Patritumab Deruxtecan Induces Clinical Activity in NSCLC Regardless of Identified Driver Genomic Alterations

Conor E. Steuer, MD

Patritumab deruxtecan (HER3-DXd) exhibited promising clinical activity in heavily pretreated patients with advanced non-small cell lung cancer (NSCLC) without EGFR-activating mutations, including activity in patients with other identified driver genomic alterations, according to results from the dose-expansion cohort of an ongoing phase 1 study (NCT03260491) presented during the 2022 ASCO Annual Meeting.

“Patritumab deruxtecan showed promising clinical activity in heavily pretreated patients with advanced NSCLC with or without identified variant genomic alterations,” said lead author Conor E. Steuer, MD, an assistant professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta, Georgia. “Some of this antitumor activity was found to be quite durable.”

At the January 28, 2022, data cut-off date, the confirmed overall response rate (ORR) by blinded independent central review (BICR) per RECIST 1.1 was 28.6% (95% CI, 11.3%-52.2%) among patients with identified genomic driver alterations (n = 21). The disease control rate (DCR) in this cohort of patients was 76.2% (95% CI, 52.8%-91.8%) and the median time to response was 2.8 months (range, 1.3-4.6). The median duration of response (DOR) was 9.4 months (95% CI, 4.2-not evaluable [NE]) and the median progression-free survival (PFS) was 10.8 months (95% CI, 2.8-16.0).

In patients without identified genomic driver alterations (n = 26), the confirmed ORR was 26.9% (95% 11.6%-47.8%) and the DCR was 73.1% (95% CI, 52.2%-88.4%). The median DOR was 9.6 months (95% CI, 1.6-NE) and the median PFS was 4.2 months (95% CI, 2.5-10.8). The median time to response was 2.1 months (range, 1.2-6.0).

The median follow-up time was 19.7 months (range, 13.8-29.2).

““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,” Steuer said. “They warrant further clinical evaluation.”

He added that this was a heavily pretreated cohort, with an average of 3 (range, 1-8) previous lines of systemic therapy.

Investigators noted that 83% of NSCLC tumors express HER3, and that HER3 overexpression has been associated with poor clinical outcomes. Moreover, patients with advanced NSCLC without EGFR-activating mutations have limited options after treatment failure with]molecularly targeted therapies or platinum-based chemotherapy with or without immunotherapy.

Patritumab deruxtecan is an antibody drug conjugate composed of a fully human anti-HER3 IgG1 monoclonal antibody. The monoclonal antibody is covalently linked to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker.

The dose-expansion part (cohort 2) of the phase 1 trial enrolled patients with squamous or nonsquamous NSCLC that did not harbor the common Ex19del, L858R, L861Q, or G719X mutations, or without any identified driver genomic alterations. Patients with non-EGFR oncogenic alterations were eligible for the trial if they had undergone at least 1 previous treatment with targeted therapy, if available. All patients in the dose-expansion portion of the trial were treated with intravenous 5.6 mg/kg patritumab deruxtecan every 3 weeks.

The primary end point was confirmed ORR by BICR per RECIST 1.1. Secondary end points included DCR, time to response, DOR, PFS, and safety.

At the data cut-off date, 47 patients in cohort 2 with a median age of 62 years (range, 29-79) had been treated with patritumab deruxtecan. Most patients in the cohort were female (53.2%) and most had an ECOG performance status of 1 (66.0%). The median sum of diameters at baseline was 67 mm (range, 18-205) and 31.9% of patients had a history of central nervous system metastases. Disease histology included adenocarcinoma (74%), squamous (17%), large cell (2%), and other (6%).

All patients had undergone prior treatment with platinum-based chemotherapy, and 95.7% had received previous immunotherapy, including anti-PD-1/anti-PD-L1 treatment. One patient previously received an anti-CTLA-4 agent. Genomic-directed therapy was previously used in 19.1% of patients.

Five (10.6%) patients remained on study at data cut-off and 89.4% discontinued treatment. Primary reasons for discontinuation included progressive disease (51.1%), clinical progression (12.8%), adverse events (AEs; 10.6%), withdrawal of consent by patient (8.5%), and death (6.4%).

Steuer said treatment with patritumab deruxtecan was manageable and led to an overall safety profile consistent with previous findings in patients with EGFR-mutant NSCLC. Treatment-emergent adverse events (TEAEs) associated with treatment discontinuation occurred in 10.6% of patients. There were no drug-related deaths reported.

TEAEs that led to dose reduction or dose interruption were reported in 23.4% and 51.1% of patients, respectively. TEAEs associated with death occurred in 14.9% of patients and 40.4% of patients experienced serious AEs.

TEAEs of grade 3 or greater included neutropenia (26%), fatigue (17%), thrombocytopenia (15%), hypokalemia (13%), anemia (11%), leukopenia (11%), and pneumonia (11%). All patients experienced a treatment-related TEAE; none of these were associated with death. Slightly more than half (51.1%) of TEAEs were grade 3 or higher and 12.8% were serious TEAEs.

Five patients developed drug-related interstitial lung disease (ILD) by central adjudication with a median time to onset of 140 days (range, 43-331). Grade 1 ILD was reported in 2.1% of patients and grade 2 ILD in 8.5% of patients. No patients experienced grade 3 or greater ILD. 

Reference

1. CE Steuer, H Hayashi, WC Su, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in advanced/metastatic non-small cell lung cancer (NSCLC) without EGFR-activating mutations. J Clin Oncol. 2022;40(suppl 16):9017. doi:10.1200/JCO.2022.40.16_suppl.9017

Funding from Daiichi Sanyko. Content Developed Independently by OncLive^®.