The HER3-directed antibody-drug conjugate patritumab deruxtecan (HER3-DXd) showed activity in patients with heavily pretreated HER3-expressing metastatic breast cancer in a phase I/II study. Ian E. Krop, MD, PhD, Associate Director, Yale Cancer Center, New Haven, Connecticut, presented these findings at the 2022 ASCO Annual Meeting.1
“HER3-DXd demonstrated clinically meaningful and durable antitumor activity in a heavily pretreated population of patients with HER3-expressing breast cancer … and across breast cancer subtypes.”— Ian E. Krop, MD, PhD
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“HER3-DXd demonstrated clinically meaningful and durable antitumor activity in a heavily pretreated population of patients with HER3-expressing breast cancer…and across breast cancer subtypes,” Dr. Krop announced. “In general, we saw very durable responses, with a median duration of response of 6 to 8 months…. The majority of patients had a meaningful diminution of tumor size.”
In the overall population, the objective response rate was 28.6%. Response rates were highest, 42.9%, among the HER2-positive cohort, although this group contained 14 patients. “We think these data are certainly encouraging enough to warrant moving forward into larger trials in all three major subtypes of breast cancer,” Dr. Krop said.
HER3 is expressed in approximately 30% to 50% of breast cancers across subtypes, is associated with a poor prognosis, and is not targeted by any current therapies. Early attempts at targeting HER3 were not successful, but advances in manufacturing antibody-drug conjugates have eliminated some obstacles. One such advance resulted in patritumab deruxtecan, which consists of an anti-HER3 monoclonal antibody covalently linked to a topoisomerase-1 inhibitor payload.
About the Study
The phase I/II study, U31402-A-J101, is evaluating HER3-DXd in 182 patients with HER3-expressing metastatic breast cancer. Efficacy data were available for 113 patients with hormone receptor–positive/HER2-negative breast cancer, 53 with triple-negative breast cancer, and 14 with HER2-positive disease. In the dose-
escalation and dose-expansion phases, dosing cohorts received 1.6 mg/kg to 8.0 mg/kg every 3 weeks.
Dr. Krop presented an analysis from the dose-escalation, dose-finding, and dose-expansion cohorts who were followed for a median of 31.9 months. Patients were heavily pretreated, with a median of 2 to 6 prior regimens (depending on the subtype, ranging from 1–13) for advanced disease. Metastases to the lung and/or liver were present in 90% of the hormone receptor–positive/HER2-negative cohort, 86% of those with HER2-positive disease, and 64% of patients with triple-negative disease. The primary endpoint was response rate by blinded independent central review.
Durable Activity Reported for HER3-DXd
Dr. Krop reported durable responses across subtypes, with an overall rate of response, for all patients, of 28.6% (Table 1). “In addition, there were responses to this agent across a wide range of HER3 expression. There was no clear relationship between the level of pretreatment HER3 expression and response to HER3-DXd,” he added.
“We were also curious about whether HER3 expression changed over time, and so we looked not only at pretreatment levels, but also at archival samples when available. We found that HER 3 expression was quite dynamic between the two time points, with substantial changes seen, both increasing in some patients and decreasing in others. This did not seem to be related to response to HER3-DXd,” he said.
What is not understood is why patients with low HER3 expression might still respond to HER3-DXd. Possible explanations include the bystander effect, payload potency, and a high drug-to-antibody ratio. For the HER2-targeting antibody-drug conjugate fam-trastuzumab deruxtecan-nxki, activity has been observed in patients with HER2-low breast cancer, Dr. Krop -pointed out.
Across all three doses, approximately 10% of patients discontinued patritumab deruxtecan because of treatment-emergent adverse events. The most common toxicities occurring in the two most used doses (4.8 and 6.4 mg/kg every 3 weeks) were nausea, vomiting, and diarrhea. At the highest dose (6.4 mg/kg), grade ≥ 3 neutropenia occurred in 52% of patients, and grade ≥ 3 thrombocytopenia was reported in 38.8%. Treatment-related interstitial lung disease developed in 6.6% of patients, which was primarily grade 1 or 2, although one patient died of this complication. Rates of grade ≥ 3 neutropenia, thrombocytopenia, and leukopenia were all higher with the higher dose, but these events were all managed with dose delays or reductions; no grade ≥ 3 bleeding events occurred.
“As a roughly similar safety profile was seen with 4.8 mg/kg and 6.4 mg/kg, a dose of 5.6 mg/kg, which is currently used in studies in non–small cell lung cancer, is being evaluated in breast cancer to refine dose optimization,” he said.
DISCLOSURE: Dr. Krop reported financial relationships with AstraZeneca, Genentech/Roche, Bristol Myers Squibb, Daiichi Sankyo, MacroGenics, Merck, Novartis, and Seattle Genetics.
1. Krop IE, Masuda N, Mukohara T, et al: Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate, in patients with HER3-expressing metastatic breast cancer. 2022 ASCO Annual Meeting. Abstract 1002. Presented June 4, 2022.
Véronique Diéras, MD
The invited discussant of the phase I/II study of patritumab deruxtecan (HER3-DXd) was Véronique Diéras, MD, of the Eugène Marquis Centre, Rennes, France. She commented that HER3-DXd showed promising activity across breast cancer subtypes with heavily pretreated...