Antibody-drug conjugate provides ‘unprecedented’ benefit in metastatic HER2-positive breast cancer
SAN ANTONIO — Trastuzumab deruxtecan conferred durable benefit to women with heavily pretreated HER2-positive metastatic breast cancer, according to results of the phase 2 DESTINY-Breast01 study presented at San Antonio Breast Cancer Symposium.
More than 60% of patients responded to treatment.
The trial confirmed interstitial lung disease is an important risk of this therapy, but the efficacy results — published simultaneously in The New England Journal of Medicine — demonstrate the potential of the agent to be a new standard of care in this setting, Ian E. Krop, MD, PhD, associate chief of the division of breast oncology at Dana-Farber Cancer institute, told Healio.
“A phase 1 trial of 115 patients showed this drug is very active in a heavily pretreated population, so it was nice to confirm those results in the phase 2 trial,” Krop said in an interview. “If you look at the aggregate information about this drug, it is somewhat unprecedented in a population like this. We have done a lot of studies of other drugs for heavily pretreated patients, and we don’t see anything close to this.”
HER2-directed therapies have improved outcomes for patients with HER2-positive advanced breast cancer; however, many patients develop resistance, and no clear standard of care exists once resistance occurs, Krop said.
Trastuzumab deruxtecan (AstraZeneca/Daiichi Sankyo) is a novel antibody-drug conjugate with three components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab (Herceptin, Genentech); a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.
The FDA granted priority review to the agent in October for treatment of HER2-positive breast cancer.
The open-label, multicenter DESTINY-Breast01 study included 253 adults with centrally confirmed HER2-positive breast cancer, all of whom received prior treatment with ado-trastuzumab emtansine (Kadcyla, Genentech). Patients with stable treated brain metastases were eligible; however, those with a history of significant interstitial lung disease were not.
The trial had three parts: a pharmacokinetic stage, a dose-finding stage and a continuation stage.
The intent-to-treat population consisted of 184 women (median age, 55 years; range, 28-96; 24% aged 65 years or older; 55% white; 38% Asian) who received the recommended phase 2 dose of 5.4 mg/kg via IV every 3 weeks.
More than half (53%) of those patients were hormone receptor positive. Patients received a median six prior treatments (range, 2-27), including trastuzumab (100%), ado-trastuzumab emtansine (100%), pertuzumab (Perjeta, Genentech; 65.8%), other HER2-targeted regimens (54.3%), hormone therapy (48.9%) or other systemic therapy (99.5%).
Objective response rate by independent central imaging facility review served as the primary endpoint. Secondary endpoints included investigator-assessed ORR, disease control rate, duration of response, clinical benefit rate, PFS, OS and pharmacokinetics.
At data cutoff, 79 patients (42.9%) remained on study and 105 patients (57.1%) had discontinued treatment primarily due to progressive disease.
Researchers reported a confirmed ORR by independent central review of 60.9% (95% CI, 53.4-68). This included 11 complete responses (6%) and 101 partial responses (54.9%). Median duration of response was 14.8 months (95% CI, 13.8-16.9) and median time to response was 1.6 months (95% CI, 13.8-16.9).
Sixty-seven women (36.4%) had stable disease, three (1.6%) had progressive disease and two (1.1%) were not evaluable. This translated to a disease control rate of 97.3% (95% CI, 93.8-99.1) and a clinical benefit rate at 6 months of 76.1% (95% CI, 69.3-82.1).
Researchers observed consistent benefit with trastuzumab deruxtecan across patient subgroups, including those who had prior pertuzumab.
Median follow-up for the survival analysis was 11.1 months (range, 0.7-19.9).
Median PFS was 16.4 months (95% CI, 12.7-not estimable) in the entire intent-to-treat population. Median PFS was 18.1 months (95% CI, 6.7-18.1) for patients with prior brain metastases; however, that group was small (n = 24). Median OS had not been reached.
Median treatment duration was 10 months (range, 0.7-20.5).
Nearly all patients (99.5%) experienced drug-related treatment-emergent adverse events, the most common of which were low-grade gastrointestinal or hematologic events.
About half (48.4%) experienced grade 3 or higher drug-related treatment emergent events, and 12.5% experienced drug-related serious treatment-emergent events. Drug-related events prompted 14.7% to discontinue treatment; these events included 11 cases of pneumonitis and five cases of interstitial lung disease.
Twenty-one percent of patients required dose reductions and 28.8% required dose interruption due to drug-related events. Two patients (1.1%) experienced treatment-emergent events associated with death.
The phase 1 study revealed a risk for interstitial lung disease with trastuzumab deruxtecan, Krop said.
In the phase 2 study, an independent adjudication committee determined 25 patients (13.6%) developed interstitial lung disease. Twenty cases were grade 1 or grade 2; 13 of them received corticosteroids.
Researchers reported one grade 3 case of interstitial lung disease, and four patients had fatal cases believed to be drug related.
Median time to onset of all interstitial lung disease cases was 193 days (range, 42-535); onset of the four fatal cases ranged from 63 to 148 days.
“Interstitial lung disease is confirmed as an important risk of trastuzumab deruxtecan,” Krop said. “It can be severe and requires careful monitoring and prompt intervention.”
That intervention should include evaluations with high-resolution CT, pulmonologist consultation and pulmonary function tests. If interstitial lung disease is diagnosed, treatment should be interrupted and prompt treatment with glucocorticoids should begin, Krop said.
Researchers acknowledged the single-arm design of the trial as a limitation, as it was not possible to determine if trastuzumab deruxtecan is more effective than other therapies.
However, enrollment is underway for three phase 3 trials. The DESTINY-Breast02 study will compare trastuzumab deruxtecan with standard of care after ado-trastuzumab emtansine in HER2-posiitve breast cancer, the DESTINY-Breast03 study will evaluate the agent vs. ado-trastuzumab emtansine in HER2-positive disease, and the DESTINY-Breast04 study will evaluate it vs. chemotherapy for patients with HER2 low-expressing disease. – by Mark Leiser
Reference: Krop IE, et al. Abstract GS1-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: AstraZeneca and Daiichi Sankyo sponsored this study. Krop reports research support from Genentech/Roche and Pfizer; consultant fees or honoraria from AstraZeneca, Context Therapeutics, Daiichi Sankyo, Genentech/Roche, Macrogenics; and data safety monitoring board roles with Merck and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.