Abstract 785: Genomic markers of response to monotherapy abemaciclib in the nextMONARCH 1 study
Authors: Hamilton Erika P. , Cortes Javier , Jerusalem Guy , Kaufman Peter A. , Ozyilkan Ozgur , Hegg Roberto , Litchfield Lacey M. , Wang Hong , Graham Hillary T. , Wijayawardana Sameera R. , Jansen Valerie M. , Martin Miguel 
Published: September 2020

Abstract
Background: Clinical data characterizing the genomic markers of response to single agent CDK4 & 6 inhibitors are lacking. Abemaciclib is the only CDK4 & 6 inhibitor indicated as monotherapy for HR+, HER2- advanced breast cancer (ABC) following progression on endocrine therapy (ET) and prior chemotherapy (CT) in the metastatic setting. We explored the genomic alterations detected in baseline circulating tumor DNA (ctDNA) from patients (pts) treated with abemaciclib monotherapy in the nextMONARCH 1 study.
Methods: nextMONARCH 1 (NCT02747004) was a Phase 2 study evaluating abemaciclib or abemaciclib + tamoxifen in women with HR+, HER2- ABC who had progressed on or after prior ET and had previously received CT. Pts (n=234) were randomized to abemaciclib 150 mg Q12H + daily tamoxifen 20mg (n=78), abemaciclib 150 mg Q12H (n=79), or abemaciclib 200 mg Q12H + prophylactic loperamide (n=77). Available baseline plasma samples for pts in the abemaciclib monotherapy arms (n=146; 94%) were analyzed by the Guardant360 next-generation sequencing (NGS)-based assay to identify potential tumor-related (i.e., somatic) genomic alterations including point mutations (SNV), indels, amplifications, and fusions in over 70 cancer-related genes.
Results: The majority of pts (91%) receiving abemaciclib monotherapy had at least one genomic alteration detected in baseline ctDNA. The intent to treat population and the translational research population had similar treatment benefit (7.4 mos [95% confidence interval, CI: 5.5, 9.1] versus 7.4 mos [CI: 5.5, 9.1], p=0.945). The most frequently altered genes detected in baseline ctDNA included: ESR1 (41%), PIK3CA (35%), TP53 (29%), FGFR1 (23%), GATA3 (20%), and MYC (20%). Overall, pts with any detectable ctDNA genomic alterations generally had a shorter median progression-free survival (mPFS) compared to pts without any detectable genomic alterations (6.8 mos [CI: 5.2, 9.0] versus 12.0 mos [CI: 5.4, 23.9], p=0.099). In particular, genomic alterations in PIK3CA, TP53, FGFR1, MYC, NF1, EGFR, ERBB2, or CCNE1 were associated with a significantly shorter mPFS in this heavily pretreated pt population. Pts with detected alterations in RB1 or ESR1 trended towards a shorter mPFS, while pts with detected alterations in GATA3 trended towards a longer mPFS.
Conclusions: To our knowledge, this is the first exploratory study to evaluate the genomic markers of response to monotherapy CDK4 & 6 inhibitor in a heavily pretreated pt population with HR+, HER2- ABC. These results provide insight into the genomic landscape of ABC and, if validated, could inform further trials of CDK4 & 6 inhibitors.
Citation Format: Erika P. Hamilton, Javier Cortes, Guy Jerusalem, Peter A. Kaufman, Ozgur Ozyilkan, Roberto Hegg, Lacey M. Litchfield, Hong Wang, Hillary T. Graham, Sameera R. Wijayawardana, Valerie M. Jansen, Miguel Martin. Genomic markers of response to monotherapy abemaciclib in the nextMONARCH 1 study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 785.