Andrew D. Seidman, MD: Welcome to this CancerNetwork® presentation, “Around the Practice, the New Treatment Landscape in HER2-PositiveMetastatic Breast Cancer.” I am your host, Dr Andrew Seidman. I’m an attending physician for the breast medicine service at Memorial Sloan Kettering Cancer Center [in New York], where I also serve as the medical director for the Bobst International Center. Joining me today are Aditya Bardia from the Massachusetts General Hospital in Boston; Mark Pegram from Stanford Health Care in Palo Alto, [California;] and Ruta Rao from Rush University Medical Center in Chicago, [Illinois]. I’d just like to give my panelists the chance to say hello and introduce themselves. Aditya?

Aditya Bardia, MD, MPH: Hello everyone. I’m Aditya Bardia. I’m a breast medical oncologist at Massachusetts General Hospital. Looking forward to the discussion today.

Andrew D. Seidman, MD: Mark?

Mark Pegram, MD: Thank you for inviting me to participate and I really appreciate being here. I’m a medical oncologist at Stanford University. I run a research laboratory there where we focus on therapeutic strategies, targeting, and HER2. I’m the medical director of the clinical translational research unit and the associate dean for clinical research quality. Good to be with you.

Dr. Seidman: Thanks, Mark. Ruta?

Ruta Rao, MD: Hi, my name is Ruta Rao. I’m a breast medical oncologist at Rush University Medical Center, and I’m excited to be with you all this evening. Thank you.

Andrew D. Seidman, MD: We’re fortunate to have the 3 of you, and we’re going to review data that have been presented at recent conferences and published to discuss some of the challenges in treating patients with HER2+ metastatic breast cancer. Perhaps not just challenges, but real opportunities. In this context, we’ll review a few patient cases, and we will involve the audience by using an interactive platform that will allow you to answer several polling questions that will allow us to reflect on your answers, to gain some new insights. I’d like to start with Dr Pegram. Mark, can you speak to the first-line systemic therapy options according to guidelines and second line, and how do you see this landscape evolving?

Mark Pegram, MD: Andy here too, for the most used first-line HER2+ metastatic disease regimen has been a CLEOPATRA-like regimen that is trastuzumab plus pertuzumab with a taxane, often using weekly low-dose paclitaxel as the preferred taxane in the regimen, based on data previously published by Chau Dang, [MD,] and colleagues at Memorial [Sloan Kettering Cancer Center]. The rationale for the enthusiasm for the CLEOPATRA-like regimens in the first line stems from the impressive overall survival [OS] results in the original CLEOPATRA trial. That trial was recently updated with a median follow-up duration now of about 99 months. The median overall survival is 57.1 months in the experimental group and 40.8 months in the placebo group, a difference of about 16.3 months. That’s a huge survival benefit that has been persistent over the 8 years since that trial first reported. It’s a very impressive result and so far, nothing has been able to dethrone a CLEOPATRA-like regimen in the first line.

Now, in terms of second line, T-DM1 [trastuzumab emtansine] historically has been firmly entrenched in treatment guideline recommendations, as well as in clinical practice, based on the EMILIA pivotal trial data that we published in New England Journal of Medicine back in 2012. We recently updated that data set back in 2017 with a final overall survival data set. In this trial, there were over 990 patients. They were randomized to either trastuzumab emtansine or capecitabine and lapatinib control. In the final analysis, the median overall survival was longer with trastuzumab emtansine compared with control, 29.9 months versus 25.9 months, hazard ratio 0.75. This is despite a crossover frequency of about 27%, which tends to dilute your overall survival signal. Despite that limitation, there was still a survival benefit. Moreover, there were fewer grade 3 or worse adverse events occurring with trastuzumab emtansine compared to capecitabine, lapatinib control. The most frequently reported grade 3 or worse adverse event with trastuzumab emtansine was thrombocytopenia.

Andrew D. Seidman, MD: Mark, just to spice it up a little bit, I just want to ask how the EMILIA trial has been regarded by some as a promising new antibody-drug conjugate versus perhaps a straw man regimen. Aditya, maybe you can speak to this because the history of how we got to cape [capecitabine] and lapatinib makes that perhaps not a formidable opponent. Any thoughts on that?

Aditya Bardia, MD, MPH: You had data that was an appropriate control, capecitabine plus lapatinib. At that time, we didn’t have new drugs neratinib or tucatinib. I remember the excitement then the results of EMILIA were presented. It was an ASCO [American Society of Clinical Oncology] plenary session where the results were presented. The excitement was 2-fold. One about the improvement in survival, and second quality of life. That was the other piece.

Andrew D. Seidman, MD: To rewind even further cape [capecitabine] and lapatinib got on the map because it was better than cape [capecitabine] alone in HER2+ breast cancer, so that became the control arm because it beat a regimen that didn’t include any HER2-targeted therapy. In any case, I just want to point that historical footnote out.

Mark Pegram, MD: Well, now that you mentioned that this may all be water under the bridge because now for the first time T-DM1 in the second line is being challenged by the phase 3 DESTINY-Breast03 pivotal clinical trial just reported at ESMO [European Society for Medical Oncology meeting]. We’ll hear more about that from Dr Bardia in the rest of this afternoon’s presentations. I should also mention that trastuzumab deruxtecan will challenge CLEOPATRA-like regimens in the first-line setting in the upcoming DESTINY-Breast09 study that will compare trastuzumab deruxtecan with or without pertuzumab versus a CLEOPATRA-like regimen control. The landscape is changing. I should mention that in the modern era, it’s not uncommon for patients with early stage HER2+ breast cancer to have already been treated with the dual-antibody regimen containing trastuzumab and pertuzumab, and if they were treated with that in the neoadjuvant setting and did not achieve a pathologic complete response, they may well have had postneoadjuvant T-DM1 also. This concept of lines of therapy now is being blurred, and necessarily we’ll probably need to shift the definition of lines to the left in the metastatic disease setting as we use all of those agents in the early disease setting in the future.

Transcript edited for clarity.