Standard-of-Care and Emerging Therapies for First-line Treatment of HER2+ mBC


Drs McArthur and Kaklamani expand upon the standard-of care regimens used for first-line treatment of patients with HER2+ metastatic breast cancer (mBC), review clinical data supporting their use, and share excitement for upcoming data readouts on novel regimens in the space.


Sara Hurvitz, MD: Now, let’s talk about first- and second-line treatment of HER2 [human epidermal growth factor receptor 2]–positive metastatic breast cancer. I’m going to turn to you, Heather. Can you take us through the standard of care regimens for the first-line treatment of HER2+ disease?

Heather McArthur, MD: So that’s an easy question right now, but next year it might not be, and in future years. Right now, our standard first-line therapy is a taxane, which has trastuzumab and pertuzumab based on the CLEOPATRA study. Again, that was a study that enrolled almost 1200 patients and randomized them to receive docetaxel with trastuzumab +/- pertuzumab and became a standard of care. We relatively recently had some long-term follow-up from that study with almost 100 months, which is remarkable to me, of median follow-up from that study. And the median survival from that study was 57.1 months vs 40.8 months in favor of pertuzumab. So a remarkable improvement in overall survival. And they also provided us with an 8-year landmark survival analysis with 37% vs 23% at 8 years, which is again, truly remarkable. So HER2-directed therapy has certainly transformed the landscape for our patients. They’re living years now, with improvements in this space. So really exciting updates from that study.

Sara Hurvitz, MD: I agree. And if you look at the ESME [Epidemiological. Strategy and Medical Economics] database, the French Comprehensive Cancer Centers came together and looked at all their patients diagnosed with metastatic breast cancer, starting around 2008 or so, and they followed every year. Every year the median overall survival for a patient diagnosed that year got better and better, and now we’re up to around 6 years. So it’s mirroring what we see with the CLEOPATRA regimen.

So I want to interrogate you more. Is there anyone that you feel would not benefit or it wouldn’t be in their best interest to give THP [docetaxel, trastuzumab, pertuzumab] at their first diagnosis of metastatic breast cancer? Would it be somebody’s hormone receptor-positive? Is it based on frailty, or should everyone really get this induction taxane-HP [trastuzumab, pertuzumab] regimen?

Heather McArthur, MD: The vast majority of the time, it really is my standard go-to, and I really think that that’s what the data best supports. I could imagine a situation where a patient had an early recurrence, potentially after their curative intent taxane-based regimen. In [that] case, I would be looking to one of the promising antibody-drug conjugates or tyrosine kinase inhibitor-based regimen to offer them something different if I really felt like they had taxane-resistant disease.

Sara Hurvitz, MD: OK, great.Virginia, Heather implied that we may have changes in our frontline regimen of choice in the not too distant future. Can you take us through that data we’re all eagerly anticipating, and maybe make a bet on what you think is going to be the winner?

Virginia G. Kaklamani, MD, DSc: So we tried with the MARIANNE trial, to find out whether T-DM1 [trastuzumab emtansine] could move up to that first-line setting in combination with pertuzumab. We failed, and I don’t know that we know why. I think we’re still puzzled by the results of MARIANNE, but now there are trials that are looking at that first-line setting. The DB09 [DESTINY-Breast09] trial with T-DXd [trastuzumab deruxtecan] in combination with pertuzumab. [That is]a 3-arm trial that has T-DXd by itself, T-DXd with pertuzumab, or the CLEOPATRA regimen. And I think we’re all excited enough about T-DXd that we feel this is going to be a positive trial.

But there is a space of hormone receptor-positive breast cancer where the addition of CDK4/6 inhibitors has already shown to be potentially beneficial. The PATINA trial is adding palbociclib to the maintenance HP, and then the HER2CLIMB-05 trial is looking at the tucatinib. And this trial was designed prior to the T-DXd data, so we have to take that into account, but at the same time, could we add to tucatinib to the HP maintenance therapy and hopefully improve outcomes with less toxicity? One of the concerns with T-DXd is going to be that 10% to 15% pneumonitis. In that first-line setting, in patients that we expect to live 5 or 6 years, it’s really hard to be dealing with pneumonitis in that first year of treatment.

Sarah Hurvitz, MD: Absolutely. I think the toxicity is a huge thing we’re going to have to grapple with as clinicians. So, Melinda, if T-DXd is available and shown to be of benefit compared to THP in the frontline setting, how are you as a clinician going to feel about giving your patients T-DXd until progression? Are there going to be patients where you have a discussion or where you use T-DXd as induction and maybe a maintenance strategy? What are we going to have to do?

Melinda L. Telli, MD: I think it’s a great question, and I feel I’m already facing it some in the second-line setting. I have patients going into complete response with second-line T-DXd, and the question they are asking, “Do I need to keep taking this drug?” And so, I’m really excited to see what T-DXd is going to do in the first line. It’s been a really special drug, and I’m expecting good things from the DB09 study. But it is a great question. One advantage of CLEOPATRA is the maintenance HP, which is really very tolerable for patients with or without endocrine therapy, depending on hormone receptor status. But I could see a situation with an induction, and potentially maintenance trastuzumab.

Transcript edited for clarity.

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