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A Phase II Study of Trastuzumab Emtansine in Patients With Human Epidermal Growth Factor Receptor 2 –Positive Metastatic Breast Cancer Who Were Previously Treated With Trastuzumab, Lapatinib, an Anthracycline, a Taxane, and Capecitabine

J Clin Oncol. 2012 May 29;[Epub Ahead of Print], IE Krop, P LoRusso, KD Miller

TAKE-HOME MESSAGE

Activity seen in heavily pretreated patients with HER2-positive breast cancer was remarkable in this phase II study (EMILIA) of the antibody–drug conjugate trastuzumab–emtansine (T-DM1). The safety profile of this agent was also encouraging.

Lee S Schwartzberg, MD FACP

EXPERT COMMENTARY

Recognition that overexpression of HER2 in a subset of patients with breast cancer is associated with a more aggressive and deadly form of this disease led to the successful development of HER2-targeted agents, such as the monoclonal antibody trastuzumab and the small molecule intracellular inhibitor lapatinib. Despite the marked success achieved in slowing down the course of the disease in the metastatic setting, HER2+ cancers eventually develop resistance and progress. A new approach to targeting HER2 is the use of antibody–drug conjugates (ADC), which couple the specificity of a monoclonal antibody with the cytotoxic power of a covalently bound chemotherapeutic moiety, which ideally delivers its cytotoxic effect only to the cancer cell, sparing normal tissues of toxicity. With emerging technology, fashioning such drugs has become feasible. The power of this approach was demonstrated in a plenary presentation of the EMILIA trial at ASCO 2012 by Blackwell. The investigators compared the novel T-DM1, an ADC coupling the potent cytotoxic maytansine to trastuzumab, to standard capecitabine and lapatinib in trastuzumab-resistant HER2+ breast cancer. T-DM1 was both more effective, improving progression-free survival by 35% and a median of 3.2 months, and less toxic, with fewer adverse events or discontinuation due to toxicity. As such, T-DM1 will be a clear practice changer when it becomes commercially available. Rationally designed drugs can achieve the holy grail of cancer treatment: better results and fewer side effects.

SUMMARY

OncologySTAT Editorial Team

Addition of lapatinib, an HER1/2 tyrosine kinase inhibitor, to capecitabine has been shown to delay time to disease progression in patients with HER2-positive advanced breast cancer after prior therapy with trastuzumab, an anthracycline, and a taxane. Unfortunately, progression subsequently occurs, with HER2 overexpression continuing beyond progression and no standard HER2-directed regimen available.The antibody–drug conjugate (ADC) trastuzumab–emtansine (T-DM1) uses a novel thioether linker molecule to combine the selective delivery of DM1, a derivative of maytansine, with trastuzumab. Thus, this linker is thought to target HER2-expressing cancer cells while limiting exposure of DM1 to normal tissue. Based on preliminary evidence, the open-label EMILIA study was designed to evaluate the antitumor activity of T-DM1 in patients with advanced HER2-positive breast cancers that were refractory to multiple lines of therapy.

Patients in the study had received trastuzumab, lapatinib, a taxane, an anthracycline, and capecitabine. In addition, patients were treated with and then progressed on >2 anti–HER2-directed therapies in the advanced disease setting. Exploratory analysis of efficacy based on biomarker status was included. The study enrolled 110 patients. Efficacy and safety analysis included all who received >1 dose of T-DM1 (given intravenously at 3.6 mg/kg every 3 weeks). Primary endpoints were overall response rate (ORR) as reviewed by an independent radiologic facility (IRF). Secondary endpoints were clinical benefit rate (CBR), duration of objective response (DOR), progression-free survival (PFS), and pharmacokinetic (PK) profile.

Excluding hormonal therapy, patients had received a median of 8.5 prior therapies; a median of 7.0 for metastatic disease. By IRF review, 38 patients achieved objective tumor responses (ORR, 34.5%; 95% CI, 26.1%–43.9%). Median PFS was 6.9 months (95% CI, 4.2–8.4 months). ORR was similar for the entire cohort and for patients with progressive disease after trastuzumab, lapatinib, and chemotherapy. Median DOR was 7.2 months (95% CI, 4.6 months–not estimable [N/E]).

By investigator review, ORR was 32.7% (95% CI, 24.1%–42.1%), median DOR was 9.7 months (95% CI, 7.1 month–N/E), and median PFS was 5.5 months (95% CI, 4.2–7.9 months).

Centrally assessed HER2 expression analysis showed HER2-positive disease in 95 patients and HER2-normal disease in 15 patients. ORR by IRF review was 41.3% (95% CI, 30.4%–52.8%) vs 20.0% (95% CI, 5.7%–44.9%), respectively. Median PFS was 7.3 months vs 2.8 months, respectively. No association between response to T-DM1 and marker status for HER2 mRNA level, FISH copy number, or phosphatidyl inositol-3-kinase (PI3K) mutation status emerged.

Safety with T-DM1 appeared promising. Therapy was discontinued because of toxicity in 7 patients. Dose reductions occurred in 18 patients, most often associated with serum transaminase abnormalities and thrombocytopenia. The most common adverse events (AEs) were fatigue (61.8%), nausea (37.3%), and thrombocytopenia (38.2%). Thrombocytopenia (9.1%), fatigue (4.5%), and cellulitis (3.6%) were the most commonly reported >grade 3 events. Grades 4 and 5 AEs were reported in 6 and 3 patients, respectively. Half-life of T-DM1 was 3.96 days, with no significant accumulation during treatment. In this study, T-DM1 was active and had acceptable toxicity in a group of patients with advanced HER2-positive breast cancer who had progressive disease despite receiving both trastuzumab and lapatinib-based therapy and multiple chemotherapy regimens. Thus, T-DM1 may offer a new standard in this population that has limited treatment options.

In addition, activity was seen in a subgroup of patients designated as HER2-normal by central testing, indicating that tumors with HER2 expression below currently used levels may respond to T-DM1. Very low plasma levels of free DM1 associated with the novel linker used in T-DM1 is likely responsible for the favorable efficacy and safety profile of this agent. Combined with recent positive data of ADC targeting CD30 in lymphoma, these data suggest that ADC may represent a novel therapeutic paradigm with broad applicability.

A phase III trial of T-DM1 will be conducted in patients randomly assigned to either single-agent T-DM1 or physician’s choice.

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