Selection Questions Remain After Broad ENHERTU Approval

  • The FDA has approved ENHERTU for both neoadjuvant and adjuvant use in early HER2+ breast cancer based on data from the DESTINY‑Breast11 and DESTINY‑Breast05 phase III trials, but clinicians say the broad label leaves unanswered questions about which patients should receive it.
  • “The FDA approval doesn’t specify the exact population for both neoadjuvant and adjuvant. They just say stage 2 or stage 3 for neoadjuvant, and they just say residual invasive disease for the adjuvant setting,” says Dr. Eleonora Teplinsky, head of breast medical oncology at Valley Health System.
  • DESTINY‑Breast05 showed a significant benefit over trastuzumab emtansine (T‑DM1), cutting invasive‑disease events or death by 53%, though ILD risk and toxicity variation make patient selection critical.
  • Experts say biomarkers and clearer risk‑stratification tools are needed as antibody-drug conjugates move earlier in treatment and potentially reshape standard care for high‑risk HER2‑positive disease.
  • “There are still questions about how to incorporate this into practice, choosing the right high‑risk patients … but even in my practice, I’ve already met patients who meet those criteria and who I’ve discussed adjuvant trastuzumab deruxtecan with,” Dana‑Farber breast oncologist Dr. Kristina Fanucci adds.

The FDA has approved AstraZeneca and Daiichi Sankyo’s ENHERTU (fam‑trastuzumab deruxtecan‑nxki) for both neoadjuvant and adjuvant treatment of HER2+ early breast cancer, based on data from the DESTINY‑Breast11 and DESTINY‑Breast05 phase III trials.

The decision marks a major advance, but it also leaves clinicians with lingering questions about exactly which patients stand to benefit most.

“The FDA approval doesn’t specify the exact population for both neoadjuvant and adjuvant. They just say stage 2 or stage 3 for neoadjuvant, and they just say residual invasive disease for the adjuvant setting,” says Dr. Eleonora Teplinsky, head of breast medical oncology at Valley Health System.

Under the new authorization:

  • ENHERTU, followed by THP (taxane, trastuzumab, pertuzumab), is approved in the neoadjuvant setting for adults with stage 2 and stage 3 HER2+ breast cancer.
  • In the adjuvant setting, ENHERTU may be used for adults with HER2+ disease who have residual invasive cancer after trastuzumab (with or without pertuzumab) and taxane‑based therapy.

DESTINY‑Breast05, which compared trastuzumab deruxtecan with trastuzumab emtansine (T‑DM1), showed a clear benefit for patients with very high‑risk disease.

“It begs the question: is it better to give the drug up front or use it later for those who are really at high risk?” asks Dr. Harold Burstein, a renowned breast cancer expert at Dana Farber Cancer Institute.

He notes that antibody‑drug conjugates (ADCs) are rapidly reshaping treatment algorithms.

“ADCs are often very active compounds and are slowly displacing chemotherapy as early‑line options … Now, for the first time, we’ve seen the current generation of ADCs entering the early‑stage setting,” Dr. Burstein says.

Patient Selection Challenges

Dr. Maysa Abu-Khalaf, a medical oncologist specializing in the management of both early-stage and metastatic breast cancer at Jefferson Health, underscores how critical patient selection and toxicity management will be as ENHERTU moves earlier in care.

She describes one patient who tolerated trastuzumab deruxtecan for more than seven years with no side effects and another who experienced severe nausea and vomiting after just two doses.

“Most people fall in the middle of those experiences, but I think they will be really more nuanced conversations,” Dr. Abu-Khalaf tells SurvivorNet Connect.

Dana‑Farber breast oncologist Dr. Kristina Fanucci echoes the need for careful risk assessment.

“There are still questions about how to incorporate this into practice, choosing the right high‑risk patients … but even in my practice, I’ve already met patients who meet those criteria and who I’ve discussed adjuvant trastuzumab deruxtecan with,” Dr. Fanucci says.

DESTINY‑Breast05 At A Glance

DESTINY-Breast05 (NCT04622319), a phase 3, open-label, international, randomized clinical trial, compared trastuzumab deruxtecan (T-DXd) with the standard of care trastuzumab emtansine (Kadcyla, T-DM1) as a potentially curative treatment for early-stage, HER2+ breast cancer with residual invasive disease and node-positive disease at surgery or inoperable disease at diagnosis.

Key findings include:

  • Risk reduction: 6.2% of patients on trastuzumab deruxtecan vs. 12.5% on T‑DM1 experienced invasive‑disease events or death, translating to a 53% lower risk with ENHERTU.
  • Three‑year invasive disease‑free survival: 92.4% with trastuzumab deruxtecan vs. 83.7% with T‑DM1.
  • Safety: Interstitial lung disease occurred in 9.6% of patients receiving trastuzumab deruxtecan, including two deaths. The most common grade 3/4 toxicities were neutropenia and low white blood cell counts.

For patients with very high‑risk HER2+ disease, the survival benefit is evident, but experts note that the drug may also be useful for patients who cannot tolerate a full course of T‑DM1.

“It’s good to have options to switch to,” Dr. Abu‑Khalaf says.

Still, the broad FDA label raises practical questions.

Dr. Teplinsky posed a few in a a social media post: “Does everyone need Enhertu? Can we do THCP like we commonly do? Can we drop carboplatin?”

She and others emphasize the need for better biomarkers, potentially including ctDNA, to guide who should receive ENHERTU in both the neoadjuvant and adjuvant settings.

“As you can see, this field is evolving very rapidly,” Dr. Teplinsky says. “There’s more to come, but it’s great to have this approval.”