Background: Palbociclib is approved for treatment of ER+, HER2- ABC at a standard dose of 125 mg po daily 3 weeks on/1 week off (STD). We evaluated the efficacy, safety, quality of life (QOL) and compliance of a 100 mg continuous daily dose (CDD) of palbociclib based on modeling data that suggested efficacy and tolerability. Methods: Canadian Cancer Trials Group (CCTG) led a randomized phase II trial (CCTG MA38) to estimate the efficacy of palbociclib 100 mg po on CDD schedule (Arm 1) relative to 125 mg po STD schedule (Arm 2) with physician choice endocrine therapy. Eligible patients had ER+, HER2- ABC, post progression on first line metastatic endocrine therapy or progressed while on/within 12 months of completion of adjuvant endocrine therapy. One line of palliative chemotherapy in ABC was allowed. Stratification factors were: visceral metastases, duration of prior endocrine therapy and planned endocrine therapy. Primary Outcome measure was investigator reported PFS; secondary outcome measures included: RR, OS, safety (CTCAE V4.0), and QOL (EORTC QLQ-C30). The sample size was 180 to enable estimation of the HR between arms with the upper bound of the 90% CI 1.36 times the estimated HR and the lower bound is 0.74 times the estimated HR. Results: 180 patients were enrolled across Canada from Dec 2015 to Feb 2017. The database was locked April 16 2018 after prespecified PFS events reached at a median follow-up of 19 months for all patients. For the whole population: median age was 60.5 years (21% ≥ 70 years); ECOG 0/1 95%; postmenopausal 91%; visceral metastases 67%. Planned endocrine therapy: aromatase inhibitor 33%, fulvestrant 57%, tamoxifen 10%. Efficacy analyses CDD vs STD: PFS stratified univariate HR 0.93 (90% CI 0.66-1.30); multivariate Cox model analysis (covariates ECOG PS, age, histology, grade): HR 0.92 (90% CI 0.67-1.25). Median PFS CDD: 9.33 months (90% CI 6.93-13.90) and STD: 11.30 months (90% CI 8.08- 13.83) Secondary analyses CDD vs STD: OS stratified univariate HR: 1.07 (90% CI 0.67-1.69); multivariate HR 1.14 (90%CI 0.75-1.75); median OS for CDD: 20.73 months (90% CI 19.29-23.30) and 21.39 months (90% CI 19.65 to 26.68) for STD. RR and median duration of response: 11.1% vs 12.4% (p=0.84) and 126 vs 169 days (p=0.86), respectively. Palbociclib drug exposure CDD vs STD: median daily dose (mg) 87 vs 125; median dose intensity (mg/week) 571.2 vs 613.5; ≥ 90% planned dose intensity, 41% vs 54%. Dose modification (withhold and/or reduction) rate CDD vs STD for neutropenia was 70% vs 40%. Grade 3/4 neutropenia 69% vs 53%; febrile neutropenia 3% each arm. Non-hematological toxicity profiles were comparable for both arms. No significant differences were seen in QOL domains. Conclusion: Palbociclib is active and tolerable when administered on either a 100 mg CDD or a 125 mg STD schedule. CDD schedule had higher rates of grade 3/4 neutropenia and dose modifications. Post approval evaluation of alternate dosing schedules for targeted therapies provides useful information regarding drug activity, toxicity and adherence. Citation Format: Parulekar WR, Joy AA, Gelmon K, Mates M, Desbiens C, Clemons M, Taylor S, Lemieux J, Bartlett J, Whelan T, Ayoub J-P, Cescon D, Bordeleau L, Rahim Y, Winch C, Chen BE. Randomized phase II study comparing two different schedules of palbociclib plus second line endocrine therapy in women with estrogen receptor positive, HER2 negative advanced/metastatic breast cancer: CCTG MA38 (NCT02630693) [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 PD1-10.

Background: In MA.31, the lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment serum biomarkers. Methods: MA.31 accrued 652 patients; 537 (82%) were centrally-confirmed HER2+. Biomarkers were categorized for univariate and multivariate predictive investigations with a median cut-point, ULN cut-points (15 ng/ml- HER2; 506 pg/ml- CAIX; 454 pg/ml- TIMP-1; 1940 pg/ml– uPA; 600 pg/ml- activin A), and custom cut-points (30 and 100 ng/ml for HER2). Stratified step-wise forward Cox multivariate analysis used continuous and categorical biomarkers for PFS in the ITT and central HER2+ populations; central HER2+ biomarker results are shown. Results: Serum was banked for 472 (72%) of 652 patients. Higher serum activin A (>median; >ULN; p<0.0001); higher CAIX (>median; >ULN; p=0.02; p=0.001); higher HER2 (>median; >15; >30; or >100 ng/ml; p=0.05-0.002) and higher TIMP-1 (>median; >ULN; p=0.001; p=0.02) had shorter univariate PFS. In multivariate analysis for PFS: higher continuous activin A (HR=6.75 with Box-Cox transformation, P<0.0001) was associated with significantly shorter PFS, along with treatment arm, prior adjuvant anthracyclines, and higher central EGFR status. In multivariate analysis for OS: higher continuous activin A (HR=85.9, with Box-Cox transformation, P<0.0001) was associated with significantly shorter OS, along with treatment arm and higher central EGFR status. The interaction terms of serum biomarkers with treatment were not significant. Elevated serum activin A was also significant at the median cutpoint for PFS (HR 1.79, p=0.0002) and OS (HR 2.39, p=0.006) in multivariate analysis. Conclusions: Higher serum activin A was a significant independent prognostic biomarker of shorter progression-free and overall survival. No serum biomarker was predictive of differential response to lapatinib vs. trastuzumab. Evaluation of activin A and CAIX-targeted therapy in addition to HER2-targeted therapy may be warranted in patients with elevated serum levels of these biomarkers. *AK, MH, DH, & JH contributed equally Grant: PA Breast Cancer Coalition. Citation Format: Kang A, Hupp M, Ho D, Huang J, Leitzel K, Ali S, Shepherd L, Parulekar WR, Ellis CE, Rocco CJ, Zhu L, Virk S, Nomikos D, Aparicio S, Gelmon KA, Truica C, Al-Marrawi Y, Rizvi S, Vasekar M, Nagabhairu V, Polimera H, Marks E, Richardson A, Ali AS, Krecko L, Carney WP, Downs S, Chen BE, Lipton A. Effect of serum biomarkers (activin A, CAIX, HER2, TIMP-1, and uPA) on outcome in HER2+ metastatic breast cancer patients treated in first line with lapatinib or trastuzumab combined with taxane: CCTG MA.31 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-06.