PERNETTA: A non-comparative randomized open label phase II trial of pertuzumab (P) + trastuzumab (T) with or without chemotherapy both followed by T-DM1 in case of progression, in patients with HER2-positive metastatic breast cancer (MBC): (SAKK 22/10 / UNICANCER UC-0140/1207)

Abstract

Background: Dual blockade with P plus T is highly active as 1st-line treatment in patients (pts) with HER2+ MBC. In 2nd line therapy T-DM1 is considered standard of care. We hypothesize that a strategy with dual blockade with T+P without chemotherapy followed by T-DM1 at progression could be less toxic with similar efficacy in terms of overall survival (OS). Methods: Pts with centrally confirmed HER2+ MBC were randomized 1:1 to receive either P+T alone (arm A) or P+T combined with weekly paclitaxel or vinorelbine (arm B), followed by maintenance treatment with T+P until progression. After progression, T-DM1 was given as second line therapy in both arms. The primary endpoint was OS at 24 months (mo), described by the proportion of successes, along with the exact Clopper-Pearson confidence interval (CI). Secondary endpoints included progression free survival (PFS) and time to failure of strategy (TFS: PD after having received both 1st and 2nd-line treatment or death to any reason). Results: Between 05/13 and 01/16, 210 pts were enrolled. Median age was 58 years, 63% of pts had lung or liver metastases, 36% of tumors were hormone receptor negative, paclitaxel / vinorelbine was given in 46/59 pts. In both arms, 2-year OS was the same. 61/44 of pts of arm A/B proceeded to 2nd line treatment with T-DM1. There were more hematologic, gastrointestinal, neurological toxicities and more alopecia in arm B. Efficacy results.Table: 288PDKaplan-Meier estimatorsP+TP+T with chemo[%/median (95% CI)][%/median (95% CI)]2-year OS (%)*Binomial with 90% CI reported;76.2 (68.4-82.9)*Binomial with 90% CI reported;76.2 (68.4-82.9)*Binomial with 90% CI reported;3-year OS (%)73.0 (62.8-80.8)73.1 (62.3-81.2)1st line PFS (median - mo)#1st CNS metastasis was ignored for this endpoint.8.4 (7.7-12.0)23.3 (17.6-32.6)2nd line PFS (T-DM1, median - mo)7.0 (4.3-11.3)5.3 (4.0-10.3)TFS (median - mo)33.6 (23.2-not reached)48.6 (39.5-not reached)* Binomial with 90% CI reported;# 1st CNS metastasis was ignored for this endpoint. Open table in a new tab Conclusions: P+T alone as first line treatment followed by T-DM1 is a reasonable therapeutic strategy in HER2+MBC. Despite shorter PFS and TFS survival at 2 and 3 years was not affected and side effects were less frequently seen in the chemotherapy free arm. T-DM1 as second line therapy is active and safe after dual blockade with T+P. Clinical trial identification: EudraCT: 2012-002556-17. Legal entity responsible for the study: Sakk-Swiss Group for Clinical Cancer Research. Funding: Roche. Disclosure: J. Huober: Travel grants, advisory board: Novartis, Roche, Pfizer, Celgene. P. Weder: Consultant, advisory board: MSD, Roche. B. Thürlimann: Stock ownership (Roche) and advisory board (Roche). E. Brain: Honoraria or consultation fees (Roche). All other authors have declared no conflicts of interest.