New HER2-Low Subgroup Expands Utility of HER2-Targeted Therapies

Targeted Therapies in OncologyDecember 2, 2022
Volume 11
Issue 18
Pages: 23

New clinical trial data have shown that patients with IHC 1+ or IHC 2+/ISH– disease, but no ERBB2 amplification, could still benefit from HER2 targeted therapies.

Shanu Modi, MD

Shanu Modi, MD

One of the biggest shifts in the oncology field from the past year was the introduction of HER2-low into clinical practice. Patients with breast cancer have typically been divided by subtype according to HER2 positivity or negativity, but emerging evidence suggests that there is now room and treatment options available for a third group of patients that was previously ignored, those characterized with HER2-low disease.

HER2 positivity is considered overexpression of HER2 as assessed by an immunohistochemistry (IHC) assay, with a score of IHC 3+, or by confirmation with an in situ hybridization (ISH) assay. Prior to 2022, if a tumor sample was considered IHC 0 or 1+, or even IHC 2+ with a negative ISH assay, the tumor was considered not sensitive to HER2-targeted therapies.1 This classification accounts for approximately 45% to 55% of all breast cancers.2 However, new clinical trial data have shown that patients with
IHC 1+ or IHC 2+/ISH– disease, but no ERBB2 amplification, could still benefit from HER2 therapies.1

With this newly accepted patient subgroup of HER2-low breast cancer, novel HER2-targeted therapies could become valuable for a wider range of patients, rather than just the 15% of breast cancers that are considered HER2 positive.1

“It’s exciting that we’ve been able to now translate HER2-targeted therapy to a broader group of patients with HER2-expressing breast cancer,” said Shanu Modi, MD, an attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

Trial Establishes New Classification and Standard of Care for HER2-Low Breast Cancer

During the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, held in June, lead study author Modi presented findings from the phase 3 DESTINY-Breast04 trial (NCT03734029) showing a meaningful clinical benefit for trastuzumab deruxtecan (Enhertu), an HER2-directed antibody-drug conjugate (ADC), for patients with HER2-low metastatic breast cancer.2

The study, which was simultaneously published in the New England Journal of Medicine, enrolled 557 patients with metastatic breast cancer who had low HER2 expression, defined as IHC 1+ or IHC 2+/ISH–.2,3

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 (n = 184), consisting of capecitabine (Xeloda; 20.1%), eribulin (Halaven; 51.1%), gemcitabine (10.3%), paclitaxel (8.2%), or nab-paclitaxel (Abraxane; 10.3%).

The median age was 57.5 years (range, 31.5-80.2) and 99.5% of participants were women. Approximately 89% of patients had hormone receptor–positive disease and 11% had hormone receptor–negative disease. More than half of all patients (57.6%) had IHC 1+ disease at baseline and an ECOG performance status of 0 (53.6%). Patients had received a median of 3 lines of prior therapy (range, 1-9).

Median progression-free survival (PFS) in the patients with hormone receptor–positive disease was the study’s primary end point, with key secondary end points being PFS among all patients and overall survival (OS) in all patients and those with hormone receptor–positive disease.

The overall 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; P < .0001). Median OS was 23.4 months (95% CI, 20.0-24.8) with trastuzumab deruxtecan compared with 16.8 months (95% CI, 14.5-20.0) for chemotherapy (HR, 0.64; 95% CI, 0.49-0.84; P = .001). Overall response rate (ORR) in the overall population was 52.3% (95% CI, 47.1%-57.4%) with trastuzumab deruxtecan compared with 16.3% (95% CI, 11.3%- 22.5%) with chemotherapy, with median durations of response (DORs) of 10.7 months and 6.8 months, respectively (TABLE2,3).

Hormone receptor–positive patients demonstrated a median PFS of 10.1 months with trastuzumab deruxtecan (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) with chemotherapy (HR, 0.51; 95% CI, 0.40-0.64; P < .0001). Median OS was 23.9 months (95% CI, 20.8- 24.8) vs 17.5 months (95% CI, 15.2-22.4) for the ADC and investigator’s choice of therapy, respectively (HR, 0.64; 95% CI, 0.48-0.86; P = .0028). ORRs were 52.6% (95% CI, 47.0%- 58.0%) with trastuzumab deruxtecan and 16.3% (95% CI, 11.0%-22.8%) with chemotherapy, and the median DORs were 10.7 months and 6.8 months, respectively.

Among patients 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), and the median OS was 18.2 months (95% CI, 13.6-not estimable) vs 8.3 months (95% CI, 5.6-20.6) with trastuzumab deruxtecan vs chemotherapy, respectively (HR, 0.48; 95% CI, 0.24-0.95). ORR was 50% (95% CI, 33.8%- 66.2%) with the ADC and 16.7% (95% CI, 3.6%- 41.4%) with investigator’s choice of treatment, and the median DORs were 8.6 months and 4.9 months, respectively.

Modi spoke with Targeted Therapies in Oncology™ during the ASCO meeting, saying that the findings were “compelling efficacy data. It is not common to see survival advantage in our more advanced [patients with breast cancer], so these are exciting results.”

Adverse events (AEs) were reported in 99.5% of patients treated with trastuzumab deruxtecan and in 98.3% of patients treated with chemotherapy. Serious AEs were observed in 27.8% of patients in the ADC arm and in 25.0% of the investigator’s choice arm.

The most common treatment-related AEs observed with trastuzumab deruxtecan and chemotherapy treatment, 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 reported with trastuzumab deruxtecan (3.8%) compared with 5 for investigator’s choice of therapy (2.9%). Adjudicated interstitial lung disease/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 approval and trial findings were further supported by data presented at the European Society for Medical Oncology Congress 2022 showing that trastuzumab deruxtecan also preserved quality of life compared with chemotherapy, with a delay in the time to definitive deterioration of global health score from 7.5 months with chemotherapy to 11.4 months with trastuzumab deruxtecan (P = .0096). Improvements were also seen across other functioning status factors and in the delay to pain symptoms.4

“I think the DESTINY-Breast04 data really establish HER2-low as a targetable population, and so, I think these data are going to compel us to rethink about subgroups within the HER2-negative category of breast cancer,” Modi said. “These findings are very specific to the drug trastuzumab deruxtecan, and so this is our new standard of care for this population of patients.”

The Impact

Presentation of the DESTINY-Breast04 trial findings were met with thunderous applause and a standing ovation by audience members at the ASCO Annual Meeting. The findings also supported the approval of trastuzumab deruxtecan as a treatment for patients with unresectable or metastatic HER2-low breast cancer only 2 months after the ASCO presentation on August 5, 2022.5

During the ASCO meeting, discussant Patricia M. LoRusso, DO, PhD, also suggested that the findings indicate a need to rethink and find new, more sensitive ways of assessing HER2 status to allow for identification of these new HER2-low patients. Going forward, other HER2-targeted therapies will be tested in the HER2-low disease setting, with several studies already under way.1


1. Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951- 1962. doi:10.1200/JCO.19.02488

2. 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):LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3

3. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/ NEJMoa2203690

4. Ueno NT, Jacot W, Yamashita T, et al. Patient-reported outcomes (PROs) from DESTINY-Breast04, a randomized phase 3 study of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low metastatic breast cancer (MBC). Ann Oncol. 2022;33(suppl 7):S88-S121. doi:10.1016/annonc/annonc1040

5. FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed November 18, 2022.

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