Intriguing Biomarker Results in Study of Avelumab in Merkel Cell Carcinoma

Howard L. Kaufman, MD, FACS

Responses to treatment with avelumab (Bavencio) monotherapy can increase in certain subtypes of patients with metastatic Merkel cell carcinoma (mMCC), per an analysis of the phase II JAVELIN Merkel 200 trial that was presented during the ASCO-SITC Clinical Immuno-Oncology Symposium.¹Although a predictive biomarker of response to avelumab therapy could not be determined in the analysis, several factors contributing to increased progression-free survival (PFS) rates were defined.

Patients with a lower disease burden showed a median PFS of 7.1 months and the median PFS had not yet been reached in patients with positive PD-L1 expression on their tumor. Both groups exceeded the median PFS of 2.7 months in the overall population.

“In this analysis, we could not definitively define a predictive biomarker to identify patients, although we did see a trend toward better response in patients who did have PD-L1 expression on their tumor,” said lead investigator Howard L. Kaufman, MD, FACS.

Patients with mMCC who had progressed following ≥1 prior line of chemotherapy in the metastatic setting were treated with 10 mg/kg of avelumab every 2 weeks in the phase II JAVELIN Merkel 200 study. The results of the multicenter, single-group, open-label trial were presented at the 2016 ASCO Annual Meeting²and published in theLancet Oncology,and led to breakthrough therapy, fast track, accelerated approval, and orphan drug designations from the FDA for avelumab. The agent received approval on March 23, for the treatment of adult and pediatric patients (≥12 years) with metastatic MCC, including those who have not received prior chemotherapy.

In the trial, 88 patients were treated. Their median age was 72.5 years (range, 33-88), most (73.9%) were male, and 55.7% had an ECOG performance status (PS) of 0, with the remainder having a PS of 1. Enrolled patients were required to have received 1 prior therapy; 26 patients (29.5%) had received 2 prior therapies and 10 (11.4%) had received ≥3 therapies.

Patients were enrolled regardless of their PD-L1 status, but 19 (21.6%) were measured as having PD-L1 expression of ≥5% in the tumor cells by immunohistochemistry. Fifty-five patients (62.5%) were negative for PD-L1 expression and 14 (15.9%) were not evaluable. Enrollment was not dependent on polyomavirus (MCPyV) status, but 46 patients (52.3%) had the virus.

In the overall population, the objective response rate (ORR) was 31.8% (95% CI, 22.3-42.6) with complete responses in 9.1% and partial responses in 22.7%. The median duration of response was not reached, and the 6-month PFS rate was 40%.

“These responses occurred quite rapidly and...the vast majority of patients who respond seem to remain in response,” said Kaufman, associate director for clinical science, Rutgers Cancer Institute of New Jersey. He also noted that avelumab was well tolerated in the trial, with most treatment-related adverse events of grade 1 or 2 and no observed grade 4 or 5 events.

The investigators looked to the subgroups established at baseline to see which patients responded better to the treatment.¹“Now that we have a minimum follow-up of 6 months or more in all the patients, we did a post hoc analysis to see if we could identify potential predictive biomarkers that would help us to better select patients who might benefit from avelumab treatment,” Kaufman said.

In patients who had only received 1 prior systemic therapy, the ORR was higher than that of the overall population (40.4% vs 31.8%), and of patients who had received &ge;2 therapies (40.4% vs 19.4%). Patients with less tumor burden also had a higher ORR of 41.0% (95% CI, 25.6-57.9) compared with 26.3% (95% CI, 13.4-43.1) for those with bulkier tumors. And patients with positive PD-L1 expression had an ORR of 52.6% (95% CI, 28.9-75.6) compared with 23.6% (95% CI, 13.2-37.0) in patients with <5% PD-L1 expression.

Responses to avelumab were durable across all subgroups. The &ge;6-month duration of response rate was 92% for the overall population with similar proportions of responses noted across all subgroups. &ldquo;Avelumab monotherapy showed durable antitumor activity across several of the important subgroups of patients with mMCC in the second-line setting,&rdquo; Kaufman said.

PFS rates did vary by subgroup, with patients who had only received 1 prior therapy demonstrating a median PFS of 3.5 months (95% CI, 2.0-9.7 months) compared with 1.4 months (95% CI, 1.3-2.8) for patients who had &ge;2 prior therapies. Patients with a lower tumor burden showed a much higher PFS rate than patients with a higher tumor burden (7.1 vs 1.4 months). However, patients with positive PD-L1 expression did not reach a median PFS compared with patients with negative PD-L1 expression in their tumor cells who had a median PFS of 1.6 months. No trends were noted based on MCPyV status or primary tumor location.

Although the trend favoring patients with positive PD-L1 expression was of interest, it was not defined as a potential predictive biomarker for patient response to avelumab.

An ongoing multicenter trial is evaluating avelumab monotherapy in the frontline for patients with mMCC, and Kaufman noted that the investigators hope to present findings from this trial at the 2017 ASCO Annual Meeting.

References:

1. Kaufman HL, Russell J, Hamid O, et al. Avelumab in chemotherapy-refractory metastatic Merkel cell carcinoma: subgroup analysis of e cacy. J Clin Oncol. 2017;35(suppl 7S; abstr 80).
2. Kaufman H, Russell JS, Hamid O, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: results of the phase 2 JAV- ELIN Merkel 200 trial. J Clin Oncol. 2016;34(suppl; abstr 9508).