patients included adults with metastatic or locally advanced solid tumors for whom standard therapy had failed or did not exist. Additional eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, no central nervous system metastases, no known autoimmune disease, and adequate end-organ function. The latter was defined as white blood cell count ≥ 3 × 10⁹ cells/L, lymphocyte count ≥ 0.5 × 10⁹ cells/L, platelet count ≥ 100 × 10⁹ platelets/L, hemoglobin ≥ 9 g/dL, total bilirubin ≤ 1.5 × upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN, and estimated creatinine clearance > 50 mL/min. Patients taking steroids or other anticancer therapies, with the exception of androgen-deprivation therapy and palliative bone-directed radiotherapy, were excluded. The primary endpoint of the dose-escalation portion of the study was safety, defined by the incidence of dose-limiting toxicities. Secondary endpoints included additional safety analysis, pharmacokinetic and pharmacodynamic profiles, best overall response, and assessment of anti-drug antibody formation.

JAVELIN Solid Tumor evaluated 53 eligible patients with a variety of solid tumors. Of these, 18 were in the dose-limiting toxicity analysis set. No dose-limiting toxicities were noted at 1, 3 or 10 mg/kg; one dose-limiting toxicity defined as an autoimmune disorder was reported at 20 mg/kg. The maximum tolerated dose was not reached and the investigators concluded that avelumab had an acceptable toxicity profile at all dose levels. The selected phase II/III dose was 10 mg/kg based on pharmacokinetics, target occupancy and immunological results.

In a multicenter, open-label, phase II trial, Kaufman et al. evaluated avelumab in patients with chemotherapy-refractory metastatic MCC (24). This study, also known as the JAVELIN Merkel 200 trial, is currently recruiting (ClinicalTrials.gov Identifier NCT02155647) with an estimated enrollment of 200 participants. Of note, this trial was recently amended to include a chemotherapy-naive MCC cohort. Key eligibility criteria include ECOG status of 0-1 and adequate hematologic, hepatic and renal function as defined by the same parameters as the phase Ia avelumab study described above. Patients were required to be immunocompetent and patient selection was independent of PD-L1 or MCPyV status. Eligible patients received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response (complete or partial). Secondary objectives included DOR, PFS, overall survival, response status at 6 and 12 months, safety, population pharmacokinetic profile and immunogenicity.

At the time of analysis, 88 patients who had failed at least one prior line of chemotherapy were enrolled and had received at least one dose of avelumab. Of these 88 patients, 28 (31.8%) achieved an objective response (95.9% CI, 21.9-43.1) including 8 complete and 20 partial responses (24). Responses were observed in MCPyV-positive and -negative tumors as well as PD-L1-positive and -negative tumors. Data also indicates the responses are durable. The median DOR was not yet reached and the durable response rate was 30.6% (95% CI, 20.9-40.3) at 6 months and 23.9% (95% CI, 15.4-34.1) at 1 year (27). Another small study analyzed patient experiences with avelumab compared to chemotherapy through the use of qualitative interviews (28). The investigators concluded that patients with MCC had a more positive experience with avelumab treatment compared to chemotherapy.

Preliminary results are now available for the safety and efficacy of avelumab in patients with chemotherapy-naive metastatic MCC (29). Thus far, 29 of 112 planned patients have been enrolled in this study which is a separate cohort of the JAVELIN Merkel 200 trial. In 16 patients with follow-up ≥ 3 months, the unconfirmed ORR was 68.8% (95% CI, 41.3-89.0), complete response was reported in 18.8%, and 5 of 5 patients with ≥ 6-month follow-up experienced an ongoing response.

In addition to the dose-escalation trial and the MCC phase II trial, studies evaluating avelumab in metastatic non-small cell lung cancer (30) and urothelial cancer (31) have been completed. Various studies evaluating avelumab as monotherapy and combination therapy in a wide array of tumor types are currently ongoing. A phase I/II study specific to patients with MCC is also recruiting (ClinicalTrials.gov Identifier NCT02584829). Participants in this study (“Localized radiation therapy or recombinant interferon beta and avelumab with or without cellular adoptive immunotherapy in treating patients with metastatic Merkel cell carcinoma”) will be assigned to 1 of 2 arms: avelumab and major histocompatibility complex (MHC) class I upregulation (group 1), or avelumab, MHC class I upregulation, and T cells (group 2). The primary objective is to assess and compare the safety and antitumor efficacy of the two groups.

