Mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose expansion results

3027 Background: Mirzotamab clezutoclax (ABBV-155; Mirzo-C) is a first-in-class antibody-drug conjugate with three components: an anti–B7-H3 monoclonal antibody, a solubilizing linker, and a BCL-X L inhibitor payload. By specific targeting of BCL-X L , synergy with other anticancer agents was observed in preclinical models. When combined with a taxane, clinical antitumor activity was reported in relapsed and/or refractory (R/R) solid tumors during the dose escalation phase of an ongoing Phase 1, open-label study (NCT03595059). Methods: In the dose expansion phase of the Phase 1 study, patients were treated as follows: (i) R/R small cell lung cancer (SCLC) with Mirzo-C monotherapy, (ii) non-small cell lung cancer (NSCLC) with Mirzo-C + docetaxel, and (iii) hormone positive, Her2 negative, post–CDK4/6 inhibitor breast cancer (BrCa) with Mirzo-C + paclitaxel. Mirzo-C was administered at the recommended Phase 2 dose determined at dose escalation. Primary objectives were safety and overall response rate (ORR). Results: As of November 18, 2022, 78 patients were enrolled (SCLC n=14; NSCLC n=36; BrCa n=28). The median (range) follow-up was 2.0 (0.6–9.1) months for the SCLC cohort, 4.9 (0.6–8.5) for NSCLC, and 10.4 (0.8–13.3) for BrCa. The median number of prior lines of systemic therapy was 2 in the SCLC cohort, 2 in NSCLC, and 6 in BrCa. Prior taxane therapy was received by 7% of patients in the SCLC cohort, 36% in NSCLC, and 64% in BrCa. The most common adverse events (AEs) in SCLC were fatigue, increased aspartate aminotransferase, diarrhea, and headache (21%, n=3 for each AE); fatigue was the most common AE in NSCLC (58%, n=21; Grade 3/4: 3%, n=1) and in BrCa (61%, n=17). Thrombocytopenia, a result of the systemic effects of BCL-X L inhibitors, was not observed in the Mirzo-C monotherapy cohort. Neutropenia/decreased neutrophil count was not observed in the SCLC monotherapy cohort but was common with BrCa paclitaxel combo (64%, n=18; Grade 3/4: 29%, n=8) and NSCLC docetaxel combo (53%, n=19; Grade 3/4: 44%, n=16); 5 patients in the NSCLC cohort (14%) and 1 in BrCa (4%) had febrile neutropenia. Confirmed ORR was 0% in the SCLC cohort, 11% in NSCLC, and 18% in BrCa. Conclusions: Mirzo-C demonstrated a tolerable safety profile as monotherapy and with taxanes. No thrombocytopenia or neutropenia was observed with monotherapy. No single-agent activity of Mirzo-C was observed in SCLC. Combination treatments were active with high best overall response (BOR) and disease control rates in heavily pretreated NSCLC and BrCa patients, where Grade 3/4 neutropenia was observed. It is unknown if Mirzo-C exacerbated the neutropenia risk associated with taxanes. Clinical trial information: NCT03595059 . [Table: see text]