Background

Neratinib (N), an irreversible pan-HER TKI, is approved in the EU for extended adjuvant treatment of early-stage HR+ HER2+ breast cancer (BC) after adjuvant trastuzumab (T)-based therapy. The CONTROL trial (NCT02400476) investigated pre-emptive antidiarrheal prophylaxis or dose escalation (DE) for prevention of diarrhea, the most frequent side effect of N.

Methods

CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients (pts) ≥18y with stage I–IIIc HER2+ BC received oral N (240 mg/d for 1y) after T-based adjuvant therapy. Pts were enrolled sequentially into separate cohorts: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) DE + loperamide PRN (2 cohorts). DE1 schedule: N 120 mg/d x w1, 160 mg/d x w2, then 240 mg/d from w3 to 12m. DE2 schedule: N 160 mg/d x w1&2, 200 mg/d x w3&4, then 240 mg/d from w5 to 12m. Primary endpoint: incidence of grade ≥3 diarrhea.

Results

563 pts were enrolled. All preventive strategies reduced grade 3 diarrhea vs ExteNET (historical control: 39%). Median cumulative duration of grade 3 diarrhea ranged from 2–3.5d in CONTROL (vs 5.0d for ExteNET). The proportion of pts discontinuing N because of diarrhea was decreased in CONTROL vs ExteNET. Key diarrhea outcomes in all CONTROL cohorts are presented in the table and will be fully detailed during the congress. Table: 73P

Patient disposition and diarrhea characteristics: All CONTROL cohorts

Conclusions

These final findings from CONTROL show improved tolerability of N with all diarrhea prophylaxis strategies and suggest that DE1 with loperamide PRN allows pts to stay on treatm.ent longer and receive full benefit from N.

Clinical trial identification

NCT02400476.

Editorial acknowledgement

Editorial/writing assistance for this abstract was provided by Lee Miller (Miller Medical Communications Ltd.). This work was funded by the study sponsor (Puma Biotechnology Inc.).

Legal entity responsible for the study

Puma Biotechnology Inc.

Funding

Puma Biotechnology Inc.

Disclosure

A. Brufsky: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc. A.J. Chien, R. Bose: Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. B. Pistilli: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc.; Financial Interests, Personal, Advisory Role, Consulting fees: Pierre Fabre; Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. D. Diprimeo, N. Foruzan, L.M. McCulloch: Financial Interests, Personal, Full or part-time Employment: Puma Biotechnology Inc.; Financial Interests, Personal, Stocks/Shares: Puma Biotechnology Inc. All other authors have declared no conflicts of interest.

Background

Palbociclib (PB), the first clinically available oral CDK4/6 inhibitor, in combination with endocrine therapy has become standard of care for HR+/HER2– advanced/metastatic breast cancer (MBC). This study compared overall survival (OS) of MBC patients treated with first-line PB+AI vs AI alone in US routine clinical practices.

Methods

We conducted a retrospective analysis of HR+/HER2– MBC patients in the Flatiron Health longitudinal database, representing more than 2.4 million actively treated cancer patients in the US. Between February 2015 and March 2020, 2888 postmenopausal MBC women and men aged ≥18 years started first-line PB+AI or AI therapy. Patients were evaluated from start of PB+AI or AI to September 2020, death, or last visit, whichever came first. Both stabilized inverse probability treatment weighting (sIPTW) and propensity score matching (PSM) statistical methods were used to balance patient characteristics.

Results

Of the eligible patients (1324 with PB+AI and 1564 with AI), median age was 70.0 years, 67.8% were white, 34.8% had de novo MBC, 29.4% had lung or liver involvement, 38.7% had bone-only disease. Median OS in PB+AI vs AI was 53.4 (95%CI=48.7-58.6) vs 40.4 (95%CI=36.3-44.9) months (mo) (HR=0.67, 95%CI=0.60-0.76, p<.0001), respectively. After sIPTW, median OS was 49.1 mo (95%CI=45.2-57.7) for PB+AI vs 43.2 mo (95%CI=37.6-48.0) for AI (HR=0.76, 95%CI=0.65-0.87, p<.0001). After 1:1 PSM, median OS was 57.8 mo (95%CI=47.2—NR) with matched PB+AI vs 43.5 mo (95%CI=37.6-48.9) with matched AI (HR=0.72, 95%CI=0.62-0.83, p<.0001). Table presents key patient characteristics and OS results.

