Avelumab ‘Important Advance’ For Advanced Merkel Cell Carcinoma

Metastatic Merkel cell carcinoma patients may benefit from checkpoint blockade

medwireNews: Programmed cell death ligand 1 (PD-L1) inhibition may be an option for patients with metastatic Merkel cell carcinoma, suggest phase II trial results showing a promising objective response rate (ORR) to the Monoclonal antibody therapy avelumab.

“Responses to avelumab were observed irrespective of PD-L1 expression or Merkel cell polyomavirus status, suggesting that avelumab might achieve a therapeutic benefit in patients whose disease response and cause are driven by different underlying mechanisms”, the investigators observe in The Lancet Oncology.

For the multicentre, open-label study, 88 patients with stage IV Merkel cell carcinoma refractory to chemotherapy were treated with the PD-L1 inhibitor at a dose of 10 mg/kg every 2 weeks.

The primary endpoint of RECIST-defined response occurred in 31.8% of the patients, including eight complete responses and 20 partial responses, report Howard Kaufman, from The State University of New Jersey in New Brunswick, USA, and co-workers.

By the first review at week 7, responses were noted in 79% of 28 patients, rising to 82% at time of data cutoff and ranging from 2.8 to 17.5 months, and the median duration was unreached. Post-hoc analysis estimated a durable response lasting at least 6 months in 29% of the treated patients, the team reports.

Median progression-free survival (PFS) was 2.7 months; 40% of patients were free from progression at 6 months and PFS reached a plateau with data still maturing. Overall survival at 6 months was achieved by 69% of patients and estimated to be a median of 11.3 months.

Grade 3 adverse events occurred in just 5% of the patients, namely two cases of lymphopenia and three of isolated elevation of creatine phosphokinase, cholesterol or hepatic aminotransferase. There were no grade 4 events or treatment-related deaths.

Possible immune-mediated grade 1 or 2 adverse events occurred in 7% of patients. Seven serious treatment-related events were reported in five (6%) patients, with one infusion-related reaction and one case each of enterocolitis, aminotransferase elevation, chondrocalcinosis, synovitis and interstitial nephritis.

 “This is an important advance over chemotherapy, which is associated with a high incidence of toxicity-related morbidity and high disease-related mortality, particularly in patients who are older than 65 years of age with stage IV malignancy”, Howard Kaufman et al write.

They note that the study’s results have led to avelumab receiving breakthrough, fast-track and orphan drug designation by the US Food and Drug Administration, while the European Medicines Agency and the Australian Therapeutic Goods Administration have awarded the PD-L1 inhibitor orphan drug status.

The authors of a linked comment say that the avelumab results, taken together with the ORR reported for first-line pembrolizumab for advanced Merkel cell carcinoma, “strongly suggest that checkpoint blockade is the best option to treat patients with advanced Merkel cell carcinoma, establishing a new standard of care, especially in view of the excellent tolerability of pembrolizumab and avelumab and the substantial comorbidities in this elderly patient cohort.”

Axel Hauschild (University Hospital Schleswig-Holstein, Kiel, Germany) and Dirk Schadendorf (University Hospital Essen, Germany) write that definitive phase III trials comparing PD-L1 inhibition with chemotherapy will be “almost impossible for ethical reasons” but hope that checkpoint blockade and associated biomarkers of response will now be investigated in other rare tumours.

“Furthermore, clinical trials to maximise synergistic benefits from combinations of checkpoint inhibitors such as CTLA-4 antibodies, PD-1 antibodies, or PD-L1 antibodies, with or without radiotherapy, should now be designed and executed”, they add.

“For the first time, there is some optimism on the horizon for treating patients with Merkel cell carcinoma and hopefully this will also expand to other non-melanoma skin cancers.”

References

Kaufman HL, Russell J, 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; Advance online publication 1 September. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30364-3

Hauschild A, Schadendorf D. Checkpoint inhibitors: a new standard of care for advanced Merkel cell carcinoma? Lancet Oncol 2016; Advance online publication 1 September. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30441-7

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