Immunotherapy improves Merkel cell carcinoma, but questions remain.
Although avelumab has changed the treatment landscape, much more needs to be learned about the role of immune checkpoint inhibitors in treatment of Merkel cell carcinoma (MCC), said Mahtab Samimi, M.D., Ph.D., here at the 26th European Academy of Dermatology and Venereology (EADV) Congress in Geneva.
The benefit of avelumab (Bavencio, EMD Serono, Inc.) is currently focused on Merkel cell carcinoma with distant metastases (stage IV), which represents approximately 10 percent of all patients, according to Dr. Samimi, of the University Hospital of Tours, France.
Most MCC patients have local or regional disease and still require standard treatments, including wide excision of the tumor and of affected lymph nodes, if present, followed by adjuvant radiation therapy. But for that stage IV subset of patients, avelumab is changing the course of management.
Until very recently, only cytotoxic drugs, particularly the combination of platinum-based molecules and etoposide, were available for metastatic disease. “These regimens are actually effective, as 50-60 percent of patients respond to such drugs, but the main issue is the rapid occurrence of chemoresistance,” Dr. Samimi said in an interview with Dermatology Times.
Moreover, compared with cytotoxic chemotherapy, avelumab “appears rather safe, which is an important issue in elderly patients,” she said.
The checkpoint inhibitor’s safety profile has been described as “acceptable” by investigators, and prescribing information for the drug notes that most common adverse reactions were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite and peripheral edema. Warnings and precautions for the drug include the risk of immune-mediated pneumonitis, hepatitis, and colitis, among other immune-mediated conditions.
JAVELIN and new data
Avelumab, a programmed cell death protein-1 ligand (PD-L1) blocking monoclonal antibody, is the first drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma (MCC).
The approval, announced in March 2017, was based on data from the open-label, single-arm phase two JAVELIN Merkel 200 trial, in which the drug was administered to 88 patients with progressive disease after a first line of chemotherapy.
Now, there is preliminary data from the ongoing part-B JAVELIN trial assessing avelumab as a first-line therapy in chemo-naïve metastatic MCC patients. The results are still immature but are promising, according to Dr. Samimi, with confirmed responses to treatment seen in 60 percent of patients enrolled.
Nivolumab, another checkpoint inhibitor targeting the PD1/PDL1 axis, is currently investigated in MCC patients (CheckMate - 358 study) and the preliminary data reported during this year's AACR annual meeting were also promising with more than 60 percent of objective responses, Dr. Samimi said.
Other immune strategies are also under investigation, such as adoptive transfer of specific T-cells, NK infusions, and intratumoral delivery of cytokines. “Maybe the future will be the combination of such strategies,” Dr. Samimi said.
Predictive markers of immunotherapy benefit have been identified, but results are inconsistent among tumor types. For example, tumor expression of PD-L1 is considered a predictive biomarker of response to PD1 antagonists in non-small cell lung cancer, but not in melanoma.
Another interesting field of research, according to Dr. Samimi, is tumor immunogenicity, which can be predicted by mutational burden, as high level of mutations lead to expression of neo-antigens.
That said, in the setting of metastatic MCC, data with immunotherapy are “still too sparse to identify any predictive markers,” she said. “Until now, neither the PD-L1 tumoral expression nor the viral status of the tumor have been shown to be associated with response to immunotherapy.”