Conclusions

This largest to date real-world comparative effectiveness study demonstrated that palbociclib +AI was significantly associated with prolonged overall survival vs AI alone, supporting first-line palbociclib plus AI as a standard of care for HR+/HER2– MBC patients. Table: 169P

Legal entity responsible for the study

Pfizer Inc.

Funding

Pfizer Inc.

Disclosure

H.S. Rugo: Financial Interests, Institutional, Financial Interests: Pfizer Inc.; Financial Interests, Institutional, Financial Interests: Merck; Financial Interests, Institutional, Financial Interests: Novartis; Financial Interests, Institutional, Financial Interests: Eli Lilly; Financial Interests, Institutional, Financial Interests: Roche; Financial Interests, Institutional, Financial Interests: Daiichi Sankyo; Financial Interests, Institutional, Financial Interests: Seattle Genetics; Financial Interests, Institutional, Financial Interests: Macrogenics; Financial Interests, Institutional, Financial Interests: Sermonix; Financial Interests, Institutional, Financial Interests: Boehringer Ingelheim; Financial Interests, Institutional, Financial Interests: Polyphor; Financial Interests, Institutional, Financial Interests: AstraZeneca; Financial Interests, Institutional, Financial Interests: Ayala; Financial Interests, Institutional, Financial Interests: Gilead; Financial Interests, Institutional, Financial Interests: Puma; Financial Interests, Institutional, Financial Interests: Samsung; Financial Interests, Institutional, Financial Interests: Mylan. A. Brufsky, X. Liu, B. Li, L. McRoy, C. Chen: Financial Interests, Institutional, Financial Interests: Pfizer Inc. R.M. Layman: Financial Interests, Institutional, Financial Interests: Pfizer Inc.; Financial Interests, Institutional, Financial Interests: Novartis; Financial Interests, Institutional, Financial Interests: Eli Lilly; Financial Interests, Institutional, Financial Interests: GlaxoSmithKline; Financial Interests, Institutional, Financial Interests: Zentalis. M. Cristofanilli: Financial Interests, Institutional, Financial Interests: Merck; Financial Interests, Institutional, Financial Interests: AstraZeneca; Financial Interests, Institutional, Financial Interests: Pfizer Inc.; Financial Interests, Institutional, Financial Interests: Menarini; Financial Interests, Institutional, Financial Interests: Eli Lilly; Financial Interests, Institutional, Financial Interests: G1 Therapeutics; Financial Interests, Institutional, Financial Interests: Novartis; Financial Interests, Institutional, Financial Interests: Sermonix; Financial Interests, Institutional, Financial Interests: Foundation Medicine. M.A. Torres: Financial Interests, Institutional, Financial Interests: Pfizer Inc.; Financial Interests, Institutional, Financial Interests: Genentech; Financial Interests, Institutional, Financial Interests: Centers for Disease Control; Financial Interests, Institutional, Financial Interests: Oncohealth; Financial Interests, Institutional, Financial Interests: MJH Life Sciences. G. Curigliano: Financial Interests, Institutional, Financial Interests: Seagen; Financial Interests, Institutional, Financial Interests: Roche; Financial Interests, Institutional, Financial Interests: Novartis; Financial Interests, Institutional, Financial Interests: Lilly; Financial Interests, Institutional, Financial Interests: Daiichi Sankyo; Financial Interests, Institutional, Financial Interests: AstraZeneca; Financial Interests, Institutional, Financial Interests: Pfizer; Financial Interests, Institutional, Financial Interests: Sanofi; Financial Interests, Institutional, Financial Interests: Pierre Fabre; Financial Interests, Institutional, Financial Interests: Gilead. R.S. Finn: Financial Interests, Institutional, Financial Interests: Pfizer Inc.; Financial Interests, Institutional, Financial Interests: Eli Lilly; Financial Interests, Institutional, Financial Interests: Novartis. A. Demichele: Financial Interests, Institutional, Financial Interests: Pfizer Inc.; Financial Interests, Institutional, Financial Interests: Novartis; Financial Interests, Institutional, Financial Interests: Calithera; Financial Interests, Institutional, Financial Interests: Genentech.

