O’Shaughnessy, Joyce

TPS1125 Background: Despite the many available treatments for patients (pts) with HR+, HER2– recurrent/metastatic breast cancer (MBC), optimal treatment after progression on CDK4/6 inhibitors (CDK4/6i) is unclear. One possible CDK4/6i resistance mechanism is increased expression of Aurora kinase A (AURKA), a key mitosis regulator associated with poor prognosis. Further implicated in CDK 4/6i resistance, high c-Myc or RB1 loss of function (LOF) are associated with transcriptional co-regulation or synthetic lethality, respectively, with AURKA. Alisertib is a highly selective, reversible, ATP-competitive, orally administered, small-molecule AURKA inhibitor with antiproliferative activity in HR+ BC-derived cell lines and BC xenograft models. Models with elevated AURKA or c-Myc expression, or RB1 LOF show greater alisertib sensitivity. Alisertib had activity in phase 1 and 2 trials, including objective response rates (ORRs) of 19.6–20% and median progression-free survival (PFS) of 5.4–5.6 months alone or with fulvestrant in pts with HR+/HER2–, endocrine-resistant MBC. The most common treatment-related grade ≥3 adverse events (AEs) were neutropenia, anemia, and leukopenia. Methods: ALISCA-Breast1 (NCT06369285) is a randomized phase 2 study. Primary objective: to determine the optimal alisertib dose administered with endocrine therapy (ET) based on AEs and serious AEs per CTCAE v5.0 and efficacy (ORR, duration of response, disease-control rate, PFS, overall survival). Secondary objectives: to identify biomarkers of efficacy and alisertib pharmacokinetics (PK). Key inclusion criteria: ≥18 years; ECOG performance status 0 or 1; confirmed HR+, HER2–, recurrent/metastatic breast adenocarcinoma not amenable to curative therapy; available tumor tissue for biomarker analyses; progression on or after ≥2 prior ET lines in recurrent/metastatic setting; prior CDK4/6i with ET in recurrent/metastatic setting. Key exclusion criteria: prior chemotherapy in recurrent/metastatic setting; prior AURKA-specific or pan-Aurora-targeted agents; unstable brain metastases. Eligible pts will be randomized 1:1:1 to alisertib 30 mg, 40 mg, or 50 mg orally twice daily on days 1−3, 8–10, and 15–17 every 28 days, plus physician’s choice of anastrozole, letrozole, exemestane, fulvestrant, or tamoxifen not previously used in recurrent/metastatic setting or progressed upon in adjuvant setting; ≤50 pts will be enrolled per arm in the USA and Europe. All pts will undergo sparse PK sampling. Tumor tissue will be centrally assessed for biomarkers, including RB1, MYC, TP53, ESR1, PI3K/AKT pathway, HER2 and AURKA genomic alterations/expression levels. The study will determine the optimal alisertib dose to combine with ET and may identify biomarker(s) defining pts with the greatest benefit from alisertib-based therapy. Clinical trial information: NCT06369285 .

Abstract The Phase 2 IMPRIME 1 study evaluated the combination of the pathogen-associated molecular pattern (PAMP) Imprime with the immune checkpoint inhibitor (ICI) pembrolizumab as second or later line of treatment (2 L+) for patients with metastatic triple-negative breast cancer (mTNBC). Eligible patients with mTNBC received weekly Imprime (4 mg/kg) intravenously in combination with pembrolizumab (200 mg every 3 weeks). Primary endpoints were overall response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression free survival (PFS), and overall survival (OS). Exploratory endpoints included correlations between immune cell activation markers in tumor tissues and blood and response to therapy. Of the 42 evaluable patients, six had a response (one complete, five partial), with an ORR of 14.3% by RECIST v1.1. Median PFS was 2.7 months, median OS was 16.4 months, and DCR was 54.8%, with responders achieving a median DoR of 15.2 months. Therapy was generally well tolerated and resulted in an increase of immune activation markers, with higher levels of activation in peripheral blood associated with response and improved survival. The combination of Imprime and pembrolizumab was safe and demonstrated immune activation in tumor tissues and peripheral blood in patients with TNBC. Improved response rates were observed compared to historical studies of ICI monotherapy in similar patient populations. Study number (ClinicalTrials.gov trial registration): NCT02981303.

