Toi, Masakazu

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 Background: Breast cancer incidence and mortality rates are increased in patients’ older than 65 years. However, there are limited reports on age-specific efficacy, safety, and drug tolerability, particularly in elderly patients older than 75 years old. Abemaciclib demonstrated clinically meaningful progression-free survival (PFS) improvement in combination with endocrine therapy (ET) in HR+, HER2- advanced breast cancer patients in the Phase 3 studies, MONARCH 2 and 3. Here we report exploratory subgroup analyses of MONARCH 2 and 3 to provide age-specific outcomes. Methods: In MONARCH 2 (NCT02107703), patients progressing while on prior ET received abemaciclib (or placebo) plus fulvestrant; in MONARCH 3 (NCT02246621), postmenopausal women with no prior systemic therapy for recurrent or metastatic breast cancer received abemaciclib (or placebo) plus letrozole or anastrozole. Exploratory outcome analyses of MONARCH 2 and 3 studies were performed for three age groups (women aged <65, 65-74, and ≥75 years). Using pooled safety data, we performed age-specific subgroup analyses of the most common treatment-emergent adverse events (TEAEs) associated with either ET or ET plus abemaciclib. To assess the impact of age on efficacy, a subgroup analysis of PFS was performed using a Cox model for each trial independently. Results: Pooled safety data were available for 1152 patients treated in MONARCH 2 and 3 trials, including 59.7% pts <65 years, 28.7% pts between 65 and 74 years, and 11.5% pts ≥ 75 years. Of those, 768 women received abemaciclib plus ET and 384 women received placebo plus ET. The most frequent TEAE was diarrhea and the most common Grade ≥3 TEAE was neutropenia. While diarrhea (any grade) occurred with similar incidence in abemaciclib-treated patients across age groups, clinically relevant diarrhea (Grade 2/3) was higher in the elderly (<65, 39.5%; 65-74, 45.2%; ≥75, 55.4%); however, in the ≥75 group, diarrhea (Grade 2/3) incidence was also higher for placebo plus ET (<65, 6.8%; 65-74, 4.5%; ≥75, 16.0%). Similarly, nausea and decreased appetite were moderately higher (by 10-20%) in the 2 abemaciclib-treated elderly subgroups. Fatigue (any grade) was higher in the 2 abemaciclib-treated elderly subgroups (<65, 34.8%; 65-74, 48.4%; ≥75, 51.8%), while no differences were found across the 3 placebo subgroups. In contrast, the rates of Grade 3/4 neutropenia did not differ as a function of age in either the abemaciclib plus ET arm (<65, 25.8%; 65-74, 27.4%; ≥75, 18.1%) or placebo plus ET arm. For efficacy, a consistent PFS benefit was observed with abemaciclib plus ET versus placebo plus ET across all three age-specified subgroups in both studies (Table). Conclusion: Abemaciclib in combination with ET demonstrates a tolerable safety profile and consistent efficacy benefit across all age subgroups examined, supporting the use of this combination in elderly patient populations. Despite the limited number of patients in the ≥75 group with potentially confounding comorbidities, the safety data suggest that patient education and appropriate management of toxicities, including dose adjustments and use of supportive medication for gastrointestinal toxicities, could maximize the benefit of abemaciclib. Table: Age-specified PFS outcomes from MONARCH 2 and 3MONARCH 2MONARCH 3Age GroupAbemaciclib + ETPlacebo + ETHR (95% CI)P-value *Abemaciclib + ETPlacebo + ETHR (95% CI)P-value *Events/NEvents/NEvents/NEvents/N<65140/29192/1330.52 (0.40, 0.68)0.69581/18065/910.48 (0.35, 0.67)0.63465-7461/11442/600.63 (0.43, 0.94)40/10631/540.64 (0.40, 1.02)≥7521/4123/300.62 (0.34, 1.11)17/4212/200.54 (0.26, 1.13)Abbreviations: CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; PFS, progression-free survival.*P-value corresponds to the interaction test between age and treatment. Citation Format: Matthew P. Goetz, Meena Okera, Hans Wildiers, Mario Campone, Eva-Maria Grischke, Luis Manso, Valerie Anne Marie Andre, Amy Lee Chong, Belen San Antonio, Masakazu Toi, George W Sledge Jr. Safety and efficacy of abemaciclib plus endocrine therapy (ET) in elderly patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+, HER2-) advanced breast cancer: An age-specific subgroup analysis of MONARCH 2 and 3 trials [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 P1-19-10.

