Mirvetuximab Soravtansine Plus Pembrolizumab Makes a Splash in pMMR/MSS FRalpha+ Endometrial Cancer

The combination of mirvetuximab soravtansine (Elahere) and pembrolizumab (Keytruda) led to responses, some of which proved durable in patients with recurrent or persistent, folate receptor a (FRa)-positive mismatch repair–proficient (pMMR)/microsatellite stable (MSS) serous endometrial cancer, according to findings from a single-arm, two-stage, investigator-initiated phase 2 trial (NCT03835819) that were presented at the 2024 AACR Annual Meeting.

At a median follow-up of 4.7 months, the objective response rate (ORR), including confirmed and unconfirmed responses, was 37.5% (n = 6). Responses varied and included 1 complete response (CR; 6.3%), 3 confirmed (18.8%) and 2 unconfirmed (12.5%) partial responses (PRs), 5 cases of stable disease (31.3%), and 4 cases of progressive disease (25.0%). One patient (6.3%) was not evaluable.

“Mirvetuximab soravtansine plus pembrolizumab exhibited evidence of clinical activity in recurrent pMMR/MSS FRa-positive serous endometrial cancer,” Rebecca L. Porter, MD, PhD, a medical oncologist and an active translational and clinical researcher in the Gynecologic Oncology Program in Dana-Farber Cancer Institute’s Susan F. Smith Center for Women's Cancers in Boston, Massachusetts, said in a presentation of the data. “Prespecified criteria were met to be worthy of further evaluation in this patient population.”

To be eligible for enrollment patients had to have histologically confirmed advanced or recurrent serous endometrial cancer with pMMR/MSS status and FRa PS2+ no less than 50% on Ventana assay; RECIST v1.1 measurable disease; at least 1 but no more than 4 prior lines of chemotherapy; and an ECOG performance status of 0 or 1. Prior anti–PD-(L)1 therapy was allowed in 19 of 35 patients.

Imaging was performed every 2 cycles and treatment was continued until disease progression or unacceptable toxicity for a maximum of 35 cycles.

In the trial 16 patients were enrolled into stage 1, wherein mirvetuximab soravtansine was administered at 6 mg/kg for adjusted ideal body weight plus 200 mg of pembrolizumab every 3 weeks. An interim assessment was then performed to determine the patients who could proceed to stage 2.

The study employed a two-stage design with co-primary end points of ORR and progression-free survival (PFS) at 6 months. Per the statistical design, type 1 and type 2 errors were limited to 0.1 and 0.15, respectively.

Prescreening results indicated that of the 143 patients screened for FOLR1 expression and 134 with interpretable findings, 44 (32.8%) were FOLR1 positive. The median FOLR1 PS2+ expression level was 30%; 20 patients had a FOLR1 PS2+ expression level of 75% or greater.

Between December 2019 and November 2023, 16 patients were enrolled to the study, 15 of whom were deemed evaluable. The one patient not evaluable withdrew from the study for non–adverse effect (AE) reasons after receiving 3 doses of the study regimen. The data cutoff for the analysis was November 22, 2023, after which an additional 2 patients had been treated with the combination therapy.

Baseline patient characteristics revealed that the median patient age was 67.2 years (range, 62.7-78.5). Most patients were White (81.3%) and had an ECOG performance status of 0 (n = 10). The majority of patients had received between 3 and 4 prior lines of therapy (n = 9; 56.3%), not including anti–PD(L)1 therapy (n = 10; 62.5%). Stage at diagnosis was evenly spread between stage I (n = 5; 31.3%), III (n = 6; 37.5%), and IV (n = 5; 31.3%). The median FOLR1 PS2+ staining level was 76 (range, 50-98); 6 and 10 patients had expression levels between 50% and 74% and 75% and 100%, respectively.

Additional results indicated that the 6-month PFS rate was 16.2% (95% CI, 2.6%-40.2%). Notably two patients, both of whom had not received prior immunotherapy, experienced prolonged response with the combination. The first patient experienced CR for over 18 months with continuing clinical benefit following treatment cessation for grade 2 pneumonitis and grade 3 adrenal insufficiency. The second patient experienced PR for 11.3 months.

Regarding safety, no new signals were identified. The most common any-grade AEs listed in order of frequency were increased aspartate aminotransferase, fatigue, nausea, diarrhea, blurred vision, anorexia, anemia, decreased platelet count, increased alanine aminotransferase, pneumonitis, peripheral sensory neuropathy, increased creatinine, pruritus, maculopapular rash, headache, decreased neutrophil count, decreased lymphocyte count, fever, vomiting, keratitis, and dry eye.

Autoimmune toxicities were limited to grade 2 and 3 and included diarrhea (n = 2 vs 0, respectively), pneumonitis (n = 2 vs 0), acute kidney injury (n = 1 vs 1), maculopapular rash (n = 1 vs 0), adrenal insufficiency (n = 0 vs 1), and hyperthyroidism (n = 1 vs 0).

Regarding dose adjustments, 6 (37.5%) patients who received the 5 mg/kg dose of mirvetuximab soravtansine required a dose reduction as did 3 (18.8%) patients who received the 4 mg/kg dose of the agent. Dose holds for mirvetuximab soravtansine and pembrolizumab occurred in 6 (37.5%) and 4 (25.0%) patients, respectively. Dose discontinuations due to mirvetuximab soravtansine and pembrolizumab-related AEs occurred in 2 (12.5%) and 1 (6.3%) patient, respectively.

An exploratory analysis to identify biomarkers of response and resistance was also performed. However, responses did not appear to be driven by FOLR1 expression, though Porter cautioned that this was a small cohort. Additional markers such as FOLR1 expression across metastatic tumor sites, tumor mutational burden and somatic alterations from next-generation sequencing, estrogen receptor, WT-1, and immune profiling of the tumor microenvironment will be analyzed.

“Studies to identify biomarkers associated with prolonged response are ongoing, but additional approaches to prolong response to this combination are needed,” Porter concluded.

Disclosures: GSKIC

Reference

Porter R, Xiong N, Tayob N, et al. A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT008.