T-DM1: A Novel and Effective Immunoconjugate for the Treatment of HER2+ Breast Cancer

Abstract

Trastuzumab-derivative of maytansine-1 (trastuzumab emtansine; T-DM1) is a novel antibody-drug conjugate that combines an antibody targeted specifically to HER2- overexpressing cancer cells with maytansine, a potent cytotoxic agent. In comparison with lapatinib and capecitabine in patients with trastuzumab-resistant HER2+ advanced breast cancer, treatment with T-DM1 resulted in improved progression-free and overall survival, with a superior safety profile. Ongoing clinical trials are investigating T-DM1-based therapy in combination with other chemotherapy agents, with other targeted agents, and as treatment for early-stage HER2+ breast cancer and other malignancies.

Between 20% and 25% of all breast cancers overexpress the HER2/neu receptor or have amplification of the HER2 (ErbB2) gene, with about half also expressing the estrogen receptor. Before the introduction of targeted therapy, HER2-expressing (HER2+) breast cancers were associated with a high risk of short-term recurrence and shorter overall survival (OS).^1,2 Trastuzumab, a humanized monoclonal antibody targeting the HER2/neu receptor, was approved by the FDA in 1998 for the treatment of HER2+ metastatic breast cancer (mBC),^3,4 and in 2006 for the treatment of early-stage disease. In the advanced-disease setting, trastuzumab administered as monotherapy exerts a modest antitumor effect but has marked synergistic antiproliferative effects when combined with cytotoxic agents.^5-7

Although trastuzumab combined with chemotherapy has become the standard of care for the treatment of HER2+ mBC, up to 50% of patients present with de novo resistance.⁸ Progression-free survival (PFS) following treatment with trastuzumab combined with taxane-based chemotherapy is only about 1 year.^9,10 PFS can be extended to about 18 months with the addition of pertuzumab, a novel HER2-targeted antibody approved in this setting by the FDA in June 2012.¹¹ Chemotherapy combined with trastuzumab in the early-stage setting has significantly improved disease-free survival (DFS) and OS; however, relapses continue to occur even years after initial treatment.^6,7,12 In addition, improved OS in both early- and late-stage disease with trastuzumab has been seen only when the antibody is given in combination with chemotherapy, and hence, concomitant chemotherapy toxicity.

Antibody-drug conjugates, which combine the specific targeting capacity of antibodies with the cytotoxic effects of highly potent fusion agents, offer a novel alternative that has the potential to both overcome resistance and reduce systemic toxicity. To date, only brentuximab vedotin (Adcetris) has been approved by the FDA and is used in clinical practice for the treatment of Hodgkin lymphoma and anaplastic large-cell lymphoma, although multiple agents are being studied in clinical trials.

Drug Design and Preclinical Studies

Three challenges exist in the creation of an effective antibody-drug conjugate. These include identification of a target uniquely expressed in the cancer of interest, a cytotoxic agent with potency at low concentration, and a linker that can deliver a toxin to the cancer cell without releasing drug into the systemic circulation. HER2 is an ideal target for this approach, given that it is not overexpressed in the majority of normal cells (the heart being a notable exception), and overexpression is preserved in tumors progressing on trastuzumab-based therapy.

Microtubule function is necessary for cell division, as well as for a number of other essential functions. Drugs that interfere with this function are effective cytotoxic agents and are highly active in the treatment of breast cancer. Both paclitaxel and docetaxel have demonstrated preclinical synergy, as well as significant antitumor efficacy when given in combination with trastuzumab for the treatment of HER2+ breast cancer.^10,13


Maytansinoids, which are derivatives of the antimitotic drug maytansine, represent a novel class of agents that disrupt microtubule function. These agents bind directly to microtubules to inhibit polymerization in a manner similar to the vinca alkaloids. Efforts to develop maytansine into a clinically useful anticancer drug proved disappointing due to severe toxicities in phase II trials.¹⁴ Antibody-drug conjugates offer a means of introducing a highly potent drug while reducing systemic toxicity by allowing delivery of a small dose of cytotoxic agent directly to cancer cells, making maytansine an ideal choice for this purpose.