Abstract Background: Abemaciclib plus nonsteroidal aromatase inhibitors (AI) demonstrated efficacy with a tolerable safety profile as initial treatment for postmenopausal women with HR+, HER2− advanced breast cancer in the MONARCH 3 trial. In the intent-to-treat (ITT) population, the updated progression-free survival (PFS) with 12 months of additional follow-up was 28.2 versus 14.8 months (HR [95% CI]: 0.525 [0.415, 0.665]; p<.0001) in the abemaciclib plus AI versus placebo plus AI arms, respectively. Here we report data from the additional 12 months of follow-up on tumor response for the ITT population and exploratory subgroups previously identified as significantly prognostic (Di Leo et al. 2018). Methods: In MONARCH 3, a randomized, double-blind, phase III trial, 493 postmenopausal women with HR+, HER2− advanced breast cancer and no prior systemic therapy in the advanced setting, received an AI (anastrozole or letrozole) plus abemaciclib or placebo. From the October 31, 2018 cutoff, secondary endpoints including objective response rate ([ORR], complete response [CR] + partial response [PR]), time to response (TTR), and duration of response ([DoR], time from a confirmed CR or PR until disease progression or death) were assessed in the ITT population and exploratory subgroups previously reported as significantly prognostic. Waterfall plots will be used to illustrate the magnitude of change in tumor size for each subgroup (to be presented). Results: In patients with measurable disease, the ORR was 62.5% (95% CI: 56.7, 68.2) in the abemaciclib plus AI arm and 44.7% (95% CI: 36.2, 53.2) in the placebo plus AI arm (p≤.001). Additional follow-up confirmed that all prognostic subgroups received benefit from the addition of abemaciclib to AI, consistent with the ITT population, as evidenced by change in ORR, with the largest effects observed in subgroups of patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or treatment-free interval of <36 months (Table). Median TTR was similar between the two treatment arms (abemaciclib plus AI: 3.62 months; placebo plus AI: 3.65 months), and this was generally consistent across subgroups. Responses were more durable in the abemaciclib plus AI arm (median DoR: 32.71 months; 95% CI: 25.74, -) versus the placebo plus AI arm (median DoR: 17.49 months; 95% CI: 11.61, 22.19), including in poor prognostic subgroups. Conclusions: Extended follow-up in the MONARCH 3 trial further confirmed that the addition of abemaciclib to AI is associated with durable tumor responses, including those in patients with clinically poor prognostic characteristics. References: Di Leo A et al. NPJ Breast Cancer. 2018;4:41. Clinical trial information: NCT02246621 This study was funded by Eli Lilly and Company Table: Objective Response RateAbemaciclib + AIPlacebo + AIORR ChangeNn (%)Nn (%)%Measurable disease population269168 (62.5)13259 (44.7)17.8Liver metastasesYes4727 (57.45)306 (20.00)37.45No222141 (63.51)10253 (51.96)11.55Progesterone receptor statusNegative6137 (60.66)298 (27.59)33.07Positive206130 (63.11)10351 (49.51)13.60Treatment-free interval<36 months3117 (54.84)225 (22.73)32.11≥36 months7442 (56.76)3216 (50.00)6.76Tumor gradeHigh5739 (68.42)2811 (39.29)29.13Intermediate/ Low13992 (66.19)7535 (46.67)19.52ECOG PS111275 (66.96)5022 (44.00)22.96015793 (59.24)8237 (45.12)14.12Bone-only diseaseNo256162 (63.28)12253 (43.44)19.84YesNA*NA*NA*NA*NA*N= total number of patients in each subgroup; n= number of responder patients; NA=not applicable*Response rate not reported for bone-only disease because majority of lesions were not measurable Citation Format: Joyce O’Shaughnessy, Stephen Johnston, Miguel Martin, Jens Huober, Masakazu Toi, Valerie AnneMarie Andre, Holly Rene Martin, Molly Catherine Hardebeck, Angelo Di Leo, Matthew Philip Goetz. Updated subgroup tumor response of abemaciclib plus aromatase inhibitor for hormone receptor positive (HR+), HER2 negative advanced breast cancer (MONARCH 3) [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 P1-19-09.

