BLA Is Withdrawn for Patritumab Deruxtecan in EGFR-Mutated NSCLC

FDA

The biologics license application (BLA) filed to the FDA seeking accelerated approval of patritumab deruxtecan for the treatment of adult patients with locally advanced or metastatic, EGFR-mutated non–small cell lung cancer (NSCLC) who received at least 2 prior systemic therapies has been voluntarily withdrawn, according to an announcement from Merck.1

The withdrawal was based on topline overall survival (OS) data from the confirmatory phase 3 HERTHENA-Lung02 trial (NCT05338970), which did not reach statistical significance. Discussions with the FDA also influenced the choice to withdraw the BLA, but the decision was unrelated to the June 2024 complete response letter that outlined results from an inspection of a third-party manufacturing facility.1,2

Prior data from HERTHENA-Lung02 demonstrated that patients who received patritumab deruxtecan experienced a statistically significant improvement in progression-free survival (PFS) compared with platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy.3 OS findings were immature at the time of this analysis.

“EGFR-mutated NSCLC has proven to be difficult to treat in the second-line metastatic setting and beyond,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a news release.1 “While we are disappointed with the OS results of HERTHENA-Lung02, we are conducting further biomarker analyses to better identify patients that 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 was an open-label study that enrolled adult patients with EGFR-mutated metastatic or locally advanced NSCLC following disease progression on 1 or 2 prior lines of an approved EGFR TKI in the metastatic or locally advanced setting, including a third-generation TKI.4 Any other prior systemic therapies in the metastatic or locally advanced setting were not allowed, and patients needed to have at least 1 measurable lesion per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate bone marrow and organ function. Neoadjuvant and/or adjuvant therapy was permitted if disease progression occurred at least 12 months after the final dose of a third-generation TKI.

Patients were randomly assigned to receive intravenous (IV) patritumab deruxtecan at a dose of 5.6 mg/kg every 3 weeks or platinum-based chemotherapy. Patients in the chemotherapy arm were treated with 500 mg/m2 of IV pemetrexed in combination with 75 mg/m2 of cisplatin or carboplatin for a target area under the plasma concentration time curve of 5 once every 3 weeks. Treatment in the chemotherapy arm continued for 4 cycles; patients without disease progression after 4 cycles were allowed to continue treatment with maintenance pemetrexed without a restriction on the number of cycles.

The primary end point was PFS per blinded independent central review per RECIST 1.1 criteria. Secondary end points included OS, investigator-assessed PFS, objective response rate (ORR), duration of response (DOR), clinical benefit rate, disease control rate, time to response, intracranial PFS, quality of life measures, and safety.

Patritumab deruxtecan was also evaluated in patients with EGFR-mutated NSCLC in the phase 2 HERTHENA-Lung01 trial (NCT04619004).5 Prior data from the study demonstrated that patients who experienced disease progression after treatment with an EGFR TKI and platinum-based chemotherapy who received patritumab deruxtecan (n = 225) achieved a confirmed ORR of 29.8% (95% CI, 23.9%-36.2%) with a complete response rate of 0.4%. The median DOR, OS, and PFS were 6.4 months (95% CI, 4.9-7.8), 11.9 months (95% CI, 11.2-13.1), and 5.5 months (95% CI, 5.1-5.9), respectively.

Safety data from HERTHENA-Lung02 revealed that the profile of patritumab deruxtecan was consistent with what was observed in previous studies of the agent in patients with lung cancer.1 No new safety signals were reported. Additional findings from HERTHENA-Lung02 will be shared during an oral presentation at the 2025 ASCO Annual Meeting.

“Lung cancer is one of the leading causes of cancer-related deaths worldwide and these results are a reminder of how challenging it can be to treat these patients with EGFR-mutated NSCLC in the second and later line settings,” Eliav Barr, MD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, added in the news release. “We would like to thank the patients, their families, and investigators for their participation in this study.”

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://www.merck.com/news/patritumab-deruxtecan-biologics-license-application-for-patients-with-previously-treated-locally-advanced-or-metastatic-egfr-mutated-non-small-cell-lung-cancer-voluntarily-withdrawn/
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://www.merck.com/news/patritumab-deruxtecan-bla-submission-receives-complete-response-letter-from-fda-due-to-inspection-findings-at-third-party-manufacturer/
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. September 17, 2024. Accessed May 29, 2025. https://daiichisankyo.us/press-releases/-/article/patritumab-deruxtecan-demonstrated-statistically-significant-improvement-in-progression-free-survival-versus-doublet-chemotherapy-in-patients-with-loc
4. HERTHENA-Lung02: a study of patritumab deruxtecan versus platinum-based chemotherapy in metastatic or locally advanced EGFRm NSCLC after failure of EGFR TKI therapy. ClinicalTrials.gov. Updated January 31, 2025. Accessed May 29, 2025. https://clinicaltrials.gov/study/NCT05338970
5. 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