The linker selected to bridge antibody and toxin must be capable of maintaining molecular stability while in circulation but must be amenable to proteolytic cleavage once inside cancer cells. ¹⁵ The thioether (MCC) linker protein (Figure), which contains a cyclohexane carboxylate spacer, was found after considerable research to fit both requirements and was selected as the conjugate linking trastuzumab to a derivative of maytansine to create trastuzumab-MCC-DM1 (T-DM1). ¹⁶ T-DM1 is internalized upon binding to HER2+tumor cells and is postulated to then undergo intracellular proteolytic degradation to release active maytansinoid (lysine-Nε- MCC-DM1). Since it is a zwitterion (a neutral molecule with a positive and a negative electrical charge at different locations within that molecule), lysine-Nε-MCC-DM1 does not readily cross the plasma membrane of adjacent normal cells, which limits nontarget toxicity.

In vivo, T-DM1 has been shown to selectively inhibit cell growth and induce cell death in HER2+ cancer cell lines. In addition, T-DM1 has been shown to inhibit growth and cause tumor regression in HER2+ breast cancer xenograft animal models.¹⁷

Clinical Studies

In the first-in-human phase I study, 24 heavily pretreated patients with HER2+ mBC who had previously progressed on trastuzumab received T-DM1 every 3 weeks in dosages ranging from 0.3 mg/kg to 4.8 mg/kg. ¹⁸ The maximum tolerated dose (MTD) was determined to be 3.6 mg/kg; the dose-limiting toxicity was transient grade 3 thrombocytopenia. Among the 15 patients who received the MTD, the clinical benefit rate (CBR) was 73%, and the objective response rate (ORR) was 44%. In a second phase I study exploring weekly dosing of T-DM1, the MTD was determined to be 2.4 mg/kg; ORR was 46%, CBR was 57%, and median duration of response (DOR) was 18.6 months. ¹⁹ In both trials, T-DM1 was relatively well tolerated.
Based on these remarkable results, two sequential phase II studies exploring dosing of T-DM1 every 3 weeks were conducted in over 100 patients with heavily pretreated HER2+ mBC. The first trial included patients progressing on prior trastuzumab and chemotherapy,²⁰ and the second trial included patients progressing on trastuzumab, the oral tyrosine kinase inhibitor lapatinib, taxanes, anthracyclines, and capecitabine.²¹ In the first trial, ORR was 37.5% and PFS was 4.6 months, with a median DOR of 9.4 months. In the second trial, results were similar despite the extensive prior treatment, with an ORR of 34.5%, CBR of 48.2%, PFS of 6.9 months, and median DOR of 7.2 months.

These trials enrolled patients who had previously progressed on trastuzumab-based therapy and chemotherapy. Hurvitz and colleagues²² reported a randomized, phase II study that com-pared T-DM1 to the combination of docetaxel and trastuzumab as first-line therapy for 137 patients with treatment-naïve HER2 + mBC. Preliminary results, which were reported at the European Society for Medical Oncology (ESMO) meeting in 2011, demonstrated a significant improvement in both ORR and PFS in patients treated in the T-DM1 arms compared with those treated with docetaxel and trastuzumab (Table 1). Interestingly, there was less toxicity in the T-DM1 arm.

Results of the first phase III trial to demonstrate superiority of T-DM1 compared with standard therapy were recently presented at the American Society of Clinical Oncology meeting in June 2012.²³ EMILIA is a randomized, phase III study comparing T-DM1 (3.6 mg/kg every 3 weeks) to capecitabine plus lapatinib in nearly 1000 patients with advanced breast cancer pro first phase III trial to demonstrate superiority of T-DM1 compared with standard therapy were recently presented at the American Society of Clinical Oncology meeting in June 2012.²³ EMILIA is a randomized, phase III study comparing T-DM1 (3.6 mg/kg every 3 weeks) to capecitabine plus lapatinib in nearly 1000 patients with advanced breast cancer progressing on trastuzumab and a taxane. The primary endpoint, PFS, was significantly longer in patients receiving T-DM1 compared with those treated with capecitabine plus lapatinib (9.6 months vs 6.4 months; P < .001). With the exception of the 138 patients older than age 65 years, this benefit was maintained across all subgroups. At the time of the initial presentation, OS was 23.3 months for the capecitabine and lapatinib group, while OS had not yet been reached in the T-DM1 group (hazard ratio [HR] = 0.621; P = .0005, not considered significant based on the EMILIA statistical plan).

