Trastuzumab Deruxtecan Is New Standard of Care for HER2-Low MBC

Shanu Modi, MD

Treatment with fam-trastuzumab deruxtecan-nxki (Enhertu) doubled progression-free survival (PFS) and reduced the risk of death by 36% compared with physician's choice of chemotherapy for patients with HER2-low, hormone receptor–positive metastatic breast cancer (MBC), according to findings from the phase 3 DESTINY-Breast04 study (NCT03734029) presented at the 2022 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.^1,2

In those with hormone receptor–positive, HER2-low MBC, which was the population explored for the primary end point of the study, trastuzumab deruxtecan elicited a median PFS of 10.1 months (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) for chemotherapy (HR, 0.51; 95% CI, 0.40-0.64; P < .0001). The median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) with trastuzumab deruxtecan compared with 17.5 months (95% CI, 15.2-22.4) for chemotherapy (HR, 0.64; 95% CI, 0.40-0.86; P = .003). Fewer grade 3 or greater adverse events (AEs) were reported with the antibody-drug conjugate (ADC) compared with chemotherapy 52.6% and 67.4% of patients, respectively.

“Trastuzumab deruxtecan is the first HER2-targeted therapy to demonstrate statistically significant and clinically meaningful improvement in PFS and OS compared [with] standard chemotherapy for patients with HER2-low metastatic breast cancer,” said lead author Shanu Modi, MD, who is a medical oncologist at Memorial Sloan Kettering Cancer Center. “The benefits of trastuzumab deruxtecan were seen across subgroups, including the hormone receptor–positive and –negative patients and [immunohistochemistry] IHC 1+ and 2+ breast cancers.”

In the DESTINY-Breast04 study, 557 patients were randomly assigned 2:1 to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice of chemotherapy at locally approved dosing (n = 184). Chemotherapy consisted of capecitabine (Xeloda; 20.1%), eribulin (Halaven; 51.1%), gemcitabine (10.3%), paclitaxel (8.2%), or nab-paclitaxel (Abraxane; 10.3%).

Low expression of HER2 was defined as an IHC score of 1+ or 2+ with a negative in situ hybridization (ISH) test, which represents approximately 65% of breast cancer diagnoses, Modi noted. Overall, 88.7% of patients were hormone receptor–positive and 11.3% were negative.

“Our currently available HER2-targeted therapies have not been effective for patients in this subgroup. We currently treat [patients with] HER2-low breast cancer as HER2-negative breast cancer, where therapy is really guided by hormone receptor status,” Modi said. “Ultimately, once we’ve exhausted endocrine therapy and a few lines of targeted agents, we have limited late-line options available for these patients, most commonly offering palliative single-agent chemotherapy, which has modest activity. We have a big unmet need for more effective therapies.”

Patient characteristics were balanced between each arm and representative of the overall population of patients with HER2-negative breast cancer. In the trastuzumab deruxtecan arm, the median age of patients was 57.5 years (range, 31.5-80.2) and 99.5% were female. HER2-low was IHC 1+ for 57.6% of patients and IHC 2+ and ISH-negative for 42.4%. ECOG performance status was split between 0 (53.6%) and 1 (46.4%). The primary locations of metastases were the brain (6.4%), liver (71.3%), and lung (32.2%). Patients had received a median of 3 (range, 1-9) prior lines of therapy, which consisted of targeted or immunotherapy (74.8%), endocrine therapy (93.0%), and chemotherapy (100%).

Across all patients enrolled in the study, the median PFS was 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan compared with 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63). The median OS in this group was 23.4 months (95% CI, 20.0-24.8) with the ADC compared with 16.8 months (95% CI, 14.5-20.0) for chemotherapy, representing a 6.6-month improvement in survival with the agent (HR, 0.64; 95% CI, 0.49-0.84; P = .001).

In those with hormone receptor–negative disease, the median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan and 2.9 months (95% CI, 1.4-5.1) for chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). The median OS in the hormone receptor–negative cohort was 18.2 months (95% CI, 13.6-not estimable) with the ADC vs 8.3 months (95% CI, 5.6-20.6) with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).

Across all patients, the overall response rate (ORR) was 52.3% (95% CI, 47.1%-57.4%) with trastuzumab deruxtecan ( compared with 16.3% (95% CI, 11.3%-22.5%) with chemotherapy. In the hormone receptor–negative arm, the ORRs were 50.0% (95% CI, 33.8%-66.2%) and 16.7% (95% CI, 3.6%-41.4%) for trastuzumab deruxtecan (n = 40) and chemotherapy (n = 18), respectively.

In those with hormone receptor–positive disease, the ORR was 52.6% (95% CI, 47.0%-58.0%) for trastuzumab deruxtecan (n = 333) vs 16.3% (95% CI, 11.0%-22.8%) for chemotherapy (n = 166). In this group, the median duration of response was 10.7 months with the ADC compared with 6.8 months for physician's choice.

