Avelumab Shows Antitumor Activity in Mismatch Repair-Deficient Endometrial Cancer

Panagiotis A. Konstantinopoulos, MD, PhD

Panagiotis A. Konstantinopoulos, MD, PhD

Avelumab (Bavencio) demonstrated promising efficacy in treating patients with mismatch repair—deficient (MMRD) endometrial cancer, according to the results of a phase II study published in theJournal of Clinical Oncology.

The response rate was 26.7% (95% CI, 7.8%-55.1%) and the progression-free survival rate (PFS) at 6 months (PFS6) was 40.0% (95% CI, 16.3%-66.7%). Responses were observed regardless of PD-L1 expression.

“…Our study findings indicate MMRD by immunohistochemistry correlates with response to avelumab in endometrial cancer, with responses observed in patients who lacked PD-L1 expression and in those with multiple prior lines of therapy and either somatic or germline origin of the MMRD,” the study authors, led by Panagiotis A. Konstantinopoulos, MD, PhD, wrote in their report. The authors noted that the study had been initiated before the tumor-agnostic approval for pembrolizumab (Keytruda) in patients with MMRD solid tumors.

The investigators assessed the use of the PD-L1 inhibitor avelumab among patients with recurrent or persistent endometrial cancer. Patients were divided between 2 cohorts including one for those who had MMRD and polymerase ε (POLE)—mutated disease and another for those with hypomutated, mismatch repair–proficient (MMRP) disease. The primary endpoint of the trial was PFS6 and second endpoints included PFS, overall survival, and safety.

Patients were required to have received at least 1 prior chemotherapy treatment, but there was no upper limit to the number of prior treatment regimens. Additionally, patients had an ECOG performance status of 0 or 1, availability of tumor tissue, and normal organ and marrow function. Those who had received a prior immune checkpoint inhibitor or had known brain metastases were excluded from the trial.

MMRD was assessed by immunohistochemical loss of expression or presence of at least 1 of the mismatch repair genes (MSH2, MSH6, MLH1,andPMS2).POLEmutation status was assessed using targeted-panel next-generation sequencing.

Sixteen patients were enrolled into the MMRP cohort before it was closed for futility and 15 patients were included in the MMRDcohort. NoPOLEmutations were identified in either patient cohort.

A majority of the patients (64.5%) had endometrioid histology and stage I disease (41.9%). Additionally, most patients (41.9%) had received at least 3 prior treatment regimens. Seven patients (28%) had PD-L1 positive expression by tumor proportion score (TPS) ≥1. In the MMRD cohort, 9 patients (60%) hadMLH1promoter hypermethylation and 3 (20%) had a germline mutation.

One patient in the MMRD cohort achieved a complete response and 3 others had partial responses. Additionally, 1 patient achieved a partial response in the MMRP cohort. Stable disease was achieved by 4 patients in the in the MMRD cohort and 4 in the MMRP cohort. In the MMRP cohort, the response rate was 6.25% (95% CI, 0.16%-30.2%) and the PFS6 rate was 6.25% (95% CI, 0.16%-30.2%). When MMRD tumors were assessed by Oncopanel, the objective response rate was 30% and the PFS6 rate was 50%.

Of note, all 4 objective responses and 5 of 6 PFS6 responses in the MMRD cohort were seen in patients who had received at least 3 prior lines of therapy (P= .011). Additionally, all of the objective responses and 5 of the 6 PFS6 responses were in patients with PD-L1—negative tumors. Neither tumor mutational burden nor tumor-infiltrating lymphocytes correlated with response to treatment.

“The finding that all objective responses and all but one PFS6 responses were observed in patients with three or more lines of therapy is intriguing and requires independent validation,” the study authors said.

“Ample evidence indicates that cytotoxic chemotherapy, radiation therapy, and targeted therapies have immunomodulatory effects and may prime tumors to respond to immune checkpoint blockade via several mechanisms, including activation of type I interferon response and upregulation of PD-L1.”

The median PFS after a median follow-up of 18.6 months (range, 4.4-22.2) was 4.4 months (95% CI, 1.7-not reached) in the MMRD cohort and 1.9 months (95% CI, 1.6-2.8) in the MMRP cohort. The median overall survival was not reached in the MMRD cohort and was 6.6 months (95% CI, 2.0-10.2) in the MMRP cohort. Four patients were still receiving treatment as of the data cutoff.

When the investigators reviewed the MMRD tumors that did not respond to avelumab treatment, they found that 3 of the tumors had 2 mutations inJAK1orB2M.The study authors noted that this could reflect biallelic inactivation of the genes, which could be associated with resistance to checkpoint inhibitors.

Treatment-related adverse events (TRAEs) of any grade were seen in 71% of patients and grade 3 TRAEs were observed in 19.4%. The most common TRAEs were fatigue (35.5%), nausea (16.1%), hypothyroidism (12.9%), and neutrophil count decrease (12.9%).

The study authors concluded that a phase II trial is ongoing to explore the combination with avelumab with Talazoparib among patients with MMRP and non—POLE-mutated endometrial cancer to explore alternative approaches for these patients.

Reference:

Konstantinopoulos PA, Luo W, Liu JF, et al. Phase II study of avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial cancer [published online August 28, 2019].J Clin Oncol.doi: 10.1200/JCO.19.01021.