Though Much on the Horizon in HER2+ Breast Cancer Treatment, There Is Still Work to Be Done

Mark Pegram, MD

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 withTargeted Oncology, 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.

TARGETED ONCOLOGY:Please discuss the current treatment landscape in HER2+ breast cancer.

Pegram:

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.

New antibody-drug conjugate strategies have emerged, as well. These look like they’d probably facilitate intercellular internalization and trafficking through the lysosome compared to T-DM1 and seem to have activity even in T-DM1—resistant preclinical models. So those molecules are moving forward, as well as MedImmune 4276 molecules that are already in human phase I studies.

There are a couple papers that came out looking at HER2 antibodies in combination with checkpoint inhibitor antibodies, including T-cell checkpoints like CTLA-4, PD-1, and PD-L1. It looks like HER2 antibodies, indeed T-DM1, may potentiate the activity of those checkpoint antibodies in preclinical models, and those are moving forward into clinical development.

Additionally, there has been some preliminary unpublished work on combinations with CD47 antibodies, which is the checkpoint for macrophage-mediated phagocytosis against tumor targets, and that looks to be synergistic in combination with trastuzumab.

TARGETED ONCOLOGY:So T-DM1 is best administered as a monotherapy rather than in combination with other agents?

Pegram:

Usually T-DM1 is given as a single agent, because the pertuzumab combination failed to show superiority over standard treatment, and the chemotherapy combinations have been problematic in terms of safety. We published a paper on weekly paclitaxel in combination with T-DM1 and pertuzumab, and that had too much neurotoxicity by my estimation to be a feasible regimen.

TARGETED ONCOLOGY:Could you discuss the role of CD47 in this setting?

Pegram:

CD47 is upregulated on most tumor types, and it decorates tumor cells and masquerades as cells against macrophage recognition and macrophage phagocytosis. So if you break that checkpoint with a blocking CD47 antibody, macrophages will then recognize the tumor cells as being foreign, engulf them through phagocytosis, and digest them.

This is true not only in breast cancer, but in many other tumor types, including acute leukemia. It’s a very interesting target, and there’s a lot of excitement and activity in this area, and a number of trials already in progress.

And there are now preclinical data looking at novel combinations with CD47 antibodies, including combinations with trastuzumab, and that data are in the public domain.

TARGETED ONCOLOGY:What trials are you most excited about?

Pegram:

I’m really excited by new antibody-drug conjugates (ADCs) targeting HER2. There was a paper published recently by a group at MIT in collaboration with others, that really looked very intensely at mathematical modeling of the fate of ADCs like T-DM1 in terms of their binding to the targets, their internalization properties, the rate at which they enter the lysosome and are degraded, the rate of efflux of the cytotoxic payload, and the rate of efflux out of the cell, which might be a resistance mechanism.

When you put all those steps together, it really looks like some of the rate-limiting steps are the internalization steps and the trafficking to the lysosome steps. In theory, if you could build new ADC molecules that facilitated those 2 steps, you might have a better drug than T-DM1.

So it’s like giving a combo of trastuzumab and pertuzumab. It binds to those same 2 epitopes, but instead of binding to those 2 epitopes on 1 HER2 molecule, instead it cross-links adjacent to the 2 receptors and causes a lattice of HER2 in the cell membrane, and that’s a very potent stimulus for receptor-mediated endocytosis. So that speeds up the receptor-mediated endocytosis internalization step, and also it probably helps trafficking through the lysosome to proceed more efficiently. So it kind of tackles some of those weaknesses, in theory, of T-DM1 and might prove to be better.

I think it’s very likely that using either combinations or sequences of different ADCs would be superior to any one alone. Just like we use sequences and combinations with chemotherapy in solid tumors, combinations and sequences are typically superior to any single agent alone. Consequently, I think that paradigm might hold up for ADCs as well. Then finally, the immune modulation with all these HER2-targeting drugs is very intriguing. It’s been shown that lapatinib, for example, causes increased display of HER2 in the membrane, so that might be more amenable to antibody-based therapeutics.

TARGETED ONCOLOGY:What do you hope to see in HER2-positive breast cancer in the next 5 to 10 years?

Pegram:

I think there will probably be a kind of renaissance, and we’ll continue seeing combinations with checkpoint inhibitors. No doubt, this class of drugs has already revolutionized solid tumor oncology for melanoma, non—small cell lung cancer, and other diseases. And I bet there’s potential in combination with HER2-targeted agents to do the same for HER2-positive metastatic breast cancer.

As I mentioned, I’m very excited about new ADCs with different targeting epitopes that facilitate internalization and trafficking and also different payloads. I think there will need to be a portfolio of HER2 ADCs from which to choose, and perhaps even sequence, to better exploit this approach. So overall, augmenting immunity, and having more clever strategies for delivering cytotoxic payloads for HER2 targets, are just a little bit of what I’d like to see.