Background In the phase 3 MARIANNE trial, trastuzumab emtansine (T‐DM1) with or without pertuzumab showed noninferior progression‐free survival and better tolerability than trastuzumab plus a taxane (HT) for the first‐line treatment of human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient‐reported outcomes and biomarker analyses. Methods OS was assessed in 1095 patients with HER2‐positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T‐DM1 plus a placebo (hereafter T‐DM1), or T‐DM1 plus pertuzumab (T‐DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted. Results The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T‐DM1, and T‐DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T‐DM1 (64.4 months) and T‐DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T‐DM1 (47.1%) or T‐DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3‐point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T‐DM1+pertuzumab (4.2 months) than T‐DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T‐DM1 arm. Conclusions These results support T‐DM1 as a first‐line treatment for patients with HER2‐positive metastatic breast cancer who are deemed unsuitable for taxane‐based therapy.

Abstract Background: In the MONARCH 3 trial, abemaciclib plus an aromatase inhibitor (AI) significantly improved progression free survival and overall response rate with a generally tolerable safety profile compared to placebo plus AI. Here we report patient-reported outcomes (PRO) including health-related quality of life (Qol), functioning, and symptoms. Methods: MONARCH 3 was a double-blind, randomized phase III study of abemaciclib or placebo plus an AI in 493 post-menopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer with no prior systemic therapy in the advanced setting. Two European Organization for Research and Treatment of Cancer (EORTC) questionnaires were included: Quality of Life Questionnaire (QLQ)-Core 30 (C30) and the EORTC QLQ-Breast 23 (BR23) that were assessed at baseline, every 2 cycles through cycle 19, then every 3 cycles until treatment discontinuation, and at short-term follow up. Higher scores on functional and health status/QoL outcomes indicate higher/better levels of functioning or health; conversely higher scores on symptom outcomes indicate higher/worse levels of symptom burden. Between-arm comparisons of change from baseline were conducted using mixed model methods. Statistical significance was set at 0.05 and clinical meaningfulness was set at ≥10 points on a 0-100 scale1. Results: PRO completion rates were >91% through cycle 19; duration of treatment was longer for abemaciclib plus AI patients (median number of cycles 19 vs.15). Compared to the placebo arm, diarrhea PRO scores in the abemaciclib arm showed a clinically (18.68 points) and statistically significant (p<0.001) increase/worsening. By-cycle analysis showed group mean diarrhea scores returned to near-baseline levels post-therapy. Other symptom PROs showed statistically significant (<0.05) but not clinically meaningful differences; fatigue (4.96; p=0.004), systemic therapy side effects (4.48, p<0.001), appetite loss (4.03; p=0.034), and nausea/vomiting (2.77; p=0.013). These results were consistent with the investigator-reported treatment emergent adverse events (TEAEs). Several non-symptom results were also statistically significant but not clinically meaningful including global health/health status (-4.36; p=0.003), role function (-4.25; p=0.025), social function (-3.41, p=0.047), and body image (-5.11, p=0.009). No statistically significant between-treatment differences were observed for physical, emotional, and cognitive functioning or for symptoms of pain, dyspnea, insomnia, constipation, or financial difficulties. Conclusions: The addition of abemaciclib to an AI resulted in clinically and statistically significant changes in diarrhea without clinically meaningful differences in other symptom scores. Increased GI-related symptoms were consistent with the manageable, reversible AE profile; the highest symptom burden was reported during early visits. No clinically meaningful differences in global health status or functional scores were observed. ClinicalTrials.gov: NCT02246621 Reference: 1. Osoba D et al. J Clin Oncol 2002;20(14):3106-13. Citation Format: Goetz MP, Johnston S, Martin M, Tokunaga E, Park IH, Huober J, Toi M, Price GL, Boye M, Li L, Forrester T, Gainford C, Gable J, Carter GC, Sood A, DiLeo A. Health-related quality of life in MONARCH 3: Abemaciclib plus an aromatase inhibitor as initial therapy in women with 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 P6-16-01.

