Mark Pegram, MD
Though some clinicians may characterize the treatment landscape of HER2-positive breast cancer as overcrowded, Mark Pegram, MD, firmly believes that there is still much to learn in this space.
“Just because we have a couple of antibodies in development, it doesn’t mean our work is done. There’s still a lot to do, and no one should consider this space closed to innovation or future breakthrough strategies,” said Pegram, who is the director of the Breast Cancer Oncology Program at Stanford Women’s Cancer Center.
In an interview with OncLive
, Pegram sheds light on some of the recent groundbreaking trials in HER2-positive breast cancer and how they have come to shape the current treatment paradigm. He also shares his excitement for the future role of antibody-drug conjugates and other emerging agents in this setting.
OncLive: Please discuss the current treatment landscape in HER2+ breast cancer.
: The CLEOPATRA trial was a phase III, double-blind, randomized, placebo-controlled trial that evaluated HER2-antibody blockade with both single-agent pertuzumab (Perjeta) and single-agent trastuzumab (Herceptin) in combination with docetaxel as first-line therapy in metastatic HER2-positive disease. And this trial originally showed us that the combination of pertuzumab, trastuzumab, and docetaxel, compared with docetaxel and trastuzumab plus placebo, prolonged progression-free survival.
More recently, the final overall survival (OS) results were reported, with a median OS of 56.5 months for patients who received the pertuzumab combination, compared with 40.8 months for patients who received the placebo combination.
So given those results we saw with the CLEOPATRA trial, it’s likely we could substitute weekly paclitaxel for docetaxel in the CLEOPATRA regimen, and enjoy similar efficacy with less toxicity, so that’s a logical next step for that regimen.
Beyond pertuzumab plus trastuzumab in the first line, T-DM1 (ado-trastuzumab emtansine; Kadcyla) has been tried in combination with pertuzumab in first-line metastatic breast cancer, but failed to beat the chemotherapy plus trastuzumab control arm in the MARIANNE study. So, as much as we would have hoped that T-DM1 could emerge as a competitor against CLEOPATRA with chemotherapy, that was not realized in the randomized phase III MARIANNE study. Consequently, the pertuzumab/trastuzumab/chemotherapy combination was named the preferred first-line regimen.
Interestingly, the TDM-1 plus pertuzumab combination has also been tested in the KRISTINE neoadjuvant study, where it failed to beat a CLEOPATRA-like regimen of docetaxel, carboplatin, trastuzumab plus pertuzumab. So that’s 2 trials where T-DM1 plus pertuzumab has failed to beat chemotherapy-containing controls with either 1 or 2 added antibodies. So that firmly locks in the CLEOPATRA regimen for the first line, or CLEOPATRA-like regimens for the first line.
In the second line, we still have T-DM1 based on the EMILIA pivotal trial data. Interestingly, the EMILIA trial was not done in the pertuzumab first-line era, so the question then becomes, how well does T-DM1 work after pertuzumab and trastuzumab and chemotherapy? That’s been answered in some community-based review papers, where T-DM1 after a CLEOPATRA-like regimen still seems to retain significant clinical activity with response rates between about 18% and 26%, depending on which paper you read.
So it looks like T-DM1 retains significant activity in the pertuzumab era, although the response rates reported from retrospective chart reviews are certainly lower than that observed in the EMILIA trial. But the amount of time to disease control is still of great clinical interest. T-DM1 seems to be locked into position in second-line metastatic disease setting following a CLEOPATRA-like regimen in the first line.
After T-DM1, most individuals are moving to small molecule kinase inhibitors. Lapatinib (Tykerb) still has a place, perhaps. It’s most frequently combined in the third line with either capecitabine or with trastuzumab, so that’s still a very popular regimen in later lines. In fourth-line, after a lapatinib-containing regimen, most clinicians default to a chemo du jour plus trastuzumab regimen, if patients are still having good performance status at that juncture.
There are also new therapeutic strategies targeting HER2 that are in clinical investigation. These include small molecule inhibitors, such as the Oncothyreon molecule (ONT-380), that has more specificity to HER2 than EGF receptor. So it has less toxicity compared to lapatinib and hopefully preserves efficacy against HER2-altered disease.