Developers Withdraw BLA for HER3-DXd in Advanced EGFR-Mutant NSCLC

In the HERTHENA-Lung01 trial, the confirmed ORR was 29.8% with patritumab deruxtecan monotherapy in patients with pretreated, advanced, EGFR-mutant NSCLC.

The developers of patritumab deruxtecan (HER3-DXd) have voluntarily withdrawn the biologics license application (BLA) that was seeking accelerated approval for the agent in the treatment of adult patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC), according to a press release from Merck, one of the developers.¹

The BLA was withdrawn due to topline overall survival (OS) results from the confirmatory phase 3 HERTHENA-Lung02 trial (NCT05338970) not meeting statistical significance; discussions with the FDA also factored into the decision. The HERTHENA-Lung02 trial is comparing the efficacy of HER3-DXd vs platinum-based chemotherapy, as measured by progression-free survival and OS, in patients with metastatic or locally advanced EGFR-mutated NSCLC after progression on a third-generation EGFR tyrosine kinase inhibitor (TKI).

Previously, in June 2024, the FDA issued a complete response letter (CRL) for HER3-DXd in advanced NSCLC harboring EGFR mutations due to issues associated with a third-party manufacturing site for the agent, with no problems related to the safety or efficacy data of HER3-DXd.² It was noted that the withdrawal of the BLA was unrelated to the prior CRL.

Initially, the BLA submission was supported by data from the phase 2 HERTHENA-Lung01 trial (NCT04619004) that evaluated the antitumor activity of HER3-DXd in patients with metastatic or locally advanced EGFR-mutated NSCLC after at least 1 EGFRTKI and 1 platinum-based chemotherapy-containing regimen.

“EGFR-mutated NSCLC has proven to be difficult-to-treat in the second-line metastatic setting and beyond,” stated Ken Takeshita, MD, global head of Research and Development at Daiichi Sankyo, in the press release.¹ “While we are disappointed with the [OS] results of HERTHENA-Lung02, we are conducting further biomarker analyses to better identify patients [who] may benefit from patritumab deruxtecan to guide our continued development in lung cancer. We remain confident in the broad development program of this HER3-directed antibody drug conjugate, which currently includes multiple clinical trials across 15 types of cancer.”

HERTHENA-Lung02

HERTHENA-Lung02 was a randomized, global, open-label trial that enrolled a total of 586 patients who were randomly assigned to receive either 5.6 mg/kg of HER3-DXd every 3 weeks or 4 cycles of pemetrexed or platinum doublet chemotherapy.

In September 2024, early results showed that the trial met its primary end point, demonstrating a statistically significant improvement in PFS compared with chemotherapy.³

Regarding safety, the profile observed in HERTHENA-Lung02 was consistent with previously observed data in lung cancer, with no new safety signals identified. It was noted that most interstitial lung disease cases were grade 1 or grade 2, although 2 instances of interstitial lung disease were grade 5.

Updated results from the trial showing the previously reported statistical significance in PFS improvement as well as the topline OS data will be presented at the 2025 American Society of Clinical Oncology Annual Meeting.

HERTHENA-Lung01

HERTHENA-Lung01 was a global, open-label, 2-arm trial that enrolled a total of 277 patients who were randomly assigned, in a 1:1 ratio, to receive 5.6 mg/kg of HER3-DXd or an uptitration regimen.

In September 2023, results from the trial were published in the Journal of Clinical Oncology.⁴

The confirmed overall response rate (ORR) by blinded independent central review (BICR) was 29.8% (95% CI, 23.9%-36.2%); the median duration of response (DOR) was 6.4 months (95% CI, 4.9-7.8), with 43.3% having a DOR of 6 months or longer. The median PFS was 5.5 months (95% CI, 5.1-5.9), and the median OS was 11.9 months (95% CI, 11.2-13.1).

In the uptitration arm, the confirmed ORR was 16.0% (95% CI, 7.2%-29.1%), and the median PFS was 6.7 months (95% CI, 4.2-8.8).

Regarding safety, treatment-emergent adverse events (TEAEs) of grade 3 or higher occurred in 64.9%, and TEAEs of grade 4 or higher affected 28.9%. The most common TEAEs of grade 3 or higher were hematologic toxicities, and those that occurred in more than 15% were thrombocytopenia (20.9%) and neutropenia (19.1%).

TEAEs were associated with dose interruption, dose reduction, and treatment discontinuation, respectively, in 40.4%, 21.3%, 7.1%. Treatment-related TEAEs resulted in death in 1.8% of patients.

References

1. Patritumab deruxtecan biologics license application for patients with previously treated locally advanced or metastatic EGFR-mutated non-small cell lung cancer voluntarily withdrawn. News release. Merck. May 29, 2025. Accessed May 29, 2025. https://tinyurl.com/5n7nbf9m
2. Patritumab deruxtecan BLA submission receives complete response letter from FDA due to inspection findings at third-party manufacturer. News release. Merck. June 26, 2024. Accessed May 29, 2025. https://tinyurl.com/mr46bnpe
3. Patritumab deruxtecan demonstrated statistically significant improvement in progression-free survival versus doublet chemotherapy in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer in HERTHENA-Lung02 phase 3 trial. News release. Daiichi Sankyo and Merck. September 17, 2024. Accessed May 29, 2025. https://tinyurl.com/4ppw5epy
4. 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.