Abstract Background: Abemaciclib is approved both for high-risk early breast cancer as well as advanced breast cancer (ABC) in the first- and second-line setting. In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with HR+, HER2- ABC with disease progression on prior endocrine therapy (ET). In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) significantly improved PFS (HR, 0.540; 95% CI, 0.418-0.698; p=0.000002) as initial therapy in HR+, HER2- ABC. At the last interim OS analysis (~252 events, at 5.8 years follow-up [FU]), a numerically favorable median OS difference (12.6 months) was observed (HR, 0.754; 95% CI, 0.584-0.974; p=0.0301, non-significant [NS]). Here, we present the final OS analysis of MONARCH 3 (NCT02246621). Methods: MONARCH 3 is a randomized, double-blind, Phase 3 study of abemaciclib + NSAI (anastrozole or letrozole) vs placebo + NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. OS was a gated secondary endpoint and chemotherapy-free survival (CFS) an exploratory endpoint. Final OS analysis was planned after approximately 315 OS events had occurred in the intent-to-treat (ITT) population with a split alpha between the ITT population and the subgroup with visceral disease (sVD) according to a prespecified graphical testing scheme. Kaplan-Meier method and stratified Cox proportional hazards models were used for time-to-event analyses. All reported p-values are two-sided. Results A total of 493 women were randomized 2:1 to receive abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). After a median FU of 8.1 years, 7% of patients were still receiving treatment in the abemaciclib arm vs 3% in the placebo arm. In the ITT population, 314 OS events were observed (198 deaths among 328 patients [60%] in the abemaciclib arm and 116 among 165 [70%] in the placebo arm; HR, 0.804; 95% CI, 0.637-1.015; p=0.0664, NS). Median OS was 66.8 months in the abemaciclib arm and 53.7 months in the placebo arm, a numerical difference of 13.1 months in the ITT population. In the sVD, 178 events were observed (113 deaths among 173 patients [65%] in the abemaciclib arm and 65 among 90 [72%] in the placebo arm; HR, 0.758; 95% CI, 0.558-1.030; p=0.0757, NS). Median OS was 63.7 months in the abemaciclib arm and 48.8 months in the placebo arm, a numerical difference of 14.9 months in the sVD. Consistent OS differences were observed across prespecified subgroups. PFS benefit was sustained (median 29.0 vs 14.8 months; HR, 0.535; 95% CI, 0.429-0.668; nominal p<0.0001) with substantial difference in 6-year PFS rates (23.3% vs 4.3% for abemaciclib vs placebo). CFS was also improved with abemaciclib vs placebo (median 46.7 vs 30.6 months; HR, 0.693; 95% CI, 0.557-0.863; nominal p=0.0010). No new safety signals were observed with longer term use. Conclusion In patients with HR+, HER2- ABC, abemaciclib in combination with a NSAI resulted in numerically longer OS compared to NSAI alone; however, statistical significance was not reached after a median FU of 8.1 years. The clinically meaningful improvement in median OS (>13 months) combined with the sustained significant improvement in median PFS (>14 months) and substantial extension in median CFS (>16 months) continue to support the use of abemaciclib in combination with NSAI as first-line therapy in ABC. Citation Format: Matthew Goetz, Masakazu Toi, Jens Huober, Joo Hyuk Sohn, Olivier Trédan, Inhae Park, Mario Campone, Shin-Cheh Chen, Luis Manual Manso, Shani Paluch-Shimon, Orit C. Freedman, Valerie Andre, Abhijoy Saha, Gertjan van Hal, Ashwin Shahir, Hiroji Iwata, Stephen RD Johnston, Joyce O'Shaughnessy, Xavier Pivot, Sara Tolaney, Sara Hurvitz, Antonio Llombart. MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2- advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-12.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.680 (95% CI, 0.599 to 0.772) for IDFS and 0.675 (95% CI, 0.588 to 0.774) for DRFS. This persistence of abemaciclib benefit translated to continuous separation of the curves with a deepening in 5-year absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with rates of 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. With fewer deaths in the abemaciclib plus ET arm compared with the ET-alone arm (208 v 234), statistical significance was not reached for OS. No new safety signals were observed. In conclusion, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence beyond the completion of treatment. The increasing absolute improvement at 5 years is consistent with a carryover effect and further supports the use of abemaciclib in patients with high-risk EBC.

