Agent provides ‘unprecedented’ response duration in heavily pretreated breast cancer
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An updated analysis of the phase 2 DESTINY-Breast01 study showed fam-trastuzumab deruxtecan-nxki continued to benefit women with heavily pretreated HER2-positive metastatic breast cancer.
Nearly three-quarters of women remained alive at 18 months and a low number of women discontinued therapy due to treatment-emergent adverse events, results presented at the virtual San Antonio Breast Cancer Symposium showed.
Risk for interstitial lung disease — shown during the preliminary analysis to be an important consideration with this therapy — appeared to decrease after 1 year of treatment.
“[Fam-trastuzumab-deruxtecan-nxki] continued to demonstrate clinically meaningful and durable efficacy, with an unprecedented median duration of response,” Shanu Modi, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Treatment resulted in a robust survival outcome ... [and the therapy] showed a generally tolerable safety profile.”
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.
Fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) — often referred to as T-DXd — 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 open-label, multicenter DESTINY-Breast01 study included 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 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 T-DXd at the recommended phase 2 dose of 5.4 mg/kg via IV every 3 weeks.
More than half (52.7%) of those women were hormone receptor positive. Women received a median six (range, 2-27) prior treatments, 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, pharmacokinetics and safety.
Findings presented at last year’s symposium — based on median follow-up of 11.1 months (range, 0.7-19.9) — showed a confirmed ORR by independent central review of 60.9% (95% CI, 53.4-68).
Median PFS was 16.4 months (95% CI, 12.7-not estimable) in the intent-to-treat population and 18.1 months (95% CI, 6.7-18.1) among the 24 women with stable treated brain metastases. Median OS had not been reached.
The FDA granted accelerated approval to T-DXd based on those results.
At this year’s symposium, Modi and colleagues presented results of an updated analysis based on median follow-up of 20.5 months (range, 0.7-31.4).
At data cutoff, 20.1% of women remained on treatment; 80 women (43.4%) had been on treatment for more than 12 months; and 11 (6%) had been on treatment for more than 24 months.
Researchers reported a confirmed ORR of 61.4% (95% CI, 54-68.5), including 12 (6.5%) complete responses and 101 (54.9%) partial responses. Median duration of response was 20.8 months (95% CI, 15-not estimable).
Median PFS in the intent-to-treat population increased to 19.4 months (95% CI, 14-not estimable). OS rates were 85% (95% CI, 79-90) at 12 months and 74% (95% CI, 67-80) at 18 months. Preliminary median OS was 24.6 months (95% CI, 23.1-not estimable); however, researchers emphasized the need for additional follow-up to obtain more mature OS data.
"While the overall survival results are not mature with a number of patients still in follow-up, the estimated 18-month landmark OS of 74% is impressive for this heavily pretreated group of patients," Modi told Healio.
T-DXd exhibited an overall safety profile consistent with prior reports.
Nearly all women (99.5%) experienced treatment-emergent adverse events (grade 3 or higher, 61.4%).
Treatment-emergent adverse events prompted treatment discontinuation for 18.5% of women, dose reductions for 23.9% and dose interruptions for 40.8%. Ten patients (5.4%) died due to treatment-emergent adverse events.
Initial results presented at last year’s symposium showed an independent adjudication committee determined 25 women (13.6%) developed interstitial lung disease. The committee identified three additional cases during extended follow-up, bringing the total to 28 (15.2%).
Five patients (2.7%) had died due to interstitial lung disease. Six cases (3.3%) were grade 1, 16 (8.7%) were grade 2 and one (0.5%) was grade 3.
The majority of first interstitial lung disease events occurred during the first 12 months of treatment. Only one patient who did not experience an interstitial lung disease event during the first 12 months of treatment subsequently developed the condition. Two cases were pending adjudication at data cutoff.
"Interstitial lung disease is a toxicity of interest, and three more cases were noted in the follow-up period," Modi told Healio. "An interesting exploratory analysis did indicate that the risk of drug-related interstitial lung disease appears lower after approximately 12 to 14 months on treatment; however, continued attention to pulmonary symptoms and monitoring are warranted throughout a patient's course on therapy."
Researchers reported four cases of left ventricle ejection fraction decrease (grade 2, n = 3; grade 3, n = 1), as well as two cases of cardiac failure (grade 1, n = 1; grade 2, n = 1) with no left ventricle ejection fraction decrease.
Phase 3 confirmatory trials are nearing completion.
"Results are eagerly anticipated," Modi said.
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Modi S, et al. Abstract PD3-06. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 8-11, 2020.
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