Early Promise Seen With Combo of Pembrolizumab and Mirvetuximab Soravtansine in Ovarian Cancer

Ursula Matulonis, MD

Ursula Matulonis, MD

A combination regimen of pembrolizumab (Keytruda) and mirvetuximab soravtansine (IMGN853) induced responses in close to half of the patients in a small study of platinum-resistant ovarian cancer .¹In initial results of the ongoing study that were presented at the 2018 Society of Gynecologic Oncology Annual Meeting, 6 of the 14 patients (43%; 95% CI, 18-71) had confirmed partial responses to the PD-1 inhibitor and the antifolate antibody-drug conjugate (ADC) combination. Five of 8 (63%; 95% CI, 25-92) patients who had moderate-to-high levels of folate receptor-alpha expression, the target of the ADC, had responses.

The median progression-free survival (PFS) was 5.2 months (95% CI, 1.6-9.5) in the entire cohort and 8.6 months (95% CI, 1.6-not evaluable) in the moderate-to-high cohort. The median duration of response was 30.1 weeks overall and 36.1 weeks in the patients with medium to high folate receptor-alpha expression.

As a reference point, pembrolizumab monotherapy led to an objective response rate of 11.5% and median progression-free survival (PFS) of 1.9 months in a phase Ib trial involving patients with PD-L1-positive ovarian cancer.²

“Even though this was a small study, we can say that this combination is safe and is clearly active in a very heavily pretreated population,” said first author Ursula Matulonis, MD, medical director and program leader of gynecologic oncology at Dana-Farber Cancer Institute. “Although the primary objectives of the study were safety and tolerability, we observed responses in almost half of the patients, and the responses were durable.

“Honestly, I haven’t been so excited about a new drug for ovarian cancer since olaparib.”

The results supported continued investigation of the combination, which is ongoing in an expansion phase that will accrue an additional 35 patients with moderate-to-high expression of folate receptor-alpha. A phase III trial of mirvetuximab soravtansine monotherapy for patients with platinum-resistant ovarian cancer also is ongoing.

Mirvetuximab soravtansine consists of an antifolate receptor-alpha antibody linked to the microtubulin inhibitor maytansinoid DM4. The agent previously demonstrated a favorable safety profile as well as clinical activity in preliminary clinical studies involving patients with heavily treated ovarian cancer expressing folate receptor-alpha. Evaluations included trials of single-agent therapy, combination therapy with bevacizumab (Avastin) in platinum-resistant disease, and combination therapy with carboplatin in platinum-sensitive ovarian cancer.

Preclinical studies showed that mirvetuximab soravtansine activates monocytes and upregulates immunogenic markers of cell death on ovarian cancer cells. The observations provided a rationale for evaluating the ADC in combination with an immune checkpoint inhibitor.

Matulonis reported findings from a dose escalation-expansion study. Eligible patients had platinum-resistant epithelial ovarian cancer, defined as disease progression from completion of the most recent platinum-containing regimen. The patients had received a median of 4.5 prior systemic regimens.

Investigators defined folate receptor-alpha positivity as ≥25% tumor cell with 2+ staining by immunohistochemistry. Five patients had high expression (≥75% of tumor cells), three had medium expression (50%-74%), and six had low expression (25%-49%).

The first 4 patients received mirvetuximab soravtansine at a dose of 5 mg/kg (adjusted ideal body weight), and the remaining 10 received the phase III dose of 6 mg/kg. All patients received a 200-mg dose of pembrolizumab.

The combination had a manageable toxicity profile, the most common adverse events being fatigue, nausea, diarrhea, and dry eye. No grade 4 adverse events occurred.

Treatment-emergent adverse events were common (13 of 14 patients), but grade ≥3 events were not. The most common grade 3 adverse events were small intestine obstruction (21%), nausea (14%), and vomiting (14%). No other grade 3 events occurred in more than 1 patient.

Enrollment in the expansion phase has begun, said Matulonis. The expansion phase will include enrichment with patients whose tumors exhibit medium- and high-level expression of folate receptor-alpha.

References

1. Matulonis UA, Moore KN, Martin LP, et al. Initial safety and activity findings from a phase 1b escalation study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with pembrolizumab in platinum-resistant epithelial ovarian cancer patients. Presented at: SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Abstract 74.
2. Varga A, Piha-Paul SA, Ott PA, et al. Pembrolizumab in patients (pts) with PD-L1—positive (PD-L1+) advanced ovarian cancer: Updated analysis of KEYNOTE-028. J Clin Oncol.2017;35(suppl; abstr 5513).