Abstract Background monarchE is a phase 3, open-label study evaluating abemaciclib combined with endocrine therapy (ET) compared to ET alone in patients with node positive, HR+, HER2-, high risk early breast cancer (EBC) that resulted in a statistically significant improvement in invasive disease-free survival (IDFS) at a pre-planned interim analysis. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and overall survival. Methods After surgery and, as indicated, radiotherapy and/or chemotherapy, 5,637 patients with HR+, HER2-, high risk EBC were randomized (1:1) to standard of care adjuvant ET with or without abemaciclib (150 mg BD for 2 years). Patients with ≥4 positive nodes, or 1-3 nodes and either grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible. Here we present results of the primary outcome IDFS analysis which was planned after approximately 390 IDFS events. Results At the primary outcome analysis, median follow-up was approximately 19 months in both arms (an increase of 3.5 months from the interim analysis). A total of 1437 (25.5%) patients had completed the 2-year treatment period; 3281 (58.2%) were still in the 2-year treatment period. With 395 IDFS events observed in the intent-to-treat population, abemaciclib plus ET continued to demonstrate superior IDFS versus ET alone, with a 28.7% reduction in the risk of developing invasive disease (p=.0009; HR = 0.713; 95% CI = 0.583, 0.871). Two-year IDFS rates were 92.3% in the abemaciclib plus ET arm and 89.3% in the ET alone arm. There was a consistent benefit of abemaciclib in all prespecified subgroups. The addition of abemaciclib to ET also resulted in an improvement in distant relapse-free survival (DRFS). Overall survival was immature at the time of analysis. A key secondary endpoint was efficacy in patients with centrally assessed high Ki-67 (≥20%) (Ki-67H) (n=2498). Disease characteristics were well balanced between the arms of this population. Abemaciclib plus ET demonstrated superior IDFS vs ET alone, with a 30.9% reduction in risk of developing invasive disease (p=.0111; HR = 0.691; 95% CI = 0.519, 0.920) and 2-year IDFS rates of 91.6% and 87.1%, respectively. An improvement in DRFS treatment effect was also observed in the Ki-67H population. At the time of data cutoff, the median treatment duration of abemaciclib was 17.3 months and the median duration of ET was balanced between the arms (18.3 months in the abemaciclib arm and 18.7 months in the ET alone arm). Safety was consistent with the results at the interim IDFS analysis and with the known safety profile of abemaciclib. Conclusions At the primary outcome analysis, with a median follow-up of approximately 19 months, abemaciclib combined with ET continued to demonstrate a clinically meaningful improvement in IDFS in patients with HR+, HER2-, node-positive, high risk, EBC with a statistically significant improvement in IDFS in patients with central Ki-67 ≥20%. ClinicalTrials.gov: NCT03155997 Table 1: PrimaryOutcome EfficacyIntent-to-Treat PopulationIntent-to-Treat PopulationKi-67 ≥20% (Ki-67H) PopulationKi-67 ≥20% (Ki-67H) PopulationEndpointAbemaciclib + ET N=2808ET alone N=2829Abemaciclib + ET N=1262ET alone N=1236IDFS# events, n (%)163 (5.8)232 (8.2)82 (6.5)115 (9.3)log rank P value, HR (95% CI)p=.0009 0.713 (0.583, 0.871)p=.0111 0.691 (0.519, 0.920)Rate (%) at 2 years (95% CI)92.3 (90.9, 93.5)89.3 (87.7, 90.7)91.6 (89.4, 93.4)87.1 (84.3, 89.5)Difference (%) in 2-year rates (95% CI)3 (1.1, 5.0)4.5 (1.2, 7.7)DRFS# events, n (%)131 (4.7)193 (6.8)65 (5.2)102 (8.3)log rank P value, HR (95% CI)p=.0009 0.687 (0.551, 0.858)0.609 (0.445, 0.833)Rate (%) at 2 years (95% CI)93.8 (92.6, 94.9)90.8 (89.3, 92.1)93.6 (91.6, 95.1)88.5 (85.7, 90.7)Difference (%) in 2-year rates (95%CI)3 (1.2, 4.8)5.1 (2.1, 8.1) Citation Format: Joyce A. O'Shaughnessy, Stephen Johnston, Nadia Harbeck, Masakazu Toi, Young-Hyuck Im, Mattea Reinisch, Zhimin Shao, Pirkko Liisa Kellokumpu Lehtinen, Chiun-Sheng Huang, Alexey Tryakin, Matthew Goetz, Hope S Rugo, Elzbieta Senkus, Laura Testa, Michael Andersson, Kenji Tamura, Guenther G. Steger, Lucia Del Mastro, Joanne Cox, Tammy Forrester, Sarah Sherwood, Xuelin Li, Ran Wei, Miguel Martin, Priya Rastogi. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-01.

