Background

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.

Methods

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+.

Results

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.

Conclusion

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.