Abstract PD1-11: nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer

Abstract

Background Abemaciclib is a selective CDK4 & 6 inhibitor approved on a continuous dosing schedule for HR+, HER2- advanced breast cancer (ABC) as monotherapy (MONARCH 1) and in combination with endocrine therapy (ET). A previous Phase 1b (NCT01394016) cohort of HR+ ABC patients (pts) demonstrated efficacy of abemaciclib monotherapy (150mg and 200mg Q12H starting dose); given the small sample size and nonrandomized design the impact of the starting dose was unclear. nextMONARCH 1 (NCT02747004) evaluated abemaciclib in 2 monotherapy arms, in a randomized setting. Abemaciclib has been associated with dose-dependent early onset diarrhea that is well managed with antidiarrheal therapy. nextMONARCH 1 also explored the 200mg Q12H abemaciclib dose in combination with prophylactic loperamide to reduce incidence/severity of diarrhea and dose adjustments. A third arm evaluated abemaciclib + tamoxifen as a strategy to overcome endocrine resistance. Methods nextMONARCH 1 is a multicenter, randomized, open-label, Phase 2 study of abemaciclib or abemaciclib + tamoxifen in women with HR+, HER2- ABC who have progressed on or after prior ET and previously received chemotherapy. Pts were stratified by presence of liver metastases and prior use of tamoxifen in the advanced setting. Randomization was 1:1:1 to abemaciclib 150mg Q12H + daily tamoxifen 20mg (Arm A) or abemaciclib 150mg Q12H (Arm B); or abemaciclib 200mg Q12H + prophylactic loperamide (Arm C). Key eligibilities were ≥2 chemotherapy regimens (1-2 administered in metastatic setting), measurable disease and no prior treatment with CDK4 & 6 inhibitors. Primary objective was progression free survival (PFS). Key secondary objectives included objective response rate (ORR), dclinical benefit rate (CBR), and safety. PFS analysis tested superiority of Arm A to C at ∼110 events across the 2 arms assuming a hazard ratio (HR) of 0.667 to achieve ∼80% power. Arm B would be considered non-inferior to Arm C if the observed PFS HR is <1.2. Results 234 pts were randomized to Arms A (n=78), B (n=79) and C (n=77). 166 PFS events have been observed (A: 57; B: 54; C: 55). Median PFS was 9.1 months in Arm A, 6.5 in Arm B and 7.4 in Arm C (A vs C: HR=.815, 95% CI, .556-1.193, p=.293; B vs C: HR=1.045, 95% CI, .711-1.535 p=.811). Investigator-assessed ORR was 34.6%, 24.1% and 32.5% (confirmed ORR: 25.6%, 19.0%, 28.6%) and CBR was 61.5%, 49.4% and 51.9% in Arms A, B and C, respectively. Prophylactic loperamide reduced the incidence and severity of diarrhea (C: 62.3%, Gr 3: 7.8%) compared to MONARCH 1 (90.2%, Gr 3: 19.7%, Dickler et al. 2017) resulting in similar rates of diarrhea with 150mg abemaciclib without prophylaxis (A: 53.8%, Gr 3: 1.3%; B: 67.1%, Gr 3: 3.8%). The adverse event profile across arms was generally consistent with other breast studies of abemaciclib. Conclusions nextMONARCH 1 confirmed single-agent activity of abemaciclib in heavily pretreated pts with HR+, HER2- ABC. Efficacy of abemaciclib monotherapy at 150mg was similar to 200mg. Combining tamoxifen with abemaciclib did not demonstrate a statistically significant improvement in PFS compared to abemaciclib monotherapy. Addition of prophylactic loperamide to abemaciclib 200mg resulted in diarrhea similar to 150mg without prophylaxis. Citation Format: Hamilton E, Cortes J, Dieras V, Ozyilkan O, Chen S-C, Petrakova K, Manikhas A, Jerusalem G, Hegg R, Lu Y, Bear MM, Johnston EL, Martin M. nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-11.

The Emerging Role of Cyclin-Dependent Kinase Inhibitors in Treating Diet-Induced Obesity: New Opportunities for Breast and Ovarian Cancers?

“…Interestingly, three different CDKIs 4/6 have recently been FDA approved for the treatment of lifelong aggressive and refractory HR+, Her2- BC therapy (palbociclib, PD0332991; ribociclib, LEE011; abemaciclib, LY835219) [ 149 , 150 , 151 ]. Several biomolecular pathways induced during the obese condition have been demonstrated to be in common with cancer mechanisms of tumor evasion, prompting the study of CDK inhibitors for the management of obesity disease [ 22 ].…”

CDK4/6 Inhibitors in Hormone Receptor-Positive Metastatic Breast Cancer: Current Practice and Knowledge

“…The study confirmed the single-agent activity of abemaciclib in heavily pretreated patients. The efficacy of abemaciclib monotherapy at 150mg was similar to 200 mg [ 25 ].…”

Landscape of Baseline and Acquired Genomic Alterations in Circulating Tumor DNA with Abemaciclib Alone or with Endocrine Therapy in Advanced Breast Cancer

“…The phase II nextMONARCH trial (NCT02747004) evaluated the safety and efficacy of abemaciclib plus tamoxifen or two different doses of abemaciclib monotherapy (150 or 200 mg) in women with previously treated HR + , HER2 − metastatic breast cancer (MBC) that progressed after prior chemotherapy and ET. In the abemaciclib monotherapy arms, mPFS was similar: 6.5 months in the abemaciclib 150 mg arm and 7.4 months in the abemaciclib 200 mg arm ( 18 ).…”