Anticancer agent – trastuzumab emtansine

Around a fifth of all breast cancers are positive for the overexpression of receptor tyrosine kinase erbB-2, or HER2. Roche’s Herceptin (trastuzumab) and GSK’s Tykerb/Tyverb (lapatinib) target this gene, but some women with HER2 positive breast cancer do not respond to this treatment, while others develop resistance to it.

Trastuzumab emtansine, an alternative being developed by Roche group companies Genentech and Chugai, links the Herceptin antibody to the antimicrotubule agent emtansine, with the antibody being used to target the cytotoxic agent directly to the tumour.¹ The two components are linked using a novel non-reducible thioether, which proved more active than the reducible disulfide groups that are typically used as linkers.

Several clinical trials have been carried out. In an open label, single arm Phase II study, 112 patients with HER2-positive metastatic breast cancer were given 3.6mg/kg of trastuzumab-DM1 every three weeks. In all the subjects, the tumours had progressed after prior treatment with a HER-2 directed therapy, and they had also received chemotherapy.² The objective response rate in this heavily pretreated patient group after at least 12 months was 26%, and the median progression-free survival time was 4.6 months. Higher response rates were seen in those women whose tumours expressed greater than median HER2 levels. It was well tolerated, with no dose limiting cardiotoxicity being observed. The most common serious adverse events were hypokalaemia, thrombocytopenia and fatigue.

In another open label, single arm Phase II trial, 110 HER2-positive metastatic breast cancer patients who had progressed on trastuzumab or lapatinib and other anticancer agents were given the same intravenous dose of the new treatment.³ Just over a third experienced an objective response, although no complete responses were observed. There was a median progression-free survival of 6.9 months, and the median duration of response was 72 months.

A further Phase II trial, this time randomised, compared 3.6mg/kg trastuzumab emtansine every three weeks with trastuzumab plus docetaxel in 137 HER2-positive metastatic breast cancer patients who had not previously been treated for metastatic disease.⁴ The group given the new agent had an overall response rate of 64%, with seven complete responses, compared with 58% with three complete responses in the combination therapy group. The incidence of adverse effects was slightly lower in the trastuzumab emtansine group.

Two Phase III trials are now underway. In one, it is being investigated when given either with or without pertuzumab compared with trastuzumab plus taxane;⁵ in the other, it is being compared with lapatinib plus capecitabine.⁶

references

1. G.D. Lewis-Phillips et al. Cancer Res. 2008, 68, 9280

2. H.A. Burris III et al. J. Clin. Oncol. 2011, 29, 398

3. I. Krop et al. Ann. Oncol. 2010, Abst 2770

4. S. Hurvitz et al. Eur. J. Cancer. 2011, 47 (suppl. 2), Abst. 5001

5. P.A. Ellis et al. J. Clin. Oncol. 2011, 29 (suppl.), Abst. TPS102

6. S. Verma et al. J. Clin. Oncol. 2011, 29 (suppl.), Abst. TPS116