HER2+ BC: A Year in Review and Updates from SABCS - Episode 9

SABCS 2020: PERTAIN Updates in HER2+, HR+ MBC

February 2, 2021
Targeted Oncology

Hatem Soliman, MD, reviews statistically significant data from the PERTAIN study, presented at the 2020 San Antonio Breast Cancer Symposium.

Hatem Soliman, MD: The discussion on how we manage toxicity and protect patients from neuropathy is important. There was an update from the standpoint of progression-free survival [PFS] looking at outcomes from a strategy for treating those we call routinely triple positive, in our practice, those who have both hormone receptor-positive and HER2-positive disease.

The update was presented by [Grazia] Arpino, [MD, PhD,] for the PERTAIN study, which was a randomized 2-arm, open-label, multicenter phase 2 trial that was assessing the efficacy and safety of first-line pertuzumab in combination with trastuzumab and chemotherapy. An aromatase inhibitor [AI] was used for those who were HER2+ and had hormone receptor-positive metastatic breast cancer, and those who were locally advanced, unresectable. We’ve known for some time that there is crosstalk between the estrogen receptor signaling pathway and HER2, and even the HER2 can be an escape mechanism for estrogen receptor sensitivity and escape.

The TAnDEM study had shown evidence of an improved outcome for these patients with triple-positive disease when combining trastuzumab with an AI over using an AI alone, albeit it was pretty modest by today’s standards, but at least it gave us that initial hint that we were doing something beneficial.

The study took post-menopausal women with HER2+ and ER-positive disease, about 206 patients who were randomized to 1 of 2 treatment arms, either getting pertuzumab and trastuzumab plus an aromatase inhibitor, or trastuzumab alone plus an aromatase inhibitor. In both groups, the patients were allowed to get induction chemotherapy with a taxane of the physician’s choice; they could’ve either been treated with docetaxel or paclitaxel for up to 24 weeks prior to switching to the endocrine therapy and anti-HER2 therapy backbone.

What the updated analysis demonstrated, based on the progression-free survival for patients who got the treatment, for the intent-to-treat population, it was 20.6 months for the pertuzumab/trastuzumab arm, and 15.8 months for the trastuzumab alone arm. This difference was highly statistically significant. The median overall survival in the intent-to-treat was 60 months for the pertuzumab/trastuzumab arm and 57.2 months for the trastuzumab alone arm. It’s in keeping with the CLEOPATRA trial, in terms of overall survival that we saw. Looking at the subset analysis for progression-free survival in patients who received induction chemotherapy versus those who did not, the median PFS of both groups that got induction was around 16.9 months. There wasn’t a big difference in the median PFS on the curves. There did appear to be a little separation in terms of the tails for the combination compared to trastuzumab alone, after that point, whereas in the patients who did not get induction chemotherapy, the median PFS was 26.6 months for the combination arm versus 12.5 months for just the trastuzumab alone, and it was highly statistically significant in that regard.

In terms of looking at efficacy, it was a reassuring signal at least that if you wanted to try to give patients a break after their induction taxane chemotherapy, or if you wanted to start with endocrine treatment right up front, these patients can have good outcomes overall. When looking at the level of toxicities, it was what we would expect with the combination and with the single-agent trastuzumab arm, in terms of a little higher diarrhea rates with the combo versus trastuzumab alone. There didn’t appear to be any major safety signals that were concerning, and the induction chemotherapy was as expected. This gives us a strategy for sparing patients from cumulative neuropathy over time, for these triple-positive patients, as well.

Andrew Seidman, MD: For the REVEAL trial, I was on the data monitoring committee, and we thought long and hard about what it meant to see a greater delta in PFS for those patients, whereby physician discretion, the doctor chose not to give chemotherapy. The choice to get lead-in taxane therapy was up to the physician, so one would think that those patients would have a higher disease burden, more visceral disease, and that was true to a certain extent. When you let doctors be doctors, and physicians choose not to give lead-in chemotherapy, giving an AI with trastuzumab and pertuzumab instead, you get a 26.6-month PFS.

This isn’t something that I do frequently, but if I have a frailer, older patient, whose heart is healthy enough to get HER2 antibodies, this is one way to avoid chemotherapy. The Novartis analysis of MONALEESA studies, where the HER2-enriched group getting ribociclib did particularly well, makes one think that in the future we may want to be thinking about anti-estrogen therapies, HER2-targeted therapies, and CDK4/6 inhibitors in this group. This is a boutique study that can still be applied to certain specific populations. It’s not going to lead to any registration, so we’re not going to be seeing advertisements from Genentech for this use, but it’s great for doctors who treat breast cancer to know that this a reasonable approach.

Transcript edited for clarity.