Phase I study of patitumab deruxtecan in patients with EGFR activating mutated squamous or non-squamous NSCLC with disease progression during or after systemic treatment for locally advanced or metastatic disease (Abstract # 9017)
Patritumab deruxtecan is a newer generation ADC that has elicited encouraging responses with acceptable safety in patients with EGFR TKI-resistant, EGFRm NSCLC. In 2021, the drug also got Breakthrough Therapy Designation (BTD) in EGFRm NSCLC patients based on the dose-escalation portion and two cohorts of a three-cohort phase I study.
On January 28, 2022, the data cut-off date, the confirmed overall response rate (ORR) by blinded independent central review (BICR) per RECIST 1.1 was 28.6% among patients with identified genomic driver alterations (n = 21). The disease control rate (DCR) in this cohort of patients was 76.2%, and the median time to response was 2.8 months. The median duration of response (DOR) was 9.4 months, and the median progression-free survival (PFS) was 10.8 months.
In patients without identified genomic driver alterations (n = 26), the confirmed ORR was 26.9%, and the DCR was 73.1%. The median DOR was 9.6 months, and the median PFS was 4.2 months. The median time to response was 2.1 months. The median follow-up time was 19.7 months.
TEAEs associated with death occurred in 14.9% of patients, and 40.4% of patients experienced serious AEs.
“These results demonstrate the promising clinical activity of patritumab deruxtecan in patients with NSCLC harboring a broad range of genomic alterations or without identified genomic alterations. They warrant further clinical evaluation.”–Expert Opinion.
HER3 is one of 4 receptor tyrosine kinases (RTKs) that make up the HER family. HER3 expression has been noted in many types of cancer, including breast, gastric, colorectal, bladder, prostate, ovarian, and NSCLC. But till today, the precise function of HER3 overexpression across these tumor types is not entirely clear. In NSCLC, HER3 overexpression in primary tumors has been associated with metastatic progression and decreased relapse-free survival time. Investigators detected HER3 expression via immunohistochemistry (IHC) analysis. Despite the rationale for HER3 inhibition, till today, not a single drug has been approved by the FDA with this mechanism. Since HER3 has limited intrinsic kinase activity, small molecule kinase inhibitors are unlikely to be useful, which has led the investigators to explore the development of HER3-targeted mAbs. Because most of the HER3-directed mAbs evaluated in clinical studies have demonstrated limited clinical activity, the focus has shifted to novel designs such as ADCs.
The current standard of care in EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, the treatment approach includes genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-directed deruxtecan demonstrated clinical activity spanning known and unknown EGFR TKI resistance. As there are currently no approved targeted therapy for the treatment of patients who progress on EGFR TKI therapy, paritumab deruxtecan being a HER3 directed therapy can help fulfill the unmet medical need of this patient segment, and if the further data continues to be positive, this agent may be able to replace the cytotoxic chemotherapy in these patients.
Companies- Boehringer Ingelheim, Roche, Merck, AbbVie, Daiichi Sankyo, Chugai Pharmaceutical, Regeneron, Sanofi, Janssen, and others