December 10, 2020 - Fam-trastuzumab deruxtecan-nxki continued to showcase impressive signals of efficacy, including prolonged, durable responses and overall survival rates, as well as a tolerable safety profile in patients with HER2-positive metastatic breast cancer.
Fam-trastuzumab deruxtecan-nxki (Enhertu) continued to showcase impressive signals of efficacy, including prolonged, durable responses and overall survival (OS) rates, as well as a tolerable safety profile in patients with HER2-positive metastatic breast cancer, according to an updated analysis of the phase 2 DESTINY-Breast01 study (NCT03248492) that was presented during the 2020 San Antonio Breast Cancer Symposium.1
Results showed that, with an additional 9.4 months of follow-up, the median duration of response (DOR) was 20.8 months and the estimated 12- and 18-month OS rates was 85% (95%, 79%-90%) and 74% (95% CI, 67%-80%), respectively. The median progression-free survival (PFS) was 19.4 months (95% CI, 14.1 months–not estimable [NE]), and the preliminary median OS, although still immature, was 24.6 months (95% CI, 23.1–NE).
“Trastuzumab deruxtecan continues to demonstrate clinically meaningful and durable efficacy with an unprecedented median duration of response of 20.8 months and an 18-month landmark OS [rate] of 74%,” lead study author Shanu Modi, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said in a prerecorded poster presentation of the data. “The safety profile continues to demonstrate general tolerability.”
Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) consisting of a humanized monoclonal anti-HER2 antibody joined to a potent topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker.
In December 2019, the FDA granted an accelerated approval to trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.
The approval is based on findings from DESTINY-Breast01, updated data of which were presented at the 2019 San Antonio Breast Cancer Symposium.2 In the study, trastuzumab deruxtecan induced a confirmed objective response rate (ORR) of 60.9% per independent central review (ICR; 95% CI, 53.4%-68.0%), including a 6.0% complete response (CR) rate, and a 54.9% partial response (PR) rate. Sixty-seven patients had stable disease (SD; 36.4%), and 3 had progressive disease (PD; 1.6%) at the data cutoff date of August 1, 2019 and a median follow-up of 11.1 months. Two patients were not evaluable. The median DOR was 14.8 months (95% CI, 13.8-16.9), and the median PFS was 16.4 months (95% CI, 12.7–NE).
Data from this study were published simultaneously in the New England Journal of Medicine.3
In the open-label, international, multicenter phase 2 registration study, investigators enrolled 184 patients with HER2-positive breast cancer who were heavily pretreated, including with ado-trastuzumab emtansine (T-DM1; Kadcyla) and other HER2-targeted treatments. The trial consisted of part 1 to evaluate pharmacokinetics (n= 65) and to determine the recommended dose (RP2D; n = 54) for part 2 (n = 134): 5.4 mg/kg fam-trastuzumab deruxtecan-nxki.
ORR per ICR served as the primary end point of the trial; secondary endpoints included DCR, DOR, and PFS. Per inclusion criteria, patients had to be at least 18 years of age, have unresectable and/or metastatic breast cancer, HER2-positivity (centrally confirmed on archival tissue), and have received prior T-DM1 therapy to participate. 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. The median age of participants was 55 years (range, 28-96 years). Fifty-three percent had hormone receptor (HR)–positive disease, 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 (Perjeta; 65.8%), other anti-HER2 antibodies or ADCs (6.0%), other HER2-targeted TKIs (50.5%), hormonal therapy (48.9%), and other prior systemic therapy (99.5%).
At a median follow-up of 20.5 months (range, 0.7-31.4), 20.1% of patients remained on therapy; 43.4% and 6.0% of patients were on treatment for longer than 1 and 2 years, respectively. With increased maturity of the data duration of responses increased, 65.2% of patients were censored.
Additional data showed that the confirmed ORR was 61.4% (95% CI, 54.0%-68.5%); the CR, PR, SD, and PD rates were 6.5%, 54.9%, 35.9%, 1.6%, and 1.1%, respectively. The time to response continued to be 1.6 months (95% CI, 1.4-2.6).
The median OS was estimated at 35% maturity, with 119 patients censored and only 17 patients at risk at 2 years. Additional follow-up is needed for more mature survival data, the authors noted in the poster.
Regarding safety, the overall safety profile of trastuzumab deruxtecan was consistent with prior reports. Treatment discontinuations due to AEs occurred at 18.5% of patients, and 17.9% were related to treatment. Treatment-emergent AEs (TEAEs) that were at least grade 3 occurred in 61.4% of patients and 52.7% were related to the study drug. TEAEs associated with discontinuations, dose reductions, and dose interruptions occurred in 17.9%, 21.2%, and 32.6% of patients, respectively. TEAEs that led to death occurred in 5.4% (n = 10) of patients, 3 of which were related to treatment.
Three additional cases of ILD were reported, as determined by an independent adjudication committee; most first ILD events occurred during the first year of treatment. Among those who did not have an ILD event for longer than 1 year, 1 patient subsequently developed ILD, and 2 were pending adjudication at the time of data cutoff. Investigators noted that the risk of adjudicated treatment-related ILD appeared lower after an estimated 1 year on treatment, which suggests that the risk of developing ILD is not related to a cumulative trastuzumab deruxtecan dose. Continued attention to pulmonary symptoms and careful monitoring is warranted, Modi said.
One additional case of left ventricle ejection fraction decrease occurred at grade 2, and no new TEAEs of cardiac failure were reported since the prior analysis. There were 4 events overall of LVEF decrease, which were of grade 2 (n = 3) and grade 3 (n = 1), and 2 total cardiac failures of grade 1 and 2 (n = 1 each); no LVEF decrease was observed during treatment.
In a poster spotlight discussion during the meeting, Tiffany A. Traina, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, commented on the updated findings.
“I'll editorialize to say that these data confirm the ongoing and impressive activity of this ADC,” Traina said. “With longer follow-up, there were 3 additional cases of treatment-related ILD, including 1 additional death, [but] discontinuation rates and overall rate of ILD were no higher in this longer follow-up period. The risk of ILD really requires awareness, careful monitoring, and adherence to dose interruption and management guidelines to allow our patients the optimal risk–benefit balance. As you may be aware, ongoing randomized Destiny Breast portfolio trials will further evaluate, and hopefully confirm, the benefit of this highly active ADC.”
The ongoing, controlled, phase 3 DESTINY-Breast02 study (NCT03523585) is evaluating trastuzumab deruxtecan compared with investigator’s choice of treatment in patients with HER2-positive breast cancer that has metastasized or cannot be surgically removed and who have received prior treatment with T-DM1.