Expanding Options for Relapsed/Refractory HER2+ Metastatic Breast Cancer - Episode 2

Trastuzumab Emtansine in HER2+ Breast Cancer

July 7, 2020
Targeted Oncology

Julie R. Gralow, MD: Mark, let’s talk about the role of T-DM1, trastuzumab emtansine, in advanced HER2 [human epidermal growth factor receptor 2]–positive breast cancer.

Mark Pegram, MD: It’s been quite awhile since the FDA approval of the EMILIA pivotal trial, the randomized phase 3 study comparing T-DM1 [trastuzumab emtansine] head-to-head against capecitabine and lapatinib in patients who had had prior taxane and trastuzumab. T-DM1 [trastuzumab emtansine] as a result of that published data has been considered the go-to second-line agent following a CLEOPATRA-like regimen now for the past several years. In the EMILIA trial, which was 991 patients, the objective response rate in the T-DM1 [trastuzumab emtansine] arm was about 43.6%, so that was higher than the control arm of about 31%. And the median duration of response was over a year in the T-DM1 [trastuzumab emtansine] arm versus about 6½ months in the control arm.

Moreover, in our final overall survival analysis that was published in Lancet Oncology in 2017, the median overall survival was also longer with T-DM1 [trastuzumab emtansine] compared with control, 29.9 months versus 25.9 months. The hazard ratio was 0.75, and that’s despite the fact that 27% of the patients actually crossed over from the control CAPE [capecitabine]–lapatinib arm to T-DM1 [trastuzumab emtansine] during the course of their treatment.

The other data set, in terms of looking at expected response rates, is the TH3RESA trial. This is a phase 3 trial in more heavily pretreated HER2-positive metastatic breast cancer patients who had had 2 or more prior lines of HER2-targeted therapy as an eligibility criteria. In that study, there was a significant improvement in progression-free survival favoring T-DM1 [trastuzumab emtansine] as compared with a control arm that was treatment of physician’s choice, which was essentially chemotherapy du jour along with trastuzumab for most of the patients. The hazard ratio favoring T-DM1 [trastuzumab emtansine] was about half with high statistical confidence.

Overall survival was significantly longer with T-DM1 [trastuzumab emtansine] versus treatment of physician’s choice as well, over 22 months versus about 16 months for the control arm. That difference was statistically significant. The response rate in the case of T-DM1 [trastuzumab emtansine] in this more heavily pretreated population was 31.3% versus 8.6% for control. Both of these set the stage for the approval of T-DM1 [trastuzumab emtansine] and its place in the landscape of treating HER2-positive in the second line following a CLEOPATRA-like regimen. That CLEOPATRA regimen has an extraordinary overall survival benefit that it remains entrenched as the first-line preferred option even in 2020, unless patients have recently been exposed to the dual-antibody combination, of course.

Julie R. Gralow, MD: What about the toxicity of T-DM1 [trastuzumab emtansine] in comparison with some of the other regimens?

Mark Pegram, MD: Of course, with T-DM1 [trastuzumab emtansine], the most frequent adverse drug reactions are going to be fatigue, nausea, muscle pain, thrombocytopenia, transaminase elevation, headache, and constipation. All those have frequencies greater than 25% in the pivotal EMILIA clinical trial. One has to be mindful of those potential adverse events, and there are dose modifications available in the prescribing information, so clinicians should refer to those religiously to mitigate against these types of complications.

I want to add also that the response data that I mentioned from EMILIA and from the TH3RESA trial were in patients who had never had pertuzumab, for the most part, in those studies since these studies were done prior to the approval of pertuzumab in metastatic breast cancer. Consequently, there have been more recent updated data looking at a cohort of 77 patients published by our colleague from Italy, Dr Pierfranco Conte. That group was previously treated with pertuzumab, and the T-DM1 [trastuzumab emtansine] objective response rate in that cohort was 27%. Nearly 40% continued on treatment for at least 6 months with disease under control.

Julie R. Gralow, MD: It’s nice that T-DM1 [trastuzumab emtansine] does not cause a lot of alopecia, as opposed to a couple of more recently approved antibody-drug conjugates in breast cancer that do. When we talk about options—and there are lots of options for patients who haven’t been head-on compared, so we don’t know the correct order—not losing your hair would be important for some of our patients. I have a patient who had a significant hepatotoxicity with T-DM1 [trastuzumab emtansine]. And I’ve used a lot of T-DM1 [trastuzumab emtansine]. This is rare, but it’s been reported. Have you had any experience with that?

Mark Pegram, MD: I’ve seen 1 case, actually. When I was giving a lecture in Asia, they presented a case to me of a patient with a rather acute onset of signs and symptoms of portal hypertension, no transaminase elevation. This is 1 syndrome that clinicians must be mindful of because it’s so important and because it happens generally without transaminase elevation. This condition is called nodular regenerative hyperplasia. The diagnosis can be established only by biopsy of the liver, so it’s critical if you see a patient like that to get a liver biopsy, confirm the diagnosis, and then T-DM1 [trastuzumab emtansine] is contraindicated thereafter. It’s a very important point. These are really uncommon, even rare. It’s a rare syndrome, but if you see it you really need to act.

Julie R. Gralow, MD: It’s serious, yeah. What excites you about some of the ongoing studies with T-DM1 [trastuzumab emtansine] in metastatic breast cancer?

Mark Pegram, MD: The most interesting ongoing trial arguably is the combination with tucatinib, and this has already reached a phase 3 trial. It’s tucatinib versus placebo in combination with T-DM1 [trastuzumab emtansine] for patients with HER2-positive advanced breast cancer; 460 patients will be enrolled. The study started in October 2019, and the estimated primary completion date will be in April 2024. There had been a prior phase 1b clinical trial of this combination, published by Virginia Borges, et al, and there was no PK [pharmacokinetic] interaction between these 2 drugs. The full dose with tucatinib was feasible, although higher doses was not. There was an expansion cohort of 50 patients, and 34 of those, that’s 68%, treated with the maximum tolerated dose had measurable disease and were evaluable for response, had objective responses, for a response rate of 47%. The median progression-free survival of that expansion cohort was about 8.2 months. That’s an interesting combination. If the pivotal trial is positive, and if it’s well tolerated, this could be a practice-changing result to look forward to in the future.

Transcript edited for clarity.