TH3RESA is a randomized phase III open-label study, reported in The Lancet Oncology and summarized in this issue of The ASCO Post, which examined the activity of ado-trastuzumab emtansine (Kadcyla) in heavily pretreated HER2-positive metastatic breast cancer.¹ Formerly known as T-DM1, ado-trastuzumab emtansine is an antibody-drug conjugate that includes a cytotoxic agent, the maytansine analog DM1, linked to the anti-HER2 monoclonal antibody trastuzumab (Herceptin). In this way the drug is a Trojan horse—the trastuzumab, which is itself an effective drug, also acts as a vehicle to deliver a potent chemotherapy drug to the intracellular component of HER2-positive breast cancer cells.

Ado-trastuzumab emtansine was approved for use in the setting of pretreated disease after the EMILIA study, which compared the agent to the commonly used second-line combination of capecitabine plus lapatinib (Tykerb) in patients previously treated with taxane and trastuzumab. This trial proved ado-trastuzumab emtansine to be both more effective, with progression-free survival of 9 months vs 6 months and overall survival of 31 months vs 25 months, and less toxic than the control regimen.²

TH3RESA studied ado-trastuzumab emtansine in the more heavily pretreated setting and compared it to treatment of the physician’s choice. TH3RESA was a “win/win”; ado-trastuzumab emtansine once again outperformed treatment of the physician’s choice in both progression-free survival and toxicity, and there was a trend toward improved overall survival, although this last endpoint is immature.¹

TH3RESA Findings

The trial design was simple. To be eligible, women needed to have centrally confirmed HER2-positive metastatic breast cancer that had progressed on both trastuzumab and lapatinib and to have previously received a taxane. Participants were heavily pretreated, with a median of four prior lines of therapy. Reflecting the nature of HER2-positive disease, approximately three-quarters of patients had visceral involvement and 50% were both HER2- and hormone receptor–positive.

Enrolled patients were randomly assigned in a 2:1 fashion to ado-trastuzumab emtansine or treatment of the physician’s choice, which could include chemotherapy, endocrine therapy, and/or HER2-targeting, but could not include palliative care alone. Most (80%) of the control arm received a trastuzumab-based regimen.

The coprimary endpoints of the study were progression-free and overall survival. Progression-free survival in the ado-trastuzumab emtansine arm was 6.2 months vs 3.3 months in the control arm (hazard ratio = 0.53), while interim overall survival analysis revealed a trend toward a survival advantage that did not cross stopping boundaries. In addition to a 3-month improvement in remaining progression-free, patients treated on the ado-trastuzumab emtansine arm had significantly fewer adverse events—only 32% had grade 3 or greater toxicity compared with 43% in the control arm.

Toxicity of ado-trastuzumab emtansine, which has been lower than the comparator arm in all trials reported to date, was similar to previous reports; 5% had grade 3 or greater thrombocytopenia, and there was no evidence of either clinical or radiologic cardiac toxicity. Forest plot analysis suggested that all patient subsets benefited from ado-trastuzumab emtansine. Interestingly, patients with central nervous system involvement by tumor, a particular problem for HER2-positive metastatic breast cancer, appeared to be similarly advantaged by the use of ado-trastuzumab emtansine, with a progression-free survival hazard ratio of 0.47.

HER2 and Oncogene Addiction

For many HER2-positive metastatic breast cancers, continued targeting of this oncogene remains effective across multiple lines of therapy. This is why HER2-positive breast cancer is considered an example of “oncogene addiction,” in which the cell becomes solely dependent upon signaling from an individual pathway for growth and proliferation. Clinical evidence in support of this precept continues to mount, including the results of TH3RESA.

We now have four approved drugs for metastatic HER2-positive breast cancer—trastuzumab, the anti-HER2 heterodimerization domain monoclonal antibody pertuzumab (Perjeta), the HER1/HER2 small-molecule inhibitor lapatinib, and ado-trastuzumab emtansine. Appropriate use of these drugs at this point in time, taking TH3RESA into account, includes trastuzumab plus pertuzumab and a taxane in the first-line setting, ado-trastuzumab emtansine in the second-line setting, then capecitabine and lapatinib, although many other regimens including HER2-targeted drugs are reasonable. However, it should be noted that since neither EMILIA nor TH3RESA allowed crossover, these recommended lines of treatment serially maximize progression-free survival; it is not at all certain that the order of use matters for overall survival.

Studies not yet reported include MARIANNE, a three-arm study in the first-line setting comparing the control arm of taxane plus trastuzumab with ado-trastuzumab emtansine or ado-trastuzumab emtansine plus pertuzumab. In the adjuvant setting, only trastuzumab added to various chemotherapy regimens is approved (although pertuzumab added to trastuzumab plus chemotherapy gained accelerated approval in the neoadjuvant setting in 2012). Large adjuvant studies incorporating pertuzumab or lapatinib are due to be reported within the next few years, and adjuvant ado-trastuzumab emtansine trials are not far behind. The multiplicity of options available for controlling HER2-positive metastatic disease may within a few years be recapitulated in a menu of (neo)adjuvant options.

Conclusions

Ado-trastuzumab emtansine is an excellent addition to the HER2-targeting armamentarium, although like all HER2-targeted drugs it is extremely expensive at nearly $10,000 per month. The optimal timing of including this treatment is not clear, and establishing optimal timing would be beneficial, since patients with metastatic HER2-positive breast cancer often receive multiple lines of HER2-directed therapy over time.

TH3RESA confirms that, in addition to benefit in earlier-line treatment shown in the EMILIA trial, ado-trastuzumab emtansine is more effective and less toxic than other options in heavily pretreated patients who have had disease progression on multiple prior HER2-targeting regimens. A role in the first-line and adjuvant settings remains to be demonstrated, but this is a drug that is clearly good at the two goals of therapy for metastatic breast cancer—disease control and tolerability. ■

Disclosure: Dr. Carey reported no potential conflicts of interest.

References

1. Krop IE, Kim SB, González-Martín A, et al: Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): A randomised, open-label, phase 3 trial. Lancet Oncol. May 1, 2014 (early release online).

2. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.