Abstract Background: Abemaciclib is an orally administered, selective CDK4 & 6 inhibitor dosed on a continuous schedule. In patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), abemaciclib demonstrated clinical activity as monotherapy in MONARCH 1 and efficacy with a generally tolerable safety profile in combination with fulvestrant in MONARCH 2. At the MONARCH 3 (NCT02246621) interim analysis, abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) significantly improved progression-free survival (PFS) (hazard ratio [HR], 0.543; 95% confidence interval [CI], 0.409, 0.723; p=.000021) and objective response rate (ORR) (measurable disease: abemaciclib arm, 59.2%; placebo arm, 43.8%; p=.004) with a generally tolerable safety profile as initial treatment for HR+, HER2- ABC. Here we present the MONARCH 3 results from the preplanned final PFS analysis. Methods: MONARCH 3 is a double-blind, Phase 3 study of abemaciclib/placebo (150 mg, twice daily continuous schedule) + NSAI (1 mg anastrozole or 2.5 mg letrozole, daily) in postmenopausal women with HR+, HER2- ABC who have had no prior systemic therapy for advanced disease. Endocrine therapy (ET) naïve pts or pts with disease relapse >12 months after (neo)adjuvant ET were randomized 2:1 and stratified by metastatic site (visceral, bone-only, or other) and prior ET (aromatase inhibitor, no ET, or other). The primary objective was investigator-assessed PFS. Additional objectives included ORR, clinical benefit rate (CBR), duration of response (DoR), overall survival (OS), and safety and tolerability. The study was powered to 80% at 1-sided α=.025 assuming a HR of 0.67 in favor of abemaciclib + NSAI, with the final analysis at 240 PFS events. Results: 493 pts were randomized to abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). At the final PFS analysis, 246 PFS events had occurred. Abemaciclib + NSAI significantly extended PFS (HR, 0.540; 95% CI, 0.418, 0.698; p=.000002; median: abemaciclib arm, 28.18 vs placebo arm, 14.76 months). PFS was improved across all subgroups. For pts with measurable disease, the ORR was 61.0% in the abemaciclib arm and 45.5% in the placebo arm (p=.003), and the CBR was 79.0% in the abemaciclib arm and 69.7% in the placebo arm (p=.037). The median DoR was 27.39 months in the abemaciclib arm compared to 17.46 months in the placebo arm. OS was immature at the time of analysis. Adverse events were consistent with previous reports. Conclusions: Abemaciclib + NSAI demonstrated a generally tolerable safety profile and was an effective initial treatment for pts with HR+, HER2- ABC, significantly improving PFS and ORR. Citation Format: Matthew P. Goetz, Miguel Martin, Angelo Di Leo, Seock-Ah Im, Ahmad Awada, Tammy Forrester, Martin Frenzel, Joanne Cox, Susana Barriga, Masakazu Toi, Hiroji Iwata, Stephen Johnston. MONARCH 3: Abemaciclib as initial therapy for patients with HR+, HER2- advanced breast cancer - Results from the preplanned final PFS analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT040.