Abstract P3-11-05: A phase Ib multi-cohort study of xentuzumab and abemaciclib in patients (pts) with solid tumors and breast cancer (BC) - Initial report of four dose-finding cohorts
Authors: Yee Douglas , Oliveira Mafalda , Iwata Hiroji , Gonçalves Anthony , García-Corbacho Javier , Sablin Marie Paule , Prat Aleix , Hardebeck Molly Catherine , Puig Marta , Huang Dennis Chin-Lun , Hsu Mingchi , LoRusso Patricia 
Published: March 2020

Abstract
Background: Insulin-like growth factor receptor-1 (IGF-1R) signaling is implicated in cancer progression, prognosis, and treatment resistance. Cross-talk between IGF-1R signaling and cyclin-dependent kinase (CDK) 4 & 6 was reported in preclinical studies, and synergy was shown with concurrent inhibition of IGF-1R signaling and CDK 4 & 6. The CDK 4 & 6 inhibitor, abemaciclib, is FDA approved for hormone receptor-positive [HR+], HER2- advanced BC (ABC) in combination with an aromatase inhibitor as initial endocrine-based therapy, with fulvestrant for progression following endocrine therapy (ET), and as monotherapy for progression following ET and prior chemotherapy in the metastatic setting. NCT03099174 is a prospective, open-label study investigating the safety and tolerability of concurrent inhibition of IGF/IGF-1R signaling with the IGF-1/2-neutralizing monoclonal antibody, xentuzumab, plus abemaciclib (provided by Eli Lilly), with or without ET. Methods: 4 dose-finding cohorts were evaluated in 2 parts using a Bayesian Logistic Regression Model with overdose control, fitted to toxicity outcomes. Part 1 (Cohort A) included pts with solid tumors who had failed/were intolerant of prior treatments, or had no other option available. The starting dose was xentuzumab 1000 mg i.v. weekly plus abemaciclib 150 mg orally (p.o.) every 12 h (Q12h). Part 1 determined the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) prior to starting Part 2. Part 2 included postmenopausal women with HR+, HER2- BC who had received 0-2 prior lines of chemotherapy in the metastatic setting and were eligible for ET. One of 3 ETs was combined with xentuzumab plus abemaciclib (doses determined in Part 1): Cohort B, letrozole; Cohort C, anastrozole; Cohort D, fulvestrant. Previous CDK 4 & 6 inhibitor therapy was not permitted. Treatment was given until progression, lack of tolerability, or withdrawal. Primary endpoints were MTD and dose-limiting toxicities (DLTs) during the first 28-day cycle. Tumor response and progression-free survival (PFS) were also assessed. Results: 27 pts were treated (26 female [96.3%]; median age, 58 years [range 34-70]); 9 pts remained on treatment at the time of analysis. Cohorts A/B/C/D included 6/7/6/8 pts. Cohort A included pts with ABC (n=3), and lung cancer, sarcoma, and colorectal cancer (n=1 each). In total, 23 pts were evaluable for MTD. MTD was xentuzumab 1000 mg i.v. weekly plus abemaciclib 150 mg p.o. Q12h in Cohorts A, B, and D (Cohort C is ongoing). During Cycle 1, 4 DLTs were reported (Cohort A: grade 3 neutrophil count decrease, n=1; Cohort B: grade 3 neutrophil count decrease, n=1; Cohort C: grade 4 thrombocytopenia, n=1; Cohort D: grade 3 neutropenia, n=1). The most common drug-related AEs (DRAEs) in Cohort A were diarrhea and decreased appetite (66.7% each), and nausea, vomiting, and asthenia (50% each). The most common DRAEs in Cohorts B/C/D were diarrhea (90.5%), asthenia (66.7%), anemia (61.9%), neutropenia (57.1%), and nausea (52.4%). Most were reversible and grade 1/2. The most common grade 3/4 DRAEs were diarrhea (16.7/0%) in Cohort A, and neutropenia (19.0/14.3%) and diarrhea (14.3/0%) in Cohorts B/C/D. 4 pts had a best overall response of partial response (Cohorts A and B, n=1; Cohort D, n=2) and 10 pts had stable disease (Cohort A/B/C/D, n=1/3/1/5; duration currently &lt;24 weeks). Median PFS (95% CI) was 1.7 (1-7.3) months in Cohort A and 12.4 (3.5-not calculable) months in Cohorts B/C/D. Conclusions: The MTD and RP2D of xentuzumab was 1000 mg i.v. weekly plus abemaciclib 150 mg p.o. Q12h with or without ET. The safety profile of xentuzumab in combination with abemaciclib, with or without ET, was tolerable and manageable, with no new safety signals. Expansion cohorts for xentuzumab plus abemaciclib and fulvestrant in HR+ HER2- BC are ongoing.
Citation Format: Douglas Yee, Mafalda Oliveira, Hiroji Iwata, Anthony Gonçalves, Javier García-Corbacho, Marie Paule Sablin, Aleix Prat, Molly Catherine Hardebeck, Marta Puig, Dennis Chin-Lun Huang, Mingchi Hsu, Patricia LoRusso. A phase Ib multi-cohort study of xentuzumab and abemaciclib in patients (pts) with solid tumors and breast cancer (BC) - Initial report of four dose-finding cohorts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-05.