Patritumab deruxtecan demonstrates antitumor activity in patients with EGFR-mutant NSCLC
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Patritumab deruxtecan induced a 39% overall response rate among patients with advanced, EGFR-mutant non-small cell lung cancer, according to phase 1 study results presented during the virtual ASCO Annual Meeting.
“EGFR inhibitors are the standard of care for patients with advanced EGFR-mutant NSCLC. However, resistance inevitably develops, and the mechanisms of resistance are diverse. As such, new therapeutic approaches are needed,” Pasi A. Jänne, MD, PhD, oncologist at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, told Healio. “HER3 is a member of the EGFR family of proteins that is expressed on the vast majority of EGFR-mutant cancers and is not known to be a mechanism of resistance to EGFR inhibitors. Patritumab deruxtecan [HER3-DXd/U3-1402, Daiichi Sankyo] is a HER3-directed antibody-drug conjugate that is undergoing testing in treatment-limited, EGFR-mutant patients who have developed resistance to EGFR inhibitors.”
The agent consists of a fully human monoclonal antibody to HER3 that is attached through a tetrapeptide-based cleavable linker to topoisomerase I inhibitor payload, according to study background.
As part of a phase 1 dose-escalation/expansion study, investigators evaluated the safety and efficacy of patritumab deruxtecan at a dose of 5.6 mg/kg IV once every 3 weeks among 57 patients (median age, 65 years; 63% women) with advanced, EGFR-mutant NSCLC. Patients received a median four (range, 1-9) prior lines of systemic therapy, including an EGFR tyrosine kinase inhibitor, and most (91%) had received prior platinum-based chemotherapy. Nearly half (47%) had a history of brain metastases.
Confirmed ORR by blinded independent central review per RECIST version 1.1 served as the primary endpoint. Duration of response, PFS and safety served as secondary endpoints.
Median follow-up was 10.2 months and median treatment duration was 5.5 months. At the time of data cutoff Sept. 24, 2020, 32% of patients remained on treatment.
Results showed ORRs of 39% (95% CI, 26-52) among the overall study population, 37% (95% CI, 23.6-51) among patients who previously received platinum-based chemotherapy and 39% (95% CI, 24-55) among patients who previously received platinum-based chemotherapy and the EGFR TKI osimertinib (Tagrisso, AstraZeneca).
Median duration of response in the overall cohort was 6.9 months (95% CI, 3.1-not reached) and median PFS was 8.2 months (95% CI, 4.4-8.3).
A comparison of patients with vs. without a history of brain metastases showed similar results between the two groups (ORR, 32% vs. 42%; median PFS, 8.2 months vs. 8.3 months).
Common grade 3 or higher adverse events appeared consistent with previous observations and included thrombocytopenia (30%), neutropenia (19%) and fatigue (14%). Four patients experienced treatment-related interstitial lung disease by central adjudication, and six patients discontinued treatment due to adverse events.
“HER3-DXd was effective in this patient population,” Jänne said. “As predicted by the mechanism, responses were observed in patients regardless of the specific EGFR inhibitor resistance mechanism. Activity was observed across different levels of HER3 expression, although there was a suggestion of a higher response in patients whose tumors expressed higher levels of HER3. Given the broad range of activity of HER3-DXd across EGFR TKI resistance mechanisms, HER3-DXd may offer a novel EGFR TKI resistance mechanism agnostic strategy for treatment of drug-resistant cancers.”
A phase 2 single-agent trial is ongoing, including patients with EGFR-mutant NSCLC who received prior osimertinib and chemotherapy, Jänne added.
“In addition, a phase 1 trial of osimertinib plus HER3-DXd has also started for patients who have recently received prior osimertinib. Future studies will continue to evaluate the relationship between HER3 expression and HER3-DXd efficacy,” Jänne said.
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Jänne PA, et al. Abstract 9007. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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