Abstract OT-34-01: Phase Ib/II trial of copanlisib in combination with trastuzumab and pertuzumab after induction treatment of HER2 positive metastatic breast cancer with PIK3CA mutation or PTEN mutation
Authors: Damodaran Senthil , Murthy Rashmi K , Nusrat Maliha , Saigal Babita , Trager Samantha C , Tripathy Debu , Meric-Bernstam Funda 
Published: February 2021

Background:The PI3K/Akt/mTOR pathway is a critical regulator of cell growth, survival, and metabolism in cancer. Its activation plays an important role in resistance to chemotherapy and HER2 targeted therapy. PIK3CA activating mutations and PTEN loss were reported in 30% and 16% of BOLERO-1 and 32% and 12% of BOLERO-3 patients, respectively. Exploratory analyses suggested that the addition of everolimus to trastuzumab and chemotherapy improved progression free survival (PFS) in patients with PIK3CA mutations and PTEN loss. In the phase III CLEOPATRA trial, while the combination of pertuzumab (P) plus trastuzumab (H) plus docetaxel (T) as compared with trastuzumab (H) plus docetaxel (T), significantly prolonged PFS (18.5 vs 12.4 months) for first-line treatment for HER2-positive (+ve) metastatic breast cancer (MBC), longer median PFS was observed in patients with wildtype versus mutated PIK3CA in both the control (13.8 v 8.6 months) and pertuzumab groups (21.8 v 12.5 months). Copanlisib is a highly selective, class 1 pan-PI3K inhibitor with predominant activity against both the δ and α isoforms. It is currently FDA approved for the treatment of adults with relapsed follicular lymphoma. This study hypothesizes that the addition of copanlisib to dual HER2 targeted therapy after first line induction treatment will improve clinical outcomes in HER2 positive MBC patients with PIK3CA or PTEN genomic alterations. Trial Design: This is a randomized, two- arm, open label, phase-2 study to evaluate the clinical activity of copanlisib added to HP maintenance after induction with THP in HER2 +ve MBC patients with PIK3CA mutations or PTEN loss. A safety run-in cohort (phase 1B) will be performed. Copanlisib will be administered weekly on D1, D8 of a 21-day cycle. Eligibility criteriaHER2 +ve MBC based on ASCO-CAP criteria (HER2 status based on metastatic tissue)• Activating mutations in PIK3CA, or PTEN loss• ECOG performance status ≤1• Normal organ and marrow function• Within 8 weeks of completion of first-line induction therapy with THP (Phase-2). Any prior treatment provided eligible to receive THP induction (Phase-1B) Specific aimsTo assess the benefit of adding copanlisib to HP in HER2+ve MBC patients with PIK3CA mutations or PTEN loss after induction treatment (Phase-2)• To determine safety and recommended phase 2 dose (RP2D) of copanlisib, HP combination in HER2 MBC patients (Phase-1B)• To correlate PFS and OS with the triplet combination with the number of induction cycles, hormone receptor status, and PTEN loss by IHC• To identify potential predictive and prognostic biomarkers for copanlisib activity Statistical methodsThe primary objective of the phase-1B portion is to determine the RP2D for the combination of copanlisib, trastuzumab, and pertuzumab. Phase 1 portion will use a 3+3 dose de-escalation design. The primary objective of the phase 2 portion is to determine a difference in PFS with the addition of copanlisib to HP maintenance after induction. Projected median PFS in control group is 8 months and 16 months in the experimental arm. We aim to detect a HR of 0.50 with power of 0.90 with 1-sided alpha of 0.1. With a sample size of 82, 12 months post-accrual follow-up, and accrual rate of 5 patients per month, the study duration is 30 months. To have 82 evaluable patients with a 15% drop-out rate, we would need to enroll 96 patients. A Wieand rule futility interim analysis will be conducted when half of the total of 54 required PFS events are observed.

Citation Format: Senthil Damodaran, Rashmi K Murthy, Maliha Nusrat, Babita Saigal, Samantha C Trager, Debu Tripathy, Funda Meric-Bernstam. Phase Ib/II trial of copanlisib in combination with trastuzumab and pertuzumab after induction treatment of HER2 positive metastatic breast cancer with PIK3CA mutation or PTEN mutation [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 OT-34-01.