Trastuzumab deruxtecan demonstrated a consistent improvement in PFS across subgroups. For patients with hormone receptor–positive disease, those with a HER2 IHC score of 1+ had a median PFS of 10.3 months (95% CI, 8.6-12.3) with trastuzumab deruxtecan compared with 5.3 months (95% CI, 4.1-7.8) with chemotherapy (HR, 0.48; 95% CI, 0.35-0.65). Among individuals with hormone receptor–positive HER2 IHC 2+ and ISH-negative disease, the median PFS was 10.1 months (95% CI, 8.2-12.2) for the experimental arm and 5.9 months (95% CI, 4.3-7.9) for the chemotherapy arm (HR, 0.55; 95% CI, 0.38-0.80).

In patients with hormone receptor–positive disease who received prior treatment with a CDK4/6 inhibitor, the median PFS was 10.0 months (95% CI, 8.3-11.4) with trastuzumab deruxtecan compared with 5.4 months (95% CI, 4.0-7.8) for chemotherapy (HR, 0.55; 95% CI, 0.42-0.73). For those with hormone receptor–positive disease who did not receive a CDK4/6 inhibitor, the median PFS was 11.7 months (95% CI, 9.5-17.7) with trastuzumab deruxtecan compared with 5.9 months (95% CI, 4.3-8.2) for chemotherapy (HR, 0.42; 95% CI, 0.28-0.64).

“Overall, these results establish HER2-low metastatic breast cancer as a targetable population with trastuzumab deruxtecan as a new standard of care in this setting,” Modi said.

At the time of the cutoff, the median treatment duration was 8.2 months for trastuzumab deruxtecan and 3.5 months for chemotherapy. Adverse events led to treatment discontinuation for 16.2% of patients in the trastuzumab deruxtecan arm compared with 8.1% for chemotherapy. Dose reductions were required due to an AE for 22.6% of patients in the trastuzumab deruxtecan group vs 38.4% for chemotherapy.

Treatment-emergent adverse events (TEAE) were experienced by 99.5% of those in the trastuzumab deruxtecan arm compared with 98.3% of those treated with physician’s choice of therapy. Exposure adjusted AE rates were 1.30 per patient year for trastuzumab deruxtecan and 2.66 for physician’s choice of chemotherapy. Serious AEs occurred in 27.8% of patients treated with trastuzumab deruxtecan and for 25.0% with physician’s choice.

The most frequently observed treatment-related AEs for trastuzumab deruxtecan and chemotherapy, respectively, were nausea (73% vs 23.8%), fatigue (47.7% vs 42.4%), skin and subcutaneous tissue disorders, including alopecia (37.7% vs 32.6%), vomiting (34% vs 9.9%), neutropenia (33.2% vs 51.2%), and anemia (33.2% vs 22.7%).

There were 14 drug-related deaths with trastuzumab deruxtecan (3.8%) compared with 5 for physician’s choice of therapy (2.9%). Adjudicated interstitial lung disease (ILD)/pneumonitis occurred in 45 patients treated with trastuzumab deruxtecan (12.1%), with 5 patients having a grade 3 event and 3 having a grade 5 event.

“The drug has been in use now for a couple years and I think we have all gotten a little more comfortable, first responding to pulmonary symptoms more quickly and also how to manage it,” said Julie R. Gralow, MD, FACP, FASCO, chief medical officer and executive vice president of ASCO, and previously director of Breast Medical Oncology at the Seattle Cancer Care Alliance. “I think it was much more of a concern a couple of years ago and now we have learned how to be more aware and to act quickly.”

In December 2019, the FDA granted an accelerated approval to trastuzumab deruxtecan for adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting. This accelerated approval was transitioned to a full regulatory approval on May 4, 2022. The prescribing information includes a box warning on the risk of ILD.

The efficacy of trastuzumab deruxtecan in HER2-low could be derived from the unique 8:1 ratio of antibody (trastuzumab) to toxic payload, which consists of a topoisomerase I inhibitor. “This is a new generation antibody-drug conjugate, and that is because it has some advanced pharmaceutical properties compared [with] other HER2 therapies,” Modi said. “The most unique thing is the high payload linked to each antibody. It is twice as much as T-DM1 [ado-trastuzumab emtansine; Kadcyla]. The payload itself is unique and novel, it is a topoisomerase I inhibitor, which is not a type of chemotherapy we usually use in breast cancer.”

“The linker technology is also very different from T-DM1, it is a cleavable linker,” she added. “When the linker is cleaved it releases the chemotherapy payload in a way that the chemotherapy retains memory permeability and now it can pass through the HER2-positive cell and into the microenvironment and has the ability to penetrate other cells in the neighboring area that may not express HER2. It offers a broader range of activity in heterogenous situations, and we know HER2 expression [in breast cancer] is very heterogenous. I think that is why, for the first time, we’re seeing activity for a HER-targeted agent.”

Several clinical trials are exploring trastuzumab deruxtecan for patients with breast cancer and other malignancies. The DESTINY-Breast05 study (NCT04622319) is comparing the agent with T-DM1 for those with residual invasive breast cancer following neoadjuvant therapy. Additionally, arm 6 of the BEGONIA study (NCT03742102) is exploring the treatment for patients with triple-negative breast cancer in combination with the PD-L1 inhibitor durvalumab (Imfinzi).

References

1. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40 (suppl 17):abstr LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3
2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. Published online June 5, 2022. doi:10.1056/NEJMoa2203690

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