Abstract No. 
2019 San Antonio Breast Cancer Symposium
December 10-14

Evaluation of patritumab/paclitaxel/trastuzumab over standard paclitaxel/trastuzumab in early stage, high-risk HER2 positive breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL

Helsten TL, Lo SS, Yau C, Kalinsky K, Elias AD, Wallace AM, Chien A, Lu J, Lang JE, Albani KS, Stringer-Reasor E, Clark AS, Boughey JC, Ellis ED, Yee D, DeMichele A, Isaacs C, Perlmutter J, Rugo HS, Schwab R, Hylton NM, Summans W, Melisko ME, van 't Veer LJ, Wilson A, Singhrao R, Asare SM, Senil A, Berry DA, Esserman LJ


I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify (graduate) regimens with ≥ 85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with pCR endpoint within signatures defined by hormone-receptor (HR), HER2 status, and MammaPrint (MP). Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or for safety as recommended by the independent DSMB. For HER2+ subjects, the control arm was 12 weekly cycles of paclitaxel+trastuzumab (TH, control) followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x4 and surgery. Patritumab is a monoclonal antibody against HER3. For this arm in HER2+ breast cancer, patritumab was given q3w x 4 cycles (18mg/kg loading dose followed by 9mg/kg/dose) concurrent with paclitaxel and trastuzumab q1w x 12 weeks (PTH, treatment), followed by AC q2-3w.


Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 weeks after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Analysis was intention to treat. Subjects who switched to non-protocol therapy count as non-pCR. Subjects on experimental therapy at time of arm closure are non-evaluable. Graduation potential was in 3 of 10 pre-defined signatures: all HER2+, HR-/HER2+, and HR+/HER2+.


PTH did not meet criteria for graduation and was stopped at the recommendation of the Safety Working Group and DSMB based on a safety event (bilateral sensorineural hearing loss, Gr 3) observed in one participant. N=31 participants had received PTH treatment at the time accrual closed due to toxicity, among which 4 subjects receiving patritumab were changed to non-protocol therapy and removed from the analysis. Evaluable participants: 27 PTH and 31 TH.  Safety and biomarker data associated with patritumab response will be reported. The participant who developed Gr3 sensorineural hearing loss 6 days after the 2nd patritumab treatment, did not recover her hearing after patritumab was stopped, and also reported Gr3 vulvovaginal pain, vulvitis, and vaginal inflammation. Other gynecological symptoms reported include: 1 pt with Gr1 vaginal hemorrhage, and 1 pt with Gr2 dyspareunia. Increased toxicity was seen on the PTH arm compared to TH alone, including Gr3 hypokalaemia (12.5% vs 3.2%) and Gr3 premature menopause (12.5% vs none). One pt reported Gr3 small intestinal obstruction which resolved with conservative management.


The I-SPY 2 study finds the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial; PTH did not reach the efficacy threshold of 85% probability of success in phase 3 in any of the 3 signatures as the arm was stopped due to safety in a curable setting. This is the first report of Gr3 hearing loss with patritumab/paclitaxel/trastuzumab.

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