Immunotherapy to Treat Metastatic HER2-Positive Breast Cancer: ESMO 2019 Coverage
Leisha Emens, M.D.
September 29, 2019

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Dr. Leisha Emens is professor of medicine in hematology/oncology at the University of Pittsburgh Hillman Cancer Center. She is also co-leader of the Hillman Cancer Immunology and Immunotherapy Program and director of translational immunotherapy for the Women’s Cancer Research Center. She is internationally recognized for her work in breast cancer immunotherapy.

At the European Society for Medical Oncology 2019 Congress, she presented overall survival results from the KATE2 study, which compared using the combination of Tecentriq, also called atezolizumab, and Kadcyla, also called T-DM1, to Kadcyla alone to treat HER2-positive metastatic breast cancer that had grown while being treated with Herceptin and chemotherapy.

Listen to the podcast to hear Dr. Emens discuss:

  • the design of the KATE2 study
  • why the study is encouraging, even though it didn't meet its primary endpoint
  • what the results mean for people diagnosed with HER2-positive metastatic breast cancer
  • her advice to people diagnosed with breast cancer who are interested in immunotherapy

Running time: 10:04

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This podcast is made possible by the generous support of Lilly Oncology. 

Jamie DePolo: Hello! Welcome to the Breastcancer.org podcast. I’m your host, Jamie DePolo, senior editor at Breastcancer.org. We’re podcasting live from the European Society for Medical Oncology 2019 Congress in Barcelona, Spain. 

My guest is Dr. Leisha Emens, professor of medicine in hematology and oncology at the University of Pittsburgh Hillman Cancer Center. She is also co-leader of the Hillman Cancer Immunology and Immunotherapy Program and director of translational immunotherapy for the Women’s Cancer Research Center. She is internationally recognized for her work in breast cancer immunotherapy. At this conference, she presented overall survival results from KATE2, which compared using the combination of Tecentriq, also called atezolizumab, and Kadcyla, also called T-DM1, to Kadcyla alone to treat HER2-positive metastatic breast cancer that had grown while being treated with Herceptin and chemotherapy. 

Dr. Emens, welcome to the podcast. 

Leisha Emens: Hi, Jamie, thank you for the invitation to come talk to you today. 

Jamie DePolo: So, to start, in case anybody isn’t familiar, could you sort of give us a brief overview of KATE2, and, you know, what you were hoping to find? 

Leisha Emens: Sure. KATE2 is a local clinical trial. It was randomized, placebo-controlled, so pretty rigorously designed, and its goal was to really determine if there was a signal of clinical benefit from adding immunotherapy to standard treatment for locally advanced or metastatic HER2-positive breast cancer. 

The trial was designed to enroll HER2-positive metastatic breast cancer patients or locally advanced breast cancer patients. They had to express HER2 according to all the commonly established criteria. They had to have progressed on therapy for metastatic disease or within 6 months or more of completing adjuvant therapy for early-stage disease, and they had to have measurable disease. 

They were randomly assigned. They actually also had to have prior treatment with trastuzumab and a taxane, as you had mentioned. They were randomly assigned to receive either T-DM1 with atezolizumab or T-DM1 with placebo, and they were then treated until they progressed or lost clinical benefit or developed side effects that were too bad to continue. 

And the primary endpoint of the study was progression-free survival in the patients overall. The study, unfortunately, did not meet its primary endpoint of improving progression-free survival in the patient group overall. However, last year in San Antonio we reported that specifically in the PD-L1 positive subgroup there was about a doubling of the progression-free survival. 

The magnitude of this doubling and the significance of it is somewhat similar to what we observed in the IMpassion130 study that resulted in the approval of immunotherapy in combination with chemotherapy for patients with metastatic triple-negative breast cancer, so a completely different breast cancer subtype. The common thing between these two groups is that expression of PD-L1 in immune cells appears to identify patients who have the potential to benefit from immunotherapy. 

We also looked at overall survival as a secondary endpoint. There was a numerical increase in overall survival in patients who received immunotherapy with T-DM1. If you look specifically at patients who have PD-L1 in their immune cells, there was an improvement in the one-year overall survival rate from about 88% to almost 95%. So, although the study did not formally meet its primary endpoint, I think we did learn some things from the study that support further testing in HER2-positive metastatic breast cancer. 

The similarities of the ability of PD-L1 immune cell expression to predict patients who have the potential to benefit is quite striking, and I think identifies an immune-activated type of tumor. And it’s patients with those types of tumors who can benefit with this type of immunotherapy that we’re currently developing and has been so successful in other tumor types. So, I guess the good news is that now it’s finally arrived in breast cancer. 

