Patritumab Deruxtecan BLA Receives Priority Review in NSCLC

The FDA has accepted and granted priority review to the biologics license application (BLA) seeking the approval of the HER3-directed antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd) for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) who previously received at least 2 systemic therapies.¹

“The acceptance of the BLA submission of patritumab deruxtecan marks an important step in potentially bringing this new medicine to previously treated patients with EGFR-mutated NSCLC, who often experience recurrence and have few remaining treatment options,” Marjorie Green, MD, Senior Vice President and Head of Late-Stage Oncology, Global Clinical Development, Merck Research Laboratories, said in a press release. “Today is the first of many important milestones from our collaboration with Daiichi Sankyo, as we work together to bring new and potentially first-in-class ADCs to people living with cancer.”¹

The regulatory decision was supported by findings from the phase 2 HERTHENA-Lung01 trial (NCT04619004), which enrolled patients with previously treated, locally advanced or metastatic NSCLC with EGFR activating mutations. Findings from the study, which were presented during the IASLC 2023 World Conference on Lung Cancer and simultaneously published in the Journal of Clinical Oncology, showed that treatment with the ADC led to an overall response rate (ORR) of 29.8% (95% CI, 23.9%-36.2%) by blinded independent central review (BICR), with 1 complete response, among patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR-directed TKI and platinum-based chemotherapy (n = 225). Additionally, the median duration of response (DOR) was 6.4 months (95% CI, 4.9-7.8), and the median progression-free survival (PFS) was 5.5 months (95% CI, 5.1-5.9).²

To be eligible for the multicenter, open-label study, patients also needed to have an ECOG performance status (PS) of 1 or 0 and have progressed after their most recent therapy. Prior therapies needed to include at least 1 EGFR-directed TKI and at least 1 platinum-based chemotherapy regimen, irrespective of sequence. After the initiation of the study, the trial protocol was amended to mandate prior therapy with osimertinib (Tagrisso); patients with previous or current evidence of interstitial lung disease were ineligible.²

Patients received intravenous patritumab deruxtecan once every 3 weeks in 1 of 2 dosing schedules. Patients in arm 1 received the agent via a fixed-dose regimen at a dose of 5.6 mg/kg. Patients in arm 2 were treated with patritumab deruxtecan via an uptitration regimen: 3.2 mg/kg on day 1 of cycle 1; 4.8 mg/kg on day 1 of cycle 2; and 6.4 mg/kg on day 1 of cycle 3 and subsequent cycles.²

The uptitration arm was closed after the enrollment of 51 patients. The fixed-dose arm enrolled 226 patients, with 225 receiving at least 1 dose of patritumab deruxtecan every 3 weeks to make up the efficacy and safety populations.²

The primary end point was ORR by BICR per RECIST 1.1. Secondary end points included DOR by BICR, PFS, disease control rate (DCR), time to response, overall survival (OS), and safety.²

At baseline, the median age was 64 years (range, 37-82), and the median number of prior lines of therapy in the locally advanced/metastatic setting was 3 (range, 1-11). Most patients were female (58.7%), never smokers (64.0%), younger than 65 years of age (53.8%), had EGFR exon 19 deletions (63.1%), had adenocarcinoma (97.8%), and had an ECOG PS of 1 (66.2%).²

At the November 21, 2022, data cutoff, at a median follow-up of 18.9 months (range, 14.9-27.5) additional findings from HERTHENA-Lung01 demonstrated that the median OS was 11.9 months (95% CI, 11.2-13.1). A total of 43.3% of patients had a DOR of at least 6 months. The DCR was 73.8% (95% CI, 67.5%-79.4%).²

In terms of safety, the median treatment duration was 5.5 months (range, 0.7-18.2). Treatment-emergent adverse effects (TEAEs) of at least grade 3 and at least grade 4 occurred at rates of 64.9% and 28.9%, respectively. The most common grade 3 or higher TEAEs included thrombocytopenia (20.9%), neutropenia (19.1%), and anemia (14%). Common grade 1 or 2 TEAEs included nausea (63%), decreased appetite (39%), and constipation (34%).²

TEAEs were associated with dose interruption, reduction, and discontinuation at rates of 40.4%, 21.3%, and 7.1%, respectively. Death-associated TEAEs occurred at a rate of 1.8%.²

Patritumab deruxtecan’s receipt of priority review from the FDA follows the breakthrough therapy designation it received from the agency in December 2021 for patients with metastatic or locally advanced EGFR-mutated NSCLC with disease progression on or after treatment with platinum-based therapy and a third-generation TKI. The FDA has set a Prescription Drug User Fee Act date of June 26, 2024, for the BLA.¹

“The FDA’s prioritization of the BLA submission reflects the strength of the data from HERTHENA-Lung01 and emphasizes the need to provide new options to patients with locally advanced or metastatic, EGFR-mutated NSCLC previously treated with 2 or more systemic therapies,” Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said in the release. “If approved, patritumab deruxtecan could become the first HER3-directed medicine approved in the US and the second DXd antibody drug conjugate approved from Daiichi Sankyo’s oncology pipeline.”¹

References

1. Patritumab Deruxtecan Granted Priority Review in the U.S. for Certain Patients with Previously Treated Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer. News release. Daiichi Sankyo and Merck. December 22, 2023. Accessed December 22, 2023. https://www.businesswire.com/news/home/20231221780782/en
2. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor–mutated non–small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. 2023;41(35):5363-5375. doi:10.1200/JCO.23.01476