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Efficacy and Safety of Patritumab Deruxtecan in EGFR-mutated NSCLC Resistant to EGFR TKI Therapy

Targeting unmet need in EGFR tyrosine kinase inhibitor resistant non-small cell lung cancer
16 Jun 2021
Anticancer agents & Biologic therapy;  Lung and other thoracic tumours;  Personalised medicine

Patritumab deruxtecan (HER3-DXd), an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker, achieved clinically meaningful, durable efficacy in a phase I dose escalation and dose expansion study conducted in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Efficacy was shown across EGFR TKI resistance mechanisms. Antitumour activity was observed across a wide range of baseline HER3 expression. Treatment was tolerable with manageable safety profile. The findings were reported by Dr. Pasi A. Jänne of the Dana-Farber Cancer Institute in Boston, MA, US at 2021 ASCO Annual Meeting (4-8 June).

Dr. Jänne said that efficacy of EGFR TKI in EGFR-mutated NSCLC has been established; however, the development of various resistance mechanisms commonly leads to disease progression. Platinum-based chemotherapy following EGFR TKI failure has limited efficacy. Salvage therapies after EGFR TKI and platinum-based chemotherapy have not been effective.

HER3 is expressed in 83% of NSCLC tumours. HER3 alterations are not known to be a mechanism of resistance to EGFR TKI in EGFR-mutated NSCLC. HER3-DXd is in clinical evaluation for NSCLC, metastatic breast cancer, and colorectal cancer.

U31402-A-U102 is a phase I dose escalation and dose expansion study in patients with NSCLC. The study team previously presented efficacy and safety data with a median follow-up of 5.4 month from this ongoing study. At ASCO 2021 Annual Meeting they presented extended follow-up of patients receiving the recommended dose for expansion of 5.6 mg/kg i.v. every 3 weeks. Patients with stable brain metastases were allowed.

The primary endpoint was confirmed overall response rate (ORR) by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS) and safety.

At data cut-off of 24 September 2020, 57 patients were treated with HER3-DXd at recommended dose of 5.6 mg/kg i.v. every 3 weeks. Median follow-up was 10.2 month (range, 5.2-19.9 month). Median number of prior anticancer regimens was 4 (range, 1-10). All patients had prior EGFR TKI, 86% prior osimertinib and 91% had prior platinum-based chemotherapy. In total, 47% had a history of brain metastases. Median treatment duration was 5.5 month (range, 0.7-18.6 month). Treatment was ongoing in 18 patients (32%).

Confirmed ORR by BICR was 39% (22 of 57 patients; 95% confidence interval [CI] 26.0%-52.4%) with 1 complete response (CR), 21 partial response (PR) and 19 stable disease (SD); 14 of 22 responses occurred within 3 month of starting HER3-DXd therapy. Disease control rate was 72% (95% CI 58.5%-83.0%).

Median DoR was 6.9 month (95% CI 3.1 month - non evaluable). Median PFS was 8.2 month (95% CI 4.4-8.3 month).

Antitumour activity was observed across diverse mechanisms of EGFR TKI resistance, including those not directly related to HER3 (EGFR C797S, MET or HER2 amplification, and BRAF fusion).

Among patients with prior platinum-based chemotherapy, ORR was 37% (19 of 52 patients; 95% CI 23.6%-51.0%). In patients with prior osimertinib and platinum-based chemotherapy, ORR was 39% (17 of 44 patients; 95% CI 24.4%-54.5%).

Among 43 patients evaluable for HER3 expression, nearly all expressed HER3; median membrane H-score by immunohistochemistry was 180 (range, 2-280). Median H-score (range; N) was 195 (92-268; 15) in patients with CR/PR, 180 (4-280; 15) in patients with SD, 126.5 (2-251; 6) in patients with progressive disease, and 180 (36-180; 7) in patients unevaluable for best overall response. HER3 expression was not correlated with time since last EGFR TKI dose. The authors reported that responses were observed in patients with a wide range of baseline HER3 membrane H-scores.

Early clearance of ctDNA was defined as non-detectable plasma of either EGFR Ex19del or EGFR L858R at week 3 or 6, where either mutation was detectable at baseline (evaluable in 40 of 57 patients). Confirmed ORR was higher with early clearance of ctDNA and PFS was prolonged in patients with early clearance of ctDNA.

The most common grade ≥3 adverse events (AEs) were thrombocytopenia (30%), neutropenia (19%), and fatigue (14%). Drug-related interstitial lung disease by central adjudication occurred in 4 patients (7%; 1 grade ≥3 [2%]; no grade 5). Six of 57 patients (11%) had AEs associated with treatment discontinuation; none were due to thrombocytopenia.

The researchers concluded that HER3-DXd at recommended dose demonstrated antitumour activity across various EGFR TKI resistance mechanisms in heavily pretreated metastatic/locally advanced EGFR-mutated NSCLC. The safety profile was consistent with previous reports. A pivotal, phase II study of HER3-DXd in patients with EGFR-mutated NSCLC after failure of EGFR TKI and platinum-based chemotherapy has been initiated.

The study was funded by Daiichi Sankyo, Inc.

Reference

Janne PA, Baik CS, Su W-C, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). J Clin Oncol 2021;39(suppl 15; abstr 9007). DOI: 10.1200/JCO.2021.39.15_suppl.9007

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