1087 Background: OlympiAD (NCT02000622) demonstrated the benefit of olaparib over standard of care in patients (pts) with HER2-negative (HER2-) metastatic breast cancer (MBC) and germline BRCA mutations (gBRCAm). LUCY (NCT03286842) aimed to provide additional data on the real-world effectiveness and safety of olaparib monotherapy in this setting. Methods: This Phase IIIb, open-label, single-arm study of olaparib 300 mg twice-daily, enrolled pts with HER2- gBRCAm MBC who had received a taxane and/or anthracycline in the (neo)adjuvant/metastatic setting, and ≤2 lines of chemotherapy for MBC. Hormone receptor-positive (HR+) pts had progressed on prior endocrine therapy (ET), and further ET was considered unsuitable. Primary endpoint: investigator-defined progression-free survival (PFS). Secondary endpoints: overall survival, time to first subsequent therapy or death (TFST), and investigator-assessed clinical response rate (CRR). The interim analysis was planned after 160 PFS events. Results: From Oct 2018-Sept 2019, 252 pts were enrolled (160 sites, 15 countries; mean age 46.2 [range 22-75] years; 73.4% ECOG PS 0). Median total treatment duration: 7.9 months (mo; range 0.2-20.0). Median PFS: 8.1 mo (95% confidence interval [CI] 6.9, 8.7; 166 events [65.9%]). Clinical trial information: NCT03286842 . Median TFST: 9.7 mo (95% CI 8.7, 11.1). CRR: 48.6% (95% CI 42.2, 55.0). Adverse events (AEs) in >20% of pts (all grades): nausea, anemia, asthenia, vomiting, and fatigue. 24.6% of pts reported a grade ≥3 AE, including anemia (n=33 [13.1%]). 4.4% of pts had an AE leading to treatment discontinuation. Conclusions: Interim results in this real-world population of pts with HER2- gBRCAm MBC were consistent with the OlympiAD study, and support olaparib as a chemotherapy-free alternative treatment for pts with gBRCAm advanced BC. [Table: see text]

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.

TPS1140^ Background: NKTR-102 is a topoisomerase I inhibitor-polymer conjugate that hydrolyzes to provide continuous exposure to SN-38. A phase 2 trial of single-agent NKTR-102 was conducted in pts with 3rd-line MBC; 2 schedules (q14d; q21d) investigated a dose of 145 mg/m2. ORR was 29% (including 3% CR) with the prior ATC subset demonstrating an ORR of 31%. Dosing q21d was better tolerated; in this arm, median PFS and OS equaled 5.3m and 13.1m, respectively. Trial Design: Pts will be randomized 1:1 to receive single-agent NKTR-102 or TPC in an open-label, randomized, multicenter phase 3 study in pts with advanced breast cancer. Key Entry Criteria: Adult females, with ECOG 0 or 1 with adequate liver, kidney and marrow function. All pts must have received prior therapy with ATC (these drugs can be administered in the neo/adjuvant or locally advanced/metastatic setting). Prior A is not mandated if contraindicated. Prior toxicities must have resolved to ≤ Grade 1 (except sensory neuropathy ≤ Grade 2; complete resolution of prior diarrhea). Pts with brain metastases may be eligible, if lesions are stable for prior 3 weeks without steroids. Methods: Primary efficacy endpoint is OS. Secondary endpoints include: ORR by RECIST v1.1, clinical benefit rate (ORR+SD > 6 months), PFS and QoL. NKTR-102 is given IV at 145 mg/m2 over 90-min every 21 days without premedications. Pts randomized to TPC receive 1 of the following: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel or nab-paclitaxel (the agent must be available at the treating institution). Pts are stratified by region, prior eribulin and receptor status (TNBC, Her2+ or Other). Target Accrual: ~840 pts will be required for sufficient events to occur in the planned follow-up time; OS will be compared using a two-sided log-rank test; 1 interim analysis will occur when 50% of the deaths are reported. PK sampling is performed in a subset of pts. CTCs (isolated by Apocell ApoStream technology) are serially assessed for potential predictive markers of response and toxicity. Enrollment is expected to remain open until late 2013.