Background

Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Enobosarm has an extensive clinical experience in 25 clinical trials including in 2 phase 2 studies conducted in patients (pts) with AR+ ER+ HER2- metastatic breast cancer (MBC). An open-label, parallel design phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- MBC that were randomized to oral daily enobosarm at a dose of 9 or 18 mg. The primary endpoint of clinical benefit rate (CBR) at 24 weeks was 32% (9 mg) and 29% (18 mg). A post-hoc AR expression subset analysis conducted in the ITT population with measurable disease at baseline revealed that the best overall response rate (ORR) was significantly higher in pts with ≥40% AR nuclei staining versus <40%, 34% and 2.7% respectively (p=0.0003) and the CBR at 24 weeks was significantly higher for ≥40% AR versus <40%, 52% and 14% respectively (p<0.0004). Overall, enobosarm was well tolerated with significant positive effects on quality-of-life measurements.

Trial design

The ARTEST trial is an ongoing phase 3 multicenter, international, randomized, and open-label study. Approximately, 210 pts with AR+ ER+ HER2- MBC and with AR nuclei staining ≥40% are being randomized 1:1 to either enobosarm 9 mg oral daily dose or an active comparator (physician’s choice of exemestane ± everolimus or SERM). Pts must have previously received a nonsteroidal AI inhibitor, fulvestrant, and a CDK 4/6 inhibitor for MBC and had a ≥ 6 months response to hormone therapy for MBC. The primary endpoint is imaging based progression free survival as measured by RECIST 1.1. The secondary endpoints on this study include the ORR, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB) and change in EORTC Quality of Life Questionnaire (EORTC-QLQ).

Clinical trial identification

NCT04869943.

Legal entity responsible for the study

Veru Inc.

Funding

Veru Inc.

Disclosure

A. Brufsky: Financial Interests, Personal, Advisory Role: Veru Inc. H. Linden, H.S. Rugo, C. Vogel, J. O'Shaughnessy, E. Mayer: Financial Interests, Institutional, Research Grant: Veru Inc. R.H. Getzenberg, K.G. Barnette, D. Rodriguez, M.S. Steiner: Financial Interests, Personal, Full or part-time Employment: Veru Inc.

Background

Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Enobosarm has an extensive clinical experience in 25 clinical trials including in 2 phase 2 studies conducted in patients (pts) with AR+ ER+ HER2- metastatic breast cancer (MBC). An open-label, parallel design phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- MBC that were randomized to oral daily enobosarm at a dose of 9 or 18 mg. The primary endpoint of clinical benefit rate (CBR) at 24 weeks was 32% (9 mg) and 29% (18 mg). A post-hoc AR expression subset analysis conducted in the ITT population with measurable disease at baseline revealed that the best overall response rate (ORR) was significantly higher in pts with ≥40% AR nuclei staining versus <40%, 34% and 2.7% respectively (p=0.0003) and the CBR at 24 weeks was significantly higher for ≥40% AR versus <40%, 52% and 14% respectively (p<0.0004). Overall, enobosarm was well tolerated with significant positive effects on quality-of-life measurements.

Trial design

The ARTEST trial is an ongoing phase 3 multicenter, international, randomized, and open-label study. Approximately, 210 pts with AR+ ER+ HER2- MBC and with AR nuclei staining ≥40% are being randomized 1:1 to either enobosarm 9 mg oral daily dose or an active comparator (physician’s choice of exemestane ± everolimus or SERM). Pts must have previously received a nonsteroidal AI inhibitor, fulvestrant, and a CDK 4/6 inhibitor for MBC and had a ≥ 6 months response to hormone therapy for MBC. The primary endpoint is imaging based progression free survival as measured by RECIST 1.1. The secondary endpoints on this study include the ORR, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB) and change in EORTC Quality of Life Questionnaire (EORTC-QLQ).

Clinical trial identification

NCT04869943.

Legal entity responsible for the study

Veru Inc.

Funding

Veru Inc.

Disclosure

A. Brufsky: Financial Interests, Personal, Advisory Role: Veru Inc. H. Linden, H.S. Rugo, C. Vogel, J. O'Shaughnessy, E. Mayer: Financial Interests, Institutional, Research Grant: Veru Inc. R.H. Getzenberg, K.G. Barnette, D. Rodriguez, M.S. Steiner: Financial Interests, Personal, Full or part-time Employment: Veru Inc.