Wijayawardana, Sameera R.

Abstract Background: Combination treatments of CDK4 & 6 inhibitors (CDK4 & 6i) with endocrine therapy (ET) have improved outcomes in patients with HR-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Aside from estrogen receptor positivity (ER+), predictive biomarkers of clinical benefit from CDK4 & 6i in combination with ET remain elusive. We assessed clinical outcomes by genomic alterations detected in baseline circulating tumor DNA (ctDNA) from patients treated with abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) versus placebo plus NSAI in the Phase 3 study MONARCH 3 (NCT02246621). Methods: MONARCH 3 randomized 493 postmenopausal women with HR+, HER2- ABC who had no prior systemic therapy in the advanced setting to treatment with abemaciclib plus NSAI or placebo plus NSAI. Biomarker analysis of baseline ctDNA was an exploratory objective; plasma was 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. Genomic alterations detected in baseline ctDNA were associated with clinical outcomes including progression-free survival (PFS) and objective response rate (ORR). Results: Baseline ctDNA results were available for 295 patients (201 abemaciclib; 94 placebo) with 83% of patients harboring one or more detectable genomic alterations. Commonly altered genes of interest (% frequency) detected in baseline ctDNA included: PIK3CA (38%); TP53 (26%); EGFR (15%); FGFR1 (12%); NF1 (12%); MYC (9%); CCND1 (9%); ESR1 (5%).Overall, patients treated with placebo plus NSAI who harbored detectable ctDNA genomic alterations had shorter median PFS compared to patients without detectable genomic alterations, as shown in the Table (14.9 months [95% CI: 11.0-23.1] vs 19.2 months [95% CI 9.4-NR]). Moreover, genomic alterations in EGFR, FGFR1, MYC, and CCND1 were associated with median PFS <12 months with placebo plus NSAI. However, consistent with the intent-to-treat population, the addition of abemaciclib to NSAI benefitted these genomic subgroups, regardless of ctDNA gene alterations. Additional genomic results, including alterations in cell cycle-associated genes, will be presented. Conclusions: In this exploratory subgroup analysis, the presence of detectable ctDNA genomic alterations was associated with shorter PFS with placebo plus NSAI. Consistently, abemaciclib added to NSAI improved outcomes for genomically identified subgroups. In contrast to prior studies, there was no subgroup (e.g., patients harboring FGFR1 alterations) that did not derive benefit from abemaciclib, supporting the efficacy of abemaciclib, including in difficult to treat tumors. These findings are hypothesis-generating and warrant further investigations in clinical studies of CDK4 & 6i in combination with ET. TableAbemaciclib + NSAIPlacebo + NSAIEvents, n/NMedian PFS (95% CI)Events, n/NMedian PFS (95% CI)Hazard Ratio (95% CI)OVERALLITT population170 / 32828.2 (23.7 - 33.9)123 / 16514.8 (11.2 - 19.2)0.52 (0.42 - 0.66)TR population93 / 20138.7 (31.1 - NR)71 / 9416.5 (11.7 - 23.1)0.45 (0.33 - 0.61)Any Gene AlterationDetected83 / 16634.1 (27.2 - 40.0)62 / 7914.9 (11.0 - 23.1)0.47 (0.34 - 0.66)Not detected10 / 35NR (36.4 - NR)9 / 1519.2 (9.40 - NR)0.31 (0.13 - 0.78)TP53Detected29 / 5327.0 (14.1 - NR)19 / 2315.4 (5.7 - 30.4)0.53 (0.30 - 0.95)Not detected64 / 14839.9 (34.1 - NR)52 / 7117.5 (11.7 - 24.2)0.42 (0.29 - 0.60)EGFRDetected10 / 26NR (32.4 - NR)16 / 1710.9 (2.1 - 24.7)0.20 (0.09 - 0.47)Not detected83 / 17536.4 (27.7 - NR)55 / 7717.6 (14.6 - 25.5)0.52 (0.37 - 0.73)FGFR1Detected15 / 2532.8 (10.1 - NR)10 / 117.6 (1.9 - 15.4)0.37 (0.16 - 0.85)Not detected78 / 17639.9 (31.1 - NR)61 / 8319.2 (14.6 - 26.5)0.45 (0.32 - 0.63)NF1Detected10 / 2435.9 (27 - NR)8 / 1014.6 (1.6 - 33.4)0.33 (0.13 - 0.84)Not detected83 / 17738.7 (30.8 - NR)63 / 8417.5 (11.7 - 24.2)0.47 (0.33 - 0.65)MYCDetected11 / 1720.1 (5.5 - NR)9 / 106.5 (1.2 - 15.7)0.33 (0.13 - 0.86)Not detected82 / 18438.9 (32.9 - NR)62 / 8419.2 (14.6 - 26.5)0.45 (0.32 - 0.63)CCND1Detected8 / 1632.8 (5.5 - NR)10 / 107.2 (3.6 - 9.0)0.28 (0.10 - 0.77)Not detected85 / 18538.7 (31.1 - NR)61 / 8417.6 (14.6 - 25.5)0.48 (0.34 - 0.67)n = number of patients with events; N = total number of patients in the corresponding population and treatment arm; NR = not reached. TR population consists of patients in the ITT population from whom a valid baseline ctDNA result has been obtained. Citation Format: Matthew P Goetz, J. Thaddeus Beck, Mario Campone, Sara Hurvitz, Seock-Ah Im, Stephen Johnston, Antonio Llombart-Cussac, Miguel Martin, Joohyuk Sohn, Masakazu Toi, Lacey M Litchfield, Hillary T Graham, Hong Wang, Sameera R Wijayawardana, Valerie M Jansen, Angelo Di Leo. Efficacy of abemaciclib based on genomic alterations detected in baseline circulating tumor DNA from the MONARCH 3 study of abemaciclib plus nonsteroidal aromatase inhibitor [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 PD2-06.

Abstract Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.