ECC 2013 - TH3RESA

TH3RESA - Phase 3 Study of T-DM1 vs. Treatment of Physician’s Choice in HER2-Positive Metastatic Breast Cancer (MBC) — Primary Results

Background: T-DM1, an antibody-drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, and is approved in several countries for patients (pts) with MBC previously treated with trastuzumab and a taxane. TH3RESA is a phase 3 study evaluating T-DM1 vs. treatment of physician’s choice (TPC) in pts with progressive disease (PD) after ≥ 2 HER2-directed regimens for MBC.

Methods: Pts with centrally confirmed HER2-positive unresectable locally advanced BC or MBC with PD after ≥ 2 HER2-directed regimens, including trastuzumab and lapatinib, in the unresectable recurrent/metastatic setting and a taxane (any setting) were randomized 2:1 to T-DM1 (3.6 mg/kg IV q3w) or TPC. Co-primary endpoints were progression-free survival (PFS) by investigator and overall survival (OS). After EMILIA data were reported, crossover from TPC to T-DM1 was allowed post-progression.

Results: At the 11 Feb 2013 cutoff, 602 pts were randomized; 44 pts in the TPC arm had crossed over to T-DM1. TPC comprised HER2-directed regimens (83.2%) and single-agent chemotherapy (16.8%). Pts had received a median of four prior regimens (excluding hormonal therapy) in the recurrent/metastatic setting, and the majority (75.1%) had visceral disease.

PFS and objective response rate (ORR) were significantly improved with T-DM1; the interim OS analysis showed a similar trend, but the stopping boundary was not crossed (Table). PFS benefit was consistent across subgroups, including age, visceral involvement, number of prior regimens, and TPC type.


The T-DM1 safety profile was consistent with prior studies. Fewer grade ≥3 adverse events (AEs) overall were reported for T-DM1 vs TPC (32.3% vs 43.5%). More grade ≥3 thrombocytopenia (4.7% vs 1.6%) was reported with T-DM1. More grade ≥3 neutropenia (2.5% vs 15.8%), febrile neutropenia (0.2% vs 3.8%), and diarrhea (0.7% vs 4.3%) were reported with TPC.

T-DM1 resulted in an improved PFS with fewer grade ≥ 3 AEs compared to TPC in pts previously treated with ≥ 2 HER2-directed regimens for HER2-positive MBC.

PFS improvement was present even though TH3RESA patients were heavily pre-treated (median four regimens), with 75% having visceral disease burden and most (83%) patients in the TPC arm continued to receive HER2 directed therapies. Although median OS was not reached in the T-DM1 arm, a reported trend was noted. Given the allowed and likely continued crossover to T-DM1 in the TPC arm, it would seems less likely that definitive OS benefit will be seen with longer follow-up.

Overall the side-effect profile and PFS benefit seen in the T-DM1 reaffirms the results from the EMILIA trail.

For our patients, having access to less toxic and more efficacious treatment options is always a good thing. T-DM1 in HER2 positive MBC seems to continue to fit this description.

For clinicians, with the increasing number of HER2 directed agents and supportive studies, the complexity of treatment decision is reflected in the ongoing discussion as to what should be considered the ideal or ‘standard’ HER2+ MBC treatment algorithm. The TH3RESA study adds to and supports the use of T-DM1 and the clinical practice of continued HER2 directed therapy in the HER2-positive MBC setting.

T-DM1 is not yet publically funded in Canada. For our Canadian healthcare system, the same old question remains, as to how can we afford to fund all of these increasingly expensive next generation therapeutics. Although, future correlative or bio-marker studies may help to decide how best to treat, currently we are not quite there yet.
— CARE Breast Cancer Faculty