Phase I study of mirvetuximab soravtansine (MIRV) and rucaparib for recurrent endometrial, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer

Objectives: Preclinical data demonstrated a synergistic and additive effect between rucaparib and taxanes in human sporadic ovarian and endometrial cancer cell lines, with cell line data demonstrating that RNA expression of FOLR1 (folate receptor alpha) positively correlates with BRCA mutation status and with being LOH high. The objective was to estimate the maximally tolerated dose (MTD) and to describe toxicities associated with MIRV and rucaparib in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer. Methods: Patients had to have evidence of folate receptor α (FRα) expression by IHC (≥25% of tumor staining at ≥2+ intensity) on archival tissue or recent biopsy. Using a 3+3 design patients were given MIRV (4, 5, or 6 mg/kg IV every 3 weeks) and rucaparib PO BID (400 mg, 500 mg, or 600 mg) depending on the dose level. A total of 6 additional patients are being enrolled to the expansion cohort. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging every 3rd cycle, using RECIST v1.1 criteria. Results: A total of 88 patients were screened for FRα expression. A total of 16 patients have been enrolled to date; 12 with ovarian cancer and 4 with endometrial cancer, all had high grade serous carcinoma. Median age was 64.5 (range 57-82) with 3 (range 1-9) prior lines of treatment (including 5 with prior PARP inhibitor). Six patients completed DL2 (5/500), however, 2 DLTs with both grade 3 fatigue, and no DLTs at DL1, let us to establish the phase 2 dose at DL1 (MIRV 5 mg/kg IV every 3 weeks and rucaparib 400 mg PO BID). Treatment related toxicities (all grades) occurring in ≥25% of patients included fatigue (73%), nausea (67%), blurred vision (60%), anemia (47%), anorexia (47%), mucositis (40%), ALT/AST elevated (40%), dry eyes (33%), vomiting (27%), thrombocytopenia (27%), weight loss (27%), leukopenia (27%), dysgeusia (27%). Grade ≥3 toxicities were fatigue (20%), pneumonitis (13%), anemia (13%), diarrhea (7%), cataract (7%), lymphopenia (7%), thrombocytopenia (7%), weight loss (7%), hypokalemia (7%). A total of 12 patients are currently evaluable for response (updated results will be presented if accepted); 5 (33%) partial response, 1 (7%) unconfirmed partial response, 6 (40%) stable disease. The ORR was 6/12 (50%). 44% (4/9) in ovarian cancer and 67% (2/3) in endometrial cancer. Median FRα expression was 80% (70 for PR, 95 for SD; range 30-100). Median PFS is 6.3 months with 95% CI (0.7, 13.8) months. Among 6 responses, 1 progressed, 1 died, 4 are censored, thus the median duration of response is not reached. Conclusions: Combination rucaparib and MIRV was tolerable with mostly manageable side effects. Encouraging activity was seen in this heavily pretreated population (including prior PARPi) of both endometrial and ovarian cancer. Notably, two patients developed pneumonitis (AESI for both agents) grade ≥3 after 14 and 24 cycles of treatment, respectively, each with a prolonged PR. Close monitoring for delayed side effects remains critically important especially in those with prolonged therapy.