We have an approval for patients with metastatic triple-negative disease where we use an antibody test to identify patients who have PD-L1 expression in their immune cells, and it’s looking like that is potentially going to be applicable to HER2-positive breast cancer patients as well. 

Jamie DePolo: Okay, and KATE2 was a phase 2 study, so smaller. 

Leisha Emens: Yes. So KATE2 was a phase 2, and it was designed to be signal-seeking and set the stage for a more definitive phase 3 trial that was similar to IMpassion130. So, you know, the results of KATE2 are not going to change practice in the near-term future and are hypothesis-generating. And really identifying questions that we need to design a more rigorous study that’s at the level of the phase 3 study, with many more patients to really formally test observations that we’ve managed to derive from the phase 2 study that we reported here at ESMO. 

Jamie DePolo: Okay. And is that something you plan to work on or are already working on? 

Leisha Emens: I think that there is a lot of discussion about the best way to take these findings forward and really firmly establish whether immunotherapy can benefit patients with HER2-positive breast cancer. 

Jamie DePolo: Okay. And can you talk a little bit about the side effects. Did you see anything unexpected, new, different, more severe at all? 

Leisha Emens: So, for KATE2, the side effect profile was really quite similar to what you see for the two drugs individually. There was a higher rate of infusion reaction. When you have the antibody drugs infused into your vein, you can have flu-like symptoms, and the rate of that was higher. That’s not terribly surprising because you’re getting two antibodies instead of one. 

Other side effects that are attributable to T-DM1, basically, comes from inflammation in the liver, elevated liver enzymes, and a lowering of the platelets were also observed in this trial at a slightly higher rate in the immunotherapy arm. But overall, we didn’t see anything unexpected. 

With regard to immune-related side effects, the most common one that you could call a serious event was rash, which is fairly easy to treat. The other one was hypothyroidism, and that tended to be low-grade, and it’s pretty simple to treat with thyroid hormone replacement. And that was actually a very common side effect in the clinical trial for triple-negative disease as well. 

Jamie DePolo: Okay. So, I know you said it’s not going to be practice-changing. If you were talking to a patient who had been diagnosed with metastatic HER2-positive disease, what would you tell them about this study? Is there anything for them to take home yet or are we still not quite there yet? 

Leisha Emens: I think we’re probably not quite there yet. I think one of the reasons these HER2-directed antibody therapies have been so successful is because they’re a form of immunotherapy in and of themselves. That is partly why it’s so attractive to think about adding another type of immunotherapy to them. What I would tell a patient is that these results from KATE2 are highly encouraging and support clinical trial participation to really definitively establish that immunotherapy can benefit patients with HER2-positive breast cancer, because I think in the end we’re going to find that that’s the case. We just have to do the work. 

Jamie DePolo: We have to get there. 

Leisha Emens: Yes. 

Jamie DePolo: Okay. And finally to wrap up, it seems like there have been quite a few presentations/studies/posters on immunotherapy for breast cancer. Compared to some of the other cancers — melanoma, non-small-cell lung cancer — it seems like breast cancer is behind as far as immunotherapy. Are we overall closer, getting there? Are you encouraged by all the work that’s being done? 

Leisha Emens: I mean, I’m actually quite encouraged. I think we have a lot of work left to do, but I think what we’ve learned from the aggregate of the data for antibody drugs that target the PD-1 pathway or the PD-L1 pathway — so it’s the same pathway, but drugs can target either end of it. So, you have pembrolizumab that targets PD-1, nivolumab targets PD-1, atezolizumab targets PD-L1, the ligand for it. 

So, drugs that target that pathway take the brakes off the T cells within the tumor, and I think what we’ve learned in breast cancer looking across all of those drugs, which are different, and across different subtypes of breast cancer is that tumors that express PD-L1 are more likely to respond to these types of agents. So, I think, you know, looking across tumor types and across the drugs there’s a consistency in the data, even though by and large it’s still pretty early days for most patients with breast cancer. I think we will at least learn part of the code for how to select patients who it could potentially benefit. 

Currently, the only immunotherapy that is approved by the FDA based on rigorous clinical evidence for treating patients with breast cancer is for triple-negative breast cancer, and that is PD-L1-positive. The other thing I think we’ve learned is that immunotherapy works better earlier on in the course of advanced disease, so I would encourage patients that are interested in immunotherapy out there who don’t meet criteria for our current standard-of-care approach to look for a clinical trial, and that will help us develop immunotherapy quicker. 

Jamie DePolo: Great, thank you so much. I appreciate your time. 

Leisha Emens: Thank you.

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