Novel Therapy Continues to Show Prolonged, Durable Responses and Survival Outcomes in Patients with HER2-Positive Metastatic Breast Cancer

An updated analysis of the phase 2 DESTINY-Breast01 trial presented at the 2020 San Antonio Breast Cancer Symposium demonstrated that treatment with Enhertu (fam-trastuzumab deruxtecan-nxki) continues 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.

Results from the updated analysis showed that, with an additional 9.4 months of follow-up, the median duration of response (DOR) to Enhertu was 20.8 months and the estimated 12- and 18-month OS rates were 85% and 74%, respectively. The median progression-free survival (the time from treatment to disease progression) (PFS) was 19.4 months and the preliminary median OS, although still immature at the time of presentation, was 24.6 months.

“(Enhertu) 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 Dr. Shanu Modi, 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.”

Enhertu is an antibody-drug conjugate (ADC) that consists of a humanized monoclonal anti-HER2 antibody joined to a potent topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker. ADC’s are a new class of drug that attach the molecule of an anticancer drug, in this case the HER2 antibody, that targets a specific antigen on the cancer cells in the patient’s body.

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 Kadcyla (ado-trastuzumab emtansine) and other HER2-targeted treatments. The trial consisted of a part one, which evaluated the movement of the therapies within the body to determine the recommended dose of Enhertu for part two of the study, which was 5.4 mg/kg.

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 six including with Herceptin (trastuzumab), T-DM1, Perjeta (pertuzumab) and other anti-HER2 antibodies or ADCs (6.0%).

At a median follow-up of 20.5 months, 20.1% of patients remained on therapy; 43.4% and 6% of patients were on treatment for longer than one and two years, respectively. With increased maturity of the data, duration of responses increased.

Additional data showed that the confirmed overall response rate was 61.4%, while the complete response, partial response, stable disease, and progressive disease rates were 6.5%, 54.9%, 35.9%, 1.6% and 1.1%, respectively. The time to response remained 1.6 months.

Additional follow-up is needed for more mature survival data, the authors noted in the poster.

Regarding safety, the overall safety profile of Enhertu was consistent with prior reports. Treatment discontinuations due to side effects occurred in 18.5% of patients. Reported side effects that were at least grade 3 (more severe) occurred in 61.4% of patients,52.7% of which were related to the study drug. Treatment side effects associated with discontinuations, dose reductions and dose interruptions occurred in 17.9%, 21.2% and 32.6% of patients, respectively. Ten patients died during the trial, three of which were related to treatment.

Three additional cases of interstitial lung disease (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 one year, one patient subsequently developed ILD, and two were pending adjudication at the time of data cutoff. Investigators noted that the risk of adjudicated treatment-related ILD appeared lower after an estimated one year on treatment, which suggests that the risk of developing ILD is not related to a cumulative Enhertu dose. Continued attention to pulmonary symptoms and careful monitoring is warranted, Modi said.

In a poster spotlight discussion during the meeting, Dr. Tiffany A. Traina, 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 three additional cases of treatment-related ILD, including one 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.”

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A version of this article originally appeared on OncLive® as “Trastuzumab Deruxtecan Continues to Show Impressive Outcomes in HER2+ Metastatic Breast Cancer