Updated survival results were presented at the ESMO meeting in Sep¬tember 2012, and were published with the full study results on the same day in The New England Journal of Medicine.²⁴ At a median follow-up of about 19 months, and after 331 deaths, OS was significantly longer in patients treated with T-DM1 compared with those treated with lapatinib and capecitabine, reaching the prespecified study endpoint (30.9 vs 25.1 months, respectively; HR = 0.682; P < .001). Final survival data are ex¬pected in 2014. These data are summarized in Table 1. An application has been submitted to the FDA for T-DM1 based on these data, and approval is expected in late 2012 or early 2013.

Toxicities

Since the targeted specificity of the antibody-drug conjugate design al¬lows targeted delivery of highly potent cytotoxic agents, side effects are significantly moderate. In clinical trials, the most common adverse events in patients treated with T-DM1 were grade 1/2 fatigue and nausea. In the phase I trial, with dosing every 3 weeks, the dose-limiting toxicity of T-DM1 was transient thrombocytopenia, with the most common grade 3 toxicities being transaminitis and thrombocytopenia. The phase II trials reported an 8% rate of grade 3/4 thrombocytopenia²⁰ and a 6% rate of grade 3/4 transaminitis. ²¹

In the recently reported EMILIA phase III trial, 89% of patients in the lapatinib/capecitabine arm experienced grade ≥3 adverse events, com¬pared with only 46% of patients in the T-DM1 arm; only 5.9% (29 patients) required treatment discontinuation due to toxicity in this arm compared with 10.7% (52 patients) treated with lapatinib plus capecitabine (Table 2). ²³ Both thrombocytopenia and transaminase elevation responded to holding drug and dose reductions, when necessary. Patients treated with lapatinib/capecitabine had a higher incidence of grade 3/4 diarrhea (20. 7 vs 1.6%) and hand-foot syndrome (16.4 vs 0%). In contrast, grade 3/4 thrombocytopenia was more common in patients treated with T-DM1 (12.8 vs 0.2%) but rarely led to hemorrhage. Transaminases were increased more frequently with T-DM1 as well, but grade 3/4 elevations occurred in less than 5% of study patients.

Thrombocytopenia associated with T-DM1 has a predictable cyclical pattern; in most patients, platelet counts are lowest at day 8 and recover by day 18. The etiology of T-DM1–associated thrombocytopenia is not well understood, although a recent article describes a model that can be used to predict the time course of this effect.²⁵ Cardiotoxicity, which is known to be associated with HER2-targeted therapy, was not increased in the T-DM1 arm compared with the control arm (1.7% vs 1.6%, respectively).²³ Patient-reported outcomes documented a significantly shorter time to symptom progression using the Functional Assessment of Cancer Therapy-Breast (FACT-B ) Trial Outcome Index in patients treated with capecitabine and lapatinib versus T-DM1 (4.6 vs 7.1 months; HR = 0.8; P = .012). In addition, and particularly important to patients with both advanced and early-stage disease, treatment with T-DM1 is not associated with significant hair loss.

Ongoing Trials

A number of clinical trials are being conducted in both the HER2+ early-stage and metastatic settings (Table 3). In these studies, T-DM1 is either given as a monotherapy or is combined with cytotoxic agents or other HER2-targeted therapy. One area of interest is treatment of small (T1b), node-negative, HER2+ breast cancers. Recent studies have reported a higher risk of recurrence in these tumors compared with patients with HER2-negative disease,²⁶ but standard chemotherapy with trastuzumab seems potentially too aggressive for the extent of disease. The favorable toxicity seen with T-DM1 marks it as an attractive agent to study in this setting. The ability of T-DM1 to overcome at least some aspect of resistance in advanced disease also makes the post-neoadjuvant setting appealing, as treatment for patients with extensive residual disease following neoadjuvant therapy containing trastuzumab. In addition, T-DM1 will be tested in HER2+ gastric cancer, another malignancy that benefits from HER2-targeted therapy.²⁷

Conclusion

Given on a dosing schedule of 3.6 mg/kg every 3 weeks, T-DM1 appears to be well-tolerated and has demonstrated marked clinical efficacy in patients with HER2+ mBC who have previously progressed on other HER2-targeted therapies. The expected approval of T-DM1 will change our approach to treating patients with HER2+ mBC, further improving therapeutic efficacy and reducing toxicity. Ongoing studies are anticipated to determine the efficacy of T-DM1 in combination with other HER2-targeted agents, in combination with chemotherapy, in early-stage disease, and in other HER2+ malignancies.

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