ESMO @ ECC 2015: Blocking PD1 Shows Promise in Merkel Cell Carcinoma
First systemic intervention with pembrolizumab in Merkel cell carcinoma shows high response rate
Five confirmed and 3 unconfirmed responses were observed in patients receiving pembrolizumab, a blocking anti-PD-1 monoclonal antibody, for Merkel cell carcinoma (MCC), according to phase II study results reported at the European Cancer Congress (ECC 2015), convening in Vienna, Austria, 25 - 29 September 2015.
The responses are especially noteworthy given the difficulty in treating MCC, which often evades the patient’s immune response. MCC is a rare but aggressive skin cancer linked to UV light exposure and the very common Merkel cell polyomavirus.
Durable responses to chemotherapy in the metastatic setting are not often achieved, with progression-free survival rates of around 90 days commonly observed.
However, MCC tumours express PD-L1, leading investigators to reason that this may provide an immunotherapeutic target, which could make MCC responsive to PD1 blockade.
Trial design includes expansion of patient cohort
On 27 September, during the proffered papers session ‘Melanoma and Skin Cancer’, UW Medicine dermatologist Fred Hutchinson and Cancer Research Center scientist Paul Nghiem, Seattle, USA, presented findings on behalf of colleagues from the Cancer Immunotherapy Trials Network (CITN) and the NCI’s Cancer Therapy Evaluation Program (CTEP).
The CITN conducted this phase II trial to determine whether blocking the PD-1 pathway has therapeutic potential in advanced MCC. At the ECC, findings from a longer follow-up and correlative studies, including tumour viral status, anti-viral immune responses, and other immune markers from tumour biopsies were presented.
The trial was planned as an open-label, single arm, Simon two-stage trial that could expand to include 24 patients if at least one response was observed among the first 9 patients. Adults with advanced, unresectable MCC that had not received previous systemic treatment were eligible. Patients were also required not to be immune suppressed or have autoimmune disease, and to have good ECOG performance status.
First radiologic and clinical evaluation shows response to pembrolizumab
This ongoing trial enrolled 18 patients who received pembrolizumab at 2 mg/kg every 3 weeks, with response (RECIST 1.1) assessments done every 9-12 weeks.
At least one radiologic and clinical response assessment has been done thus far in 10 of the patients enrolled, which revealed one patient has achieved complete response (CR), and one patient has an unconfirmed CR (uCR). Partial response (PR) was observed in 4 patients and 2 patients have an unconfirmed PR. Two patients experienced disease progression and discontinued the study.
The remaining 8 patients have not yet had initial scans; of these, 3 patients with clinically measurable disease showed regression of clinically evaluable lesions following pembrolizumab, although visceral disease status awaits radiologic evaluation.
Adverse events included grade 4 myocarditis in one patient after the first dose, and one patient had grade 4 transaminase elevation after receiving 2 doses; both patients improved after the study drug was discontinued and steroids were given.
Interestingly, both of these patients demonstrated favourable tumour responses, with one patient showing regression of skin metastases, while the other patient continues to show an ongoing PR of extensive visceral metastases.
Dr Caroline Robert who discussed the study results underlined the high medical needs for orphan diseases such as Merkel cell carcinoma. She said that the high objective response rate was seen in the presented study. Carefully planned translational research may add to the importance of the findings. Phase II immunotherapy study has just finished recruitment with another immunotheraputic agent, anti-PDL-1 antibody in pre-treated patients.
The authors pointed out that this is the first report of PD-1 blockade in Merkel cell carcinoma. They noted that among the 10 patients evaluated receiving pembrolizumab monotherapy as the first systemic intervention, 8 have shown evidence (5 confirmed and 3 unconfirmed by subsequent scans) of response to PD-1 pathway blockade and 3 of 3 additional patients with clinically evaluable metastases have shown clinical regression of tumours (prior to first scan). Of the 18 patients enrolled, 14 continue to receive anti-PD-1 on trial.
The investigators speculated that this high response rate may in part be due to the immune response to antigens from the polyomavirus that often drives MCC.
The authors concluded that reporting these data may benefit patients with this aggressive cancer by encouraging accelerated clinical testing of PD-1 pathway blocking agents in MCC.
22LBA Activity of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell carcinoma