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Clinical Trial
. 2018 Jan 19;6(1):7.
doi: 10.1186/s40425-017-0310-x.

Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial

Howard L Kaufman  1   2 , Jeffery S Russell  3   4 , Omid Hamid  5 , Shailender Bhatia  6 , Patrick Terheyden  7 , Sandra P D'Angelo  8 , Kent C Shih  9 , Céleste Lebbé  10 , Michele Milella  11 , Isaac Brownell  12 , Karl D Lewis  13 , Jochen H Lorch  14 , Anja von Heydebreck  15 , Meliessa Hennessy  16 , Paul Nghiem  17
Affiliations
Clinical Trial

Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial

Howard L Kaufman et al. J Immunother Cancer. .

Abstract

Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab-a human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody-showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease.

Patients and methods: Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Results: Patients (N = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1-positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status.

Conclusions: With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy.

Trial registration: Clinicaltrials.gov identifier: NCT02155647.

Keywords: Avelumab; Javelin; Merkel cell carcinoma; Pd-L1.

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Conflict of interest statement

Ethics approval and consent to participate

All patients were enrolled in accordance with approved protocols, international standards of good clinical practice, institutional review board approvals, and institutional safety monitoring. Written informed consent was provided.

Consent for publication

Not applicable.

Competing interests

HLK reports consultancy for and honoraria from Amgen, Celldex, Compass Therapeutics, EMD Serono, Prometheus, Sanofi, Turnstone Biologics, and Merck KGaA, Darmstadt, Germany; reports research funding from Amgen, EMD Serono, Prometheus, Viralytics, and Merck KGaA, Darmstadt, Germany; and is a member of a speaker’s bureau for Merck KGaA, Darmstadt, Germany. JSR reports consultancy for EMD Serono. OH reports consultancy for Amgen, Novartis, Roche, Bristol-Myers Squibb, and Merck KGaA, Darmstadt, Germany; is a member of a speaker’s bureau for Bristol-Myers Squibb, Genentech, Novartis, and Amgen; and has received research funding from Astra Zeneca, Bristol-Myers Squibb, Celldex, Genentech, Immunocore, Incyte, Merck KGaA, Darmstadt, Germany, Merck Serano, MedImmune, Novartis, Pfizer, Rinat and Roche. SB received research support from EMD Serono. PT has received reimbursement and non-financial support from other commercial sponsors, outside the submitted work. SPD reports employment at Memorial Sloan Kettering Cancer Center and is a member of advisory boards for EMD Serrano, Nektar, and Amgen. CL reports advisory and consultancy for Roche, Bristol-Myers Squibb, Novartis, Amgen, GlaxoSmithKline, and Merck, Sharpe, and Dohme; has received research support from Roche and Bristol-Myers Squibb; is a member of a speaker’s bureau for Bristol-Myers Squibb, Amgen, Roche, and Novartis; has received honoraria from Roche, Bristol-Myers Squibb, Novartis, Amgen, and Merck, Sharpe, and Dohme; and has received travel accommodations from Roche, Bristol-Myers Squibb, and Novartis. KDL has received research support from EMD Serono. JHL has received research support from Novartis, Takeda-Millennium, and Bristol-Myers Squibb; and is a member of an advisory board for Bristol-Myers Squibb and Eisai. AvH reports employment at and is a stock shareholder of Merck KGaA, Darmstadt, Germany. MH reports employment at EMD Serono. PN has received research support from EMD Serono and Bristol-Myers Squibb; and has received personal fees from EMD Serono and Pfizer outside the submitted work. The remaining authors have no conflicts of interest to disclose.

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Figures

Fig. 1
Fig. 1
Clinical activity of avelumab in patients with mMCC at ≥1 year of follow-up. Time to and duration of response and duration of treatment in 29 patients with a confirmed response. CR, complete response; DOR, duration of response; PD, progressive disease; PR, partial response
Fig. 2
Fig. 2
Survival outcomes in patients with mMCC receiving avelumab. Kaplan-Meier estimates of (a) progression-free survival (PFS) and (b) overall survival (OS). Vertical lines indicate censored events. Also depicted in (a) are Kaplan-Meier estimates of PFS for recent retrospective studies of second-line (2 L) or second-line and later (2 L+) chemotherapy in patients with mMCC [–15]. NE, not estimable. a Includes both immunocompetent and immunocompromised patients. All patients progressed; therefore, none were censored. b PFS rate at 6 months was 0%. c One patient with PR had PFS lasting 354 days; 95% of patients receiving second-line chemotherapy had progressed at 230 days
Fig. 3
Fig. 3
Objective response rates in patient subgroups. The ORR and associated 95% CI values are graphed and shown for the indicated subgroups. MCPyV, Merkel cell polyomavirus; ORR, objective response rate; PD-L1, programmed death-ligand 1; SLD, sum of target lesion diameters. a PD-L1 expression in tumor samples was assessed using a proprietary immunohistochemistry assay (Dako PD-L1 IHC 73-10 pharmDx). Determination of PD-L1–positive status at different PD-L1 cutoff levels was based on tumor cell staining of any intensity
Fig. 4
Fig. 4
Response durability in patient subgroups. The proportions of responding patients with response duration ≥1 year are depicted for the indicated patient subgroups. The associated median DOR and 95% CI for each subgroup is shown on the right. DOR, duration of response; MCPyV, Merkel cell polyomavirus; NE, not estimable; NR, not yet reached; PD-L1, programmed death-ligand 1; SLD, sum of target lesion diameters. a One patient missing information on site of the primary tumor had an ongoing response for <1 year (8.8+ months). b Of 3 patients with a response to avelumab and PD-L1–negative status (<1% tumor-cell staining cutoff), the response was ongoing in all 3 patients for <1 year (3.9+, 11.1+, and 11.1+ months)
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