Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated locally advanced or metastatic (LA/M) non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: Preliminary results from a phase 2 study.

Abstract

8615 Background: Pts with NSCLC harboring uncommon EGFR mutations generally have limited treatment options compared to those with the more common EGFR mutations. Sac-TMT (MK-2870/SKB264) is a TROP2 ADC developed with a hydrolytically cleavable linker to conjugate a belotecan-derivative topoisomerase I inhibitor. Sac-TMT has shown encouraging antitumor activity in NSCLC pts with the more common EGFR mutations (Fang et al . AACR 2024). Here we present the preliminary efficacy and safety of sac-TMT in treating uncommon EGFR -mutated advanced NSCLC from the Phase 2, open-label, multiple-cohort study (NCT05631262). Methods: Advanced NSCLC pts harboring uncommon EGFR mutations, including G719X in exon 18, S768I in exon 20, L861Q in exon 21 and exon 20 insertions (ex20ins), who had progressed on or after standard systemic therapy were enrolled. Pts received sac-TMT 5 mg/kg Q2W until disease progression or unacceptable toxicity. Tumor response was assessed per RECIST v1.1 by investigator. Results: As of 01 Dec 2024, 42 pts (median age 61 years; 33.3% male; 85.7% ECOG PS 1) were enrolled, including 23 pts with EGFR G719X in exon 18, S768I in exon 20, or L861Q in exon 21 and 19 pts with EGFR ex20ins. Median number of prior treatment regimens for advanced disease was 2 with 35.7% of pts having ≥3. After a median follow-up of 9.2 months, the objective response rate (ORR) was 35.7% (15/42, 3 pending confirmation). The disease control rate (DCR) was 85.7%. Responses were durable with the median duration of response (mDoR) not yet reached, and the 6-month DoR rate was 90.9%. The median progression-free survival (mPFS) was 9.5 months (95% CI: 5.6, 10.9). In the subset of pts with uncommon non-ex20ins, the ORR was 34.8% (8/23, 1 pending confirmation); the mPFS was 10.9 months (95% CI: 5.6, NE). In the subset of pts with ex20ins, the ORR was 36.8% (7/19, 2 pending confirmation); the mPFS was 9.0 months (95% CI: 2.4, NE). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 52.4% of pts. The most frequent grade ≥3 TRAEs (≥5%) were neutrophil count decreased (45.2%), WBC count decreased (21.4%), anemia (14.3%), and stomatitis (9.5%). No TRAE led to treatment discontinuation or death. No cases of interstitial lung disease/pneumonitis were reported. Conclusions: Sac-TMT monotherapy demonstrated promising clinical activity with a manageable safety profile in previously treated advanced NSCLC pts with uncommon EGFR mutations. These findings warrant further investigation of sac-TMT as a potential therapy for this population. Clinical trial information: NCT05631262 .