Durability and Intracranial Efficacy Observed With T-DXd in HER2+ MBC

Ian Krop, MD, PhD (Moderator)

Professor of Internal Medicine (Medical Oncology)

Yale School of Medicine

Director, Clinical Trials Office

Chief Clinical Research Officer

Associate Director, Clinical Sciences

Yale Cancer Center

New Haven, CT

DISCUSSION QUESTION

• Were you aware of the 43-month follow-up data from the DESTINY-Breast03 trial (NCT03529110) of trastuzumab deruxtecan (T-DXd, Enhertu) vs trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive metastatic breast cancer (MBC)?​
  • What are your general impressions of the data presented? ​
  • What stands out to you?

Ian Krop, MD: Were you aware of this longer follow-up data that came out for DESTINY-Breast03, and…do you have any impressions of the data?

Joanna Metzner, MD: I was aware of it, and it's very impressive with the 66% [partial response].¹ It's a very good drug. I’ve used it. I haven't seen any interstitial lung disease [ILD]. I was lucky [and I hope] I won't [see ILD], but it's an amazing drug that's very well tolerated.

Krop: Certainly, almost everybody's getting some benefit.

Kwabena Osei-Boateng, MD: I think the data are very compelling, even with crossover, to have that degree of difference [in overall survival (OS)]. Also, I was very impressed with the duration of response; for the 80% of people [who responded], they had a long duration of response, too.

Ruiling Yuan, MD: First of all, I think the overall response rate is quite impressive at approximately 80%. The duration of response was 30 months [for T-DXd] vs 17 months [for T-DM1]. The OS benefit, despite the crossover, is quite impressive [HR, 0.73; 95% CI, 0.56-0.94]. I have not [seen] any ILD.... But what I always think is that for grade 2 ILD, [the patient must] permanently discontinue the drug, unlike with [ILD associated with] immunotherapy. In the future, I'm not sure if there will be some changes about this, because I do think this is a great drug.

Krop: Thank you for pointing that if you have grade 1 ILD, asymptomatic ILD, and then recover, you can restart the drug.² We know that a substantial fraction of people can stay on the drug after rechallenge, but with symptomatic ILD of grade 2 or higher, we have to permanently discontinue because we don't have data on rechallenging in those patients. As you are alluding to, we really need those data, because it's very frustrating for us and even more frustrating for our patients, when they're doing well on this drug, and you say they have to permanently stop [even though] the benefits are substantial.

Would anybody modify treatment recommendations for a patient who did not have brain metastases? What if the patient did have symptomatic brain metastases?

You could potentially give her radiation. Maybe you don’t want to. Let's say she had multiple brain metastases, but they weren't symptomatic. You don't want to give whole brain [radiation] because you're worried about long-term toxicity, so you want to treat with systemic therapy. Would anybody give tucatinib [Tukysa] first? We know tucatinib is active in that population. Would anybody give tucatinib if she had [several] asymptomatic brain metastases?

Margaret Howard, MD: I think in this setting I would still do the T-DXd but certainly keep in mind the option for tucatinib. As long as she's able to tolerate it, and there doesn't seem to be any contraindication, then I would stay with my initial treatment approach.

Krop: Until pretty recently, I was still using tucatinib in somebody who had dominant brain metastases. If brain metastases were their big problem, and their extracranial disease wasn't very much, I was still thinking that it made sense to use tucatinib in that small number of patients, because we had these prospective data from HER2CLIMB [NCT02614794].³ But I think now, between the aggregate pooled data from the previous randomized T-DXd trials, and now the DESTINY-Breast12 [NCT04739761] data that just came out, you get it seemingly the same—at least the same level—of intracranial response, plus you get much greater extracranial disease control with T-DXd, so that's where I'm personally leaning.^4,5

_References:

_{1. Cortés J, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat Med. 2024;30(8):2208-2215. doi:10.1038/s41591-024-03021-7}

_{2. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2024. Accessed January 13, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761139s028lbl.pdf}

_{3. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775}

_{4. Hurvitz SA, Modi S, Li W, et al. 377O A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINY-Breast (DB) -01, -02, and -03. Ann Oncol. 2023;34(suppl 2):S335-S336. doi:10.1016/j.annonc.2023.09.554}

_{5. Harbeck N, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. 2024;30(12):3717-3727. doi:10.1038/s41591-024-03261-7}