Experts Explain Impact of Trastuzumab Deruxtecan Approval in HER2+ Breast Cancer

Jessica Hergert

Sara A. Hurvitz, MD, an associate professor at the David Geffen School of Medicine and medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit at the University of California, Los Angeles

Sara A. Hurvitz, MD

The recent approval of the novel antibody–drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) has added a remarkable asset to the armamentarium in HER2-positive metastatic breast cancer, said Sara A. Hurvitz, MD. However, questions remain regarding sequencing strategies with the agent and concerns over the potential risk of interstitial lung disease (ILD).

In December 2019, the FDA granted accelerated approval to trastuzumab deruxtecan for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti–HER2-based regimens in the metastatic setting.

The approval was based on findings from the single-arm phase II DESTINY-Breast01 study in which trastuzumab deruxtecan elicited a confirmed objective response rate of 60.3% per independent central review (95% CI, 52.9-67.4) for patients with heavily pretreated advanced HER2-positive disease. This included a 4.3% complete response rate and a 56% partial response rate.

"It seems that a new drug hits the news every month, so it is an exciting time to be treating breast cancer," said Hurvitz. "As DESTINY-Breast01 was not comparative, I am intrigued to see data from ongoing trials comparing the agent with standard of care capecitabine-based therapy and head-to-head with ado-trastuzumab emtansine (T-DM1; Kadcyla). Also, I am awaiting further data regarding ILD because we need to dive into it from a research perspective."

Several other experts provided their thoughts on the ADC including: In an interview with OncLive, these faculty voiced their opinion on the clinical utility of trastuzumab deruxtecan in patients with metastatic HER2-positive breast cancer.

OncLive: How has HER2-positive breast cancer treatment evolved in recent years?

Hurvitz: We have new agents available to our patients and are seeing a rise in patients being treated with systemic therapy in the neoadjuvant setting.

We have multiple agents including trastuzumab (Herceptin) and pertuzumab (Perjeta) for the first-line treatment of patients. Neratinib (Nerlynx) is approved for extended use after 1 year of adjuvant trastuzumab. Additionally, T-DM1 is approved for patients whose disease is not completely treated in the neoadjuvant setting and there is residual disease at the time of surgery.

As such, it has become challenging for clinicians to keep up with the data to understand when to use 1 agent over another.

Krill-Jackson: At this point in the evolution of metastatic breast cancer treatment, we typically treat patients with a first-line trastuzumab/pertuzumab–based regimen followed by T-DM1 in the second-line.
 
Elisa Krill-Jackson, MD, the associate director of community outreach for women's health at the Sylvester Cancer Center of the University of Miami Health System

Elisa Krill-Jackson, MD

Historically, patients who progress on T-DM1 received a hodgepodge of multiple treatments, none of which seem to keep patients in long-term remission.

With the approval of trastuzumab deruxtecan, we hope to see longer remissions in these patients. Data show that patients who respond to trastuzumab deruxtecan can often have a prolonged response. It is a great drug to add to our armamentarium and it adds a lot of hope for our patients to potentially extend life.

How is trastuzumab deruxtecan currently being utilized in the clinic?

Krill-Jackson: It is generally being used in the third- and fourth-line setting now after trastuzumab/pertuzumab/chemotherapy, after T-DM1, and in some patients, after an oral drug, such as lapatinib (Tykerb) or neratinib.

The data for trastuzumab deruxtecan shows prolonged responses of more than 1 year of progression-free survival (PFS) in these patients who generally would have progressed within months on a third- or fourth-line treatment.

What makes ADCs unique in treating patients with HER2-positive breast cancer? What is the clinical rationale for implementing trastuzumab deruxtecan?

Krill-Jackson: ADCs are really exciting because we are delivering chemotherapy closer to the cancer as opposed to systemically throughout the body. Although there are toxicities like ILD, pneumonitis, and cytopenia, they are not [congruent to] the toxicities we associate with intravenous chemotherapy. They have been an asset to our patients.
 