Safety

In vitro studies analyzed the potential of avelumab to induce cytokine release by PBMCs from human healthy donors after in vitro exposure to avelumab (19). The results of these studies indicated the potential for cytokine release 6 and 24 hours post incubation. However, increases in serum concentrations of proinflammatory cytokines at 48 hours were minimal. Although cytokine concentrations varied with the dose and timing of avelumab, investigators noted no consistent pattern. Further evaluation is required.

Table I provides a summary of treatment-related adverse events (TRAEs) attributed to avelumab. In the JAVELIN Solid Tumor phase Ia trial, the most commonly reported TRAEs were fatigue, influenza-like symptoms, fever and chills (19). Nine of 53 patients experienced a grade 3-4 AE, 6 had a TRAE that led to treatment discontinuation, and 6 had a serious TRAE.

Table I.

Summary of treatment-related adverse events reported in the JAVELIN Solid Tumor phase la and Merkel cell carcinoma (MCC) phase II trials.

Common (≥ 5%) grade 1-2 treatment-related adverse events
	JAVELIN Solid Tumor phase Ia N of 53 (%)	MCC phase II N of 88 (%)
Fatigue	21 (40%)	21 (24%)
Influenza-like symptoms	11 (21%)	NR
Fever	8 (15%)	NR
Chills	6 (11%)	NR
Infusion-related reaction	4 (8%)	15 (17%)
Diarrhea	4 (8%)	8 (9%)
Nausea	3 (6%)	8 (9%)
Asthenia	NR	7 (8%)
Rash	3 (6%)	6 (7%)
Grade 3-4 treatment-related adverse events
	JAVELIN Solid Tumor phase Ia Patients (N)	MCC phase II Patients (N)
Autoimmune disorder	3	NR
Increased creatine phosphokinase	2	1
Increased aspartate or alanine aminotransferase	3	1
Increased alkaline phosphatase	1	NR
Fatigue	1	NR
Decreased lymphocyte count	1	2
Increased lipase	1	NR
Increased amylase	1	NR
Lower abdominal pain	1	NR
Increased cholesterol	NR	1

NR, not reported.

Three patients with thymoma experienced a variety of autoimmune toxicities associated with antitumor effects, which were classified by the investigators as an “autoimmune disorder.” In a phase II trial of avelumab in MCC, the most commonly reported AEs (≥ 5% of patients) were fatigue, infusion-related reaction, diarrhea, nausea, asthenia and rash (24). One patient discontinued treatment because of a TRAE; 5 experienced a serious TRAE. Similar toxicities were reported in the chemotherapy-naive cohort. TRAEs were reported in 69% of patients of which 17.2% were grade 3 or 4. Five patients discontinued treatment due to AEs including infusion-related reactions (2 patients), elevated AST/ALT, cholangitis and paraneoplastic syndrome (1 patient each).

Indications and Administration

On the basis of the significant objective responses reported in the MCC phase II trial, avelumab received FDA approval for the treatment of adult and pediatric patients 12 years and older with metastatic MCC (23). Avelumab is administered every 2 weeks at a dose of 10 mg/kg via intravenous infusion over 60 minutes through a sterile, nonpyrogenic, low protein binding 0.2 micron in-line filter. The solution is commercially available as 200 mg/10 mL in a single-dose vial and must be diluted with 0.9% or 0.45% sodium chloride for injection prior to administration. To mitigate infusion-related reactions, acetaminophen and an antihistamine should be administered prior to each of the first four infusions then subsequently if needed.

Drug Interactions

No formal drug–drug interaction studies with avelumab have been completed. However, it has been speculated that high doses of steroids may alter the efficacy of checkpoint inhibitors (32). Both JAVELIN Solid Tumor and JAVELIN Merkel 200 prohibited concurrent administration of corticosteroids and immunosuppressive agents during treatment with avelumab (19, 24), as well as live vaccines for the prevention of an infectious disease. Until further information is available, caution is advised when administering these agents concurrently and patient-specific benefits and risks must be evaluated.

Conclusions

MCC is a rare and aggressive carcinoma of the skin. Although it is considered chemotherapy sensitive, MCC has shown only short-lived responses to cytotoxic chemotherapy agents, and survival data for these agents are limited. Avelumab, a PD-L1 inhibitor, has demonstrated an acceptable toxicity profile and a significant response rate in patients with MCC. Avelumab is thus a promising new treatment option for chemotherapy-refractory metastatic MCC.