FDA Issues CRL for Patritumab Deruxtecan in Pretreated EGFR+ NSCLC


Key Takeaways

  • The FDA's CRL for patritumab deruxtecan cited third-party manufacturing issues, not efficacy or safety concerns.
  • Phase 2 HERTHENA-Lung01 trial showed a 29.8% overall response rate and 11.9 months median overall survival.
Ken Takeshita, MD

Ken Takeshita, MD

The FDA has issued a complete response letter (CRL) to the biologics license application (BLA) seeking the approval of patritumab deruxtecan (HER3-DXd) for the treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR mutations who previously received with 2 or more systemic therapies.1

According to an announcement from Merck, the CRL cited findings regarding an inspection of a third-party manufacturing facility. The CRL did not identify any issues regarding the efficacy or safety of patritumab deruxtecan.

“We will work closely with the FDA and the third-party manufacturer to address the feedback as quickly as possible in order to bring the first HER3-directed medicine to patients with previously-treated EGFR-mutated NSCLC,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a news release. “We remain confident in the ability to develop this medicine to its full potential.”

The BLA was supported by data from the phase 2 HERTHENA-Lung01 trial (NCT04619004). Findings showed that in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR-directed TKI and platinum-based chemotherapy (n = 225), the HER3-targeted antibody-drug conjugate (ADC) elicited an overall response rate (ORR) of 29.8% (95% CI, 23.9%-36.2%) per blinded independent central review (BICR) assessment. One patient (0.4%) achieved a complete response, and the rates of partial response (PR), stable disease (SD), and progressive disease (PD) were 29.3%, 44.0%, and 19.1%, respectively. The disease control rate (DCR) was 73.8% (95% CI, 67.5%-79.4%).2

Furthermore, the median duration of response (DOR) was 6.4 months (95% CI, 4.9-7.8), and the 6-month DOR rate was 43.3%. The median progression-free survival (PFS) was 5.5 months (95% CI, 5.1-5.9), and the median overall survival (OS) was 11.9 months (95% CI, 11.2-13.1).

HERTHENA-Lung01 was a multicenter, open-label, randomized, two-arm, study that enrolled patients at least 18 years of age with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations. Patients were required to have disease that progressed on or after their most recent therapy, and previous therapies needed to include at least 1 EGFR TKI and at least 1 platinum-based chemotherapy regimen in any sequence. Prior treatment with osimertinib (Tagrisso) was added to the study protocol after the start of enrollment. An ECOG performance status of 0 or 1 was required.

Patients with clinically inactive or treated brain metastases that were asymptomatic were allowed to enroll. However, patients with previous or current evidence of interstitial lung disease were not included.

Enrolled patients received 1 of 2 dosing regimens of patritumab deruxtecan. In arm 1, the ADC was given at fixed dose of 5.6 mg/kg once every 3 weeks. Arm 2 featured an uptitration regimen, where patritumab deruxtecan was given at 3.2 mg/kg on cycle 1, day 1, at 4.8 mg/kg on cycle 2, day 1, and at 6.4 mg/kg on cycle 3, day 1 and subsequent cycles.

The primary end point was BICR-assessed confirmed ORR per RECIST 1.1 criteria. Secondary end points consisted of BICR-assessed DOR; investigator-assessed confirmed ORR and DOR; PFS; DCR; time to response; OS; and safety.

Additional data showed that patients who received a prior third-generation EGFR TKI (n = 209) achieved an ORR of 29.2% (95% CI, 23.1%-35.9%), including a CR rate of 0.5%, a PR rate of 28.7%, a SD rate of 43.5%, and a PD rate of 19.6%. The DCR was 72.7% (95% CI, 66.2%-78.6%) in this patient population, and the median DOR was 6.4 months (95% CI, 5.2-7.8). The median PFS and OS were 5.5 months (95% CI, 5.1-6.4) and 11.9 months (95% CI, 10.9-13.1), respectively.

Regarding safety, the respective rates of grade 3 or higher and grade 4 or higher treatment-emergent adverse effects (TEAEs) were 64.9% and 28.9%. The most common TEAEs reported in at least 10% of patients included nausea (grade 1/2, 63%; grade ≥3, 3%), thrombocytopenia (23%; 21%), decreased appetite (39%; 3%), neutropenia (16%; 19%), constipation (34%; 0%), anemia (19%; 14%), fatigue (25%; 6%), diarrhea (26%; 1%), vomiting (26%; 1%), leukopenia (16%; 10%), alopecia (25%; 0%), dyspnea (14%; 4%), increased aspartate aminotransferase (16%; 1%), hypokalemia (12%; 5%), cough (16%; 0%), abdominal pain (16%; 0%), stomatitis (11%; 1%), headache (12%; 0%), increased alanine aminotransferase (11%; 1%), pyrexia (11%; 0%), and decreased weight (10%; 0%).

“Patients with previously treated EGFR-mutated NSCLC often experience recurrence and have limited treatment options,” Marjorie Green, MD, senior vice president and head of Oncology, Global Clinical Development, at Merck Research Laboratories, added in a news release.1 “We are committed to working with Daiichi Sankyo and the FDA to prioritize making patritumab deruxtecan available to these patients in need.”


  1. 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 June 27, 2024.
  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
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