Emerging Therapies for HER2-Positive Metastatic Breast Cancer - Episode 5

Trastuzumab Deruxtecan for the Treatment of HER2+ Breast Cancer

December 24, 2019

Ian Krop, MD, PhD:As we discussed, T-DM1 [ado-trastuzumab emtansine] provided proof of concept that a HER2-directed antibody-drug conjugate can have efficacy and favorable tolerability in patients with pretreated HER2+ breast cancer.

Trastuzumab-deruxtecan is a new antibody-drug conjugate directed against HER2 that was designed to basically improve upon the benefits of the current generation of anti-HER2 therapies. Trastuzumab-deruxtecan is similar to T-DM1 [ado-trastuzumab emtansine] in that it’s based on a trastuzumab-like antibody. The antibody in trastuzumab-deruxtecan has the same amino acid sequence as trastuzumab. But it differs in that the payload, rather than being a microtubular inhibitor, is a topoisomerase 1 inhibitor payload. It’s actually a very potent version of a topoisomerase 1 [TOP1]. It’s roughly 10 times more potent than FM38, which is the active metabolite, or irinotecan.

The advantage potentially of using a TOP1 inhibitor is that this is not a kind of chemotherapy that’s typically used in breast cancer. So there’s less chance that cancers will have already seen this agent and have developed resistance to this type of chemotherapy. In addition, each antibody in trastuzumab-deruxtecan has approximately 8 payload molecules attached to it. This is roughly twice the number of cytotoxic molecules attached to the antibody as was seen with T-DM1 [ado-trastuzumab emtansine] and other antibody-drug conjugates. Potentially it can deliver more of the payload to each cancer cell.

And lastly, the payload of trastuzumab-deruxtecan is membrane permeable, which means that once it enters the cell, brought there by the antibody, it can then defuse back out of the cell and kill neighboring cells that weren’t targeted by the drug originally. This is the so-called bystander effect and is not felt to be the case with TDM-1 [ado-trastuzumab emtansine].

The trastuzumab-deruxtecan was initially evaluated in a phase I study in 115 patients who had had pretreated HER2+ breast cancer. All these had received TDM-1 [ado-trastuzumab emtansine] in the past. And in this patient population, trastuzumab-deruxtecan had a response rate of almost 60%. It looked [as if] it was an active drug, so the DESTINY-Breast01 study was designed as a phase II trial to confirm that this agent, trastuzumab-deruxtecan was active in pretreated HER2+ breast cancer.

This trial enrolled patients who had centrally confirmed HER2-positive advanced breast cancer. All the patients had had prior T-DM1 [ado-trastuzumab emtansine], and in fact this was a very heavily pretreated population. The median number of prior lines of therapy was 6, and these were all in the advanced disease setting.

All the patients had received prior trastuzumab, all had received prior T-DM1 [ado-trastuzumab emtansine]. Two-thirds had received prior pertuzumab, and over half had received other HER2-directed agents, mostly lapatinib. Again, a patient population whose cancers had progressed on most other HER2-directed therapies. All the patients received trastuzumab-deruxtecan at 5.4 mg/kg. There were 184 patients in this analysis. The drug is given every 3 weeks.

In terms of efficacy, the primary end point of the study was confirmed objective response by an independent radiology review. And in this study of 184 patients, this response rate was 60.9%: 6% were complete responses, and 55% were partial responses. So there was a very high response rate in this population, and these tended to be durable responses. The median duration of response was over 14 months, and the median progression-free survival was over 16 months. So this was not only widely active but also with durable benefit.

Also, when we looked at how the activity varied by different subgroups, it didn’t seem to matter whether patients had had prior pertuzumab or not. The response rate in patients who had prior pertuzumab was over 64%. Patients who had stable treated brain metastases also seemed to benefit similarly to those who did not have treated brain metastases.

Turning to the adverse effects of this drug, in general the most common adverse effects are gastrointestinal toxicities, such as nausea and vomiting, and fatigue. But these are almost all low-grade. However, neutropenia was also seen in about 35% of patients, but febrile neutropenia was very rare, less than 2% of patients. And alopecia happens in about half the patients.

But 1 toxicity that was noticed in the first phase I trial was pneumonitis, or interstitial lung disease. Because of that, in the phase II trial this toxicity was monitored closely, actually by an independent expert panel. This review identified 25 patients, or 13.6%, who had pneumonitis or interstitial lung disease [ILD]. Most of the cases were mild but 4 patients, or 2.2 %, actually had fatal ILD that were felt to be drug related.

Going forward, it’s important to monitor patients closely for symptoms of ILD, which include dyspnea, cough, or fever. If that’s noticed, this should be worked up promptly, the drug should be stopped, and corticosteroids should be started if ILD or pneumonitis is suspected.

Transcript edited for clarity.