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).
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).
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: 288PD
|Kaplan-Meier estimators||P+T||P+T with chemo|
|[%/median (95% CI)]||[%/median (95% CI)]|
|2-year OS (%)*||76.2 (68.4-82.9)*||76.2 (68.4-82.9)*|
|3-year OS (%)||73.0 (62.8-80.8)||73.1 (62.3-81.2)|
|1st line PFS (median - mo)#||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.
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
Legal entity responsible for the study
Sakk-Swiss Group for Clinical Cancer Research.
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.