Oludamilola (Lola) A. Olajide, MD, an adjunct professor and medical oncologist at the Rex Cancer Center of UNC Health

Oludamilola (Lola) A. Olajide, MD

Olajide: Patients do progress on T-DM1, so there is a need for additional treatments beyond that. Trastuzumab deruxtecan is another ADC that utilizes the same topoisomerase chemotherapy backbone but hits more targets on the HER2 molecule. The agent showed significant PFS improvement in heavily pretreated patients.

How does the approval of trastuzumab deruxtecan impacted the treatment landscape of HER2-positive disease?

Olajide: The data with trastuzumab deruxtecan showing significant efficacy for patients who progressed beyond 6 or 7 lines of therapy is amazing. We all have patients in our clinics who have gotten to the end of the rope in terms of treatment options. Some patients have been through so many novel combinations that we may try to utilize older drugs in conjunction with trastuzumab or other available TKIs. Having trastuzumab deruxtecan work in those patients is important.

With regard to the indication [the agent is approved for], we can utilize trastuzumab deruxtecan early for patients who had ≥2 prior lines of therapy. That is a welcomed space to consider using a drug like this.

Thompson: I haven't had the chance to use trastuzumab deruxtecan yet, which is a good thing for my patients.
 
Forrest Thompson, MD, a hematologist and medical oncologist at the Levine Cancer Institute of Atrium Health

Forrest Thompson, MD

The response rates [with the agent] were pretty amazing— about 60% in the seventh-line setting. Aside from ILD, the toxicities don't appear to be significant and the nausea can be managed.

What is the risk of ILD with trastuzumab deruxtecan? How is it being mitigated in practice?

Olajide: The potential for ILD is worrisome. Though the incidence rate of ILD was quite low in the initial trials, it was about 2% in subsequent trials. It sounds like a small number, but the toxicity can be potentially fatal.

It is important that clinicians recognize the potential for ILD occurrence. Patients should be screened early and monitored closely.

Patients should also be informed about the potential of toxicity so they can tell an on-call doctor should they find themselves in the emergency room overnight or on a weekend.

At this point, the [protocol] is to hold the drug and treat the patient with steroids. Some patients in the initial studies did not respond to initial steroid therapy so it is imperative to involve pulmonologists and to treat patients quickly.

Krill-Jackson: The ILD associated with trastuzumab deruxtecan is certainly a little scary because there is a mortality to it, and we don't currently know whether early intervention decreases that mortality risk.

However, the benefit we are seeing with the agent is worth this risk. Treatment-related deaths are always difficult, but the good outweighs the bad with this drug. We are hopeful that early recognition and treatment of ILD as well as stopping trastuzumab deruxtecan in cases of ILD will mitigate the risk of death in the future.

Thompson: I have not used trastuzumab deruxtecan yet, but it appears that imaging patients frequently and stopping the drug when patients develop grade I toxicity or ground glass opacity abnormalities on CT scans [is recommended].

In your opinion, how will this agent be utilized in the future?

Thompson: Trastuzumab deruxtecan may be used earlier in treatment and eventually take the place of T-DM1 in the second line. I'll be using it in the future, but it'll be for the right patient at the right time.

Krill-Jackson: Early studies with trastuzumab deruxtecan look better than those with T-DM1, especially for patients with HER2-low 2+ fluorescence in situ hybridization (FISH)-positive disease. I am hopeful that if we can manage the ILD toxicity, we can move trastuzumab deruxtecan earlier in treatment, and possibly into adjuvant therapy.

The agent is also being studied in HER2 1+ 2+ FISH-negative patients, which may open another option for patients who are not HER2-positive. I see this drug having a broader reach in the earlier treatment of metastatic breast cancer.

Hurvitz: There is a study going on looking at trastuzumab deruxtecan in combination with abemaciclib (Verzenio) in HER2-low expressing patients. The agent has shown activity in HER2-low 1+ 2+ tumors, which account for about half of all breast cancers. This drug may work in non–HER2-positive disease, so I am excited about that.
Krop IE, Saura C, Yamashita T, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: a phase 2, multicenter, open-label study (DESTINY-Breast01) [published online ahead of print December 11, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1914510
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