In heavily pretreated patients with advanced HER2-positive breast cancer, trastuzumab deruxtecan induced a confirmed objective response rate of almost 61% and a durable benefit, according to results from the phase II DESTINY-Breast01 trial presented at the 2019 San Antonio Breast Cancer Symposium.
Ian Krop MD, PhD
In heavily pretreated patients with advanced HER2-positive breast cancer, trastuzumab deruxtecan (T-DXd; DS-8201) induced a confirmed objective response rate (ORR) of almost 61% and a durable benefit, according to results from the phase II DESTINY-Breast01 trial presented at the 2019 San Antonio Breast Cancer Symposium (SABCS).1
ORR per independent central review (ICR) was 60.9% (95% CI, 53.4-68.0), including 11 complete responses (CRs; 6.0%), 101 partial responses (PRs; 54.9%), 67 with stable disease (SD; 36.4%), and 3 with progressive disease (PD; 1.6%). Two patients were not evaluable. ORRs were consistent across subgroups, including those with prior treatment with pertuzumab (Perjeta; 64%) and those with ≥ 3 prior regimens (59%).
These data present the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2 positive breast cancer,” Ian Krop MD, PhD, associate chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, said during a press briefing held at the meeting.
Moreover, the investigational HER2-targeted antibody-drug conjugate yielded a median duration of response (DOR) of 14.8 months (95% CI, 13.8-16.9), and a disease control rate (DCR) of 97.3% (95% CI, 93.8-99.1). Clinical benefit ratio at 6 months was 76.1% (95% CI, 69.3%-82.1%), and median time to response was 1.6 months (95% CI, 1.4-2.6 months). Activity of T-DXd across all major subgroups appeared consistent.
After a median follow-up of 11.1 months (range, 0.7-19.9 months), median progression-free survival (PFS) of 16.4 months (95% CI, 12.7-NE). Median PFS in the 24 patients with brain metastases was 18.1 months (95% CI, 6.7-18.1 months). Median overall survival was not reached (95% CI, NE-NE).
In the open-label, international, multicenter phase II registration study, investigators enrolled 253 patients with HER2-positive breast cancer who were heavily pretreated, including with T-DM1 (Kadcyla) and other HER2-targeted treatments. The trial consisted of part 1 to evaluate pharmacokinetics (n= 65) and to determine recommended dose (RP2D; n = 54) for part 2 (n = 134): 5.4 mg/kg T-DXd. Data from this study were published simultaneously in the New England Journal of Medicine.2
ORR per ICR served as the primary endpoint. Secondary endpoints included DCR, DOR, and PFS.
Inclusion criteria included ≥18 years of age, unresectable and/or metastatic breast cancer, HER2-positive (centrally confirmed on archival tissue), prior T-DM1 therapy. Patients with a history of significant interstitial lung disease (ILD) were excluded. Those with stable, treated brain metastases were allowed.
All patients were female, the majority were white (55%), and 38% were Asian. Median age was 55 years (range, 28-96 years). Fifty-three percent were hormone receptor (HR)-positive and 45% were HR-negative. At baseline, the median number of prior treatment regimens was 6 (range, 2-27), including trastuzumab (Herceptin; 100%), T-DM1 (100%), pertuzumab (65.8%), and other HER2-targeted regimens (54.3%). The reported best response to T-DM1 before enrollment on the study were a CR and PR rate of 22%, 21% of patients with SD, and 36% with PD. Twenty-one percent were not evaluable.
As of the data cutoff (August 1, 2019), 79 patients (42.9%) are still on treatment, while 105 patients (57.1%) discontinued treatment, primarily for progressive disease (28.8%). In total, 184 patients enrolled on the study have received 5.4 mg/kg T-DXd for a median treatment duration of 6.9 months (range, 0.7-16 months).
Treatment-emergent adverse events (TEAE) occurred in 99% of patients, 51% being grade ≥ 3. The most common any-grade TEAEs were nausea (77%), alopecia (48%), fatigue (48%), vomiting (45%), constipation (34%), decreased neutrophil count (31%), decreased appetite (29%), diarrhea (27%), and anemia (26%). The most common grade ≥ 3 AEs were decreased neutrophil count (in 31% of the patients), nausea (7.6%), and anemia (in 26%).
Of note, 25 patients (13.6%) experienced ILD related to T-DXd by an independent adjudication committee. However, ILD was primarily grade 1 (2.7%) or 2 (8.2%). Median time to investigator-reported onset of ILD was 193 days (range, 42-535 days), and 13 of the 20 patients with grade ≥2 ILD received corticosteroids. Overall, 7 patients recovered, 2 were recovering at data cutoff, 12 were either outcome unknown or not followed until resolution, and 4 died. Of the 4 fatal cases, onset was from 63 to 148 days, of which 3 received steroids as part of their treatment, and death occurred 9 to 60 days after ILD diagnosis.
“(An independent) expert panel, after looking over this data (noted that in) future studies of trastuzumab deruxtecan patients (should) be monitored closely for symptoms of ILD, that trastuzumab deruxtecan be held, and the steroids started as soon as ILD is suspected,” Krop said.
T-DXd is a novel antibody drug conjugate that is comprised of 3 components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase I inhibitor payload, an exatecan derivative; and a tetrapeptide-based cleavable linker.
Phase I data, previously published in The Lancet Oncology, showed that T-DXd demonstrated an ORR of 59.5% (95% CI, 49.7-68.7) in patients with advanced HER-2 positive breast cancer previously treated with T-DM1.3 The FDA granted priority review to the agent in October.
“This is a fantastic result in heavily pretreated patients. If we move this treatment to earlier stage disease, I suspect the impact could be greater in these patients. This is great news for patients with HER2-positive breast cancer, concluded SABCS co-director and press briefing moderator Carlos Arteaga, MD, AACR past president and director of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center.