Trastuzumab Deruxtecan Shows Promise in Heavily Pretreated Patients With HER2+ BC

Trastuzumab deruxtecan (T-DXd; DS-8201) showed improved and durable response rates in heavily pretreated patients with advanced HER2-positive breast cancer, according to results from the phase II DESTINY-Breast01 trial presented at the San Antonio Breast Cancer Symposium, held December 10-14, in San Antonio, Texas.¹

“This is a very heavily pretreated population, where a median of 6 prior lines of therapy were received…To put it into context the progression-free survival is 16.0 months, response rate of 60%, those roughly double or triple what is typically seen in other studies of this third or later line population,” 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. 

“This data really are quite distinctive in how the efficacy is compared to what we would see in typical studies in this population where the median progression-free survival has been in the 4.0- to 5.0-month range as opposed to 16.0 months here,” he added.

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.

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 (66%), and other HER2-targeted regimens (54%). 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.

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%).

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), essentially at the time of the first re-staging, Krop explained.

Activity of T-DXd across all major subgroups appeared consistent, including those who received prior trastuzumab where the response rate was about 65%, he added. 

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).

“Trastuzumab deruxtecan has several distinct features,” Krop explained. “One is the payload is a potent topoisomerase I inhibitor. This is a kind of chemotherapy that is not typically used in HER2-positive breast cancer so it is less likely that cancers will develop resistance to this agent. There are about 8 of these payload molecules per antibody, and this is a higher drug-antibody ratio than is typically seen in current antibody conjugates. Lastly, the payload is membrane permeable so in preclinical studies it allows it to diffuse out of the cell and kill neighboring tumor cells regardless of their HER2 expression.”

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 (TEAEs) occurred in 99.5% of patients, 57.1% 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%). TEAEs that led to discontinuation in ≥2 patients included pneumonitis (n = 11) and interstitial lung disease (n = 5). The most common grade ≥ 3 AEs were decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%).

Of note, 25 patients (13.6%) experienced interstitial lung disease (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 1 or 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.

“ILD is confirmed as an important risk of trastuzumab deruxtecan. It can be severe and requires careful monitoring and prompt prevention,” Krop said.

He noted that future studies are already underway for this agent. “These data present the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2 positive breast cancer. There are several phase III studies of this agent underway both in HER2-overexpressing cancers as well as HER2-low expressing cancers.”

Reference:

1. Krop IE, Saura C, Yamashita T, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previouslytreated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01). Presented at: the San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract GS1-03.

2. Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. NEJM. doi:10.1056/NEJMoa1914510.