Sheppard, Aaron

e20731 Background: Selective RET (REarranged during Transfection) inhibitors (RETi) have become standard treatment for RET fusion-positive non-small cell lung cancer ( RET + NSCLC), which represent 1–2% of NSCLC cases. Clinical factors that drive front-line versus later-line RETi use and outcomes are not well understood. This retrospective chart review evaluates physician decision drivers alongside real-world effectiveness and safety for pralsetinib (PRAL) in RET + NSCLC. Methods: A retrospective chart review was conducted via a standardized web-based form among US oncologists treating advanced RET + NSCLC. Eligible patients initiated PRAL for RET + NSCLC between October 2020 and December 2024. Data gathered included physician treatment considerations, patient baseline characteristics, and efficacy outcomes. Results: Eighty-two charts from patients who received PRAL as their first (index) RETi were collected from 43 physicians across both academic (41.9%) and community (58.1%) sites. Of the 82 patients, 51.2% received PRAL front line (1L) and 31.7% in the second line (2L). From a predefined list, physicians most often cited comorbidities (36.6%) and ECOG performance status (31.7%) as clinical factors when considering index PRAL therapy and efficacy profile (56.1%), followed by intracranial activity (24.4%) and hypersensitivity to immuno-oncology agents (24.4%) as therapy-related considerations. Although not a primary therapy selection driver, in 13 patients with safety as a consideration, 6 (46.2%) had myelosuppression noted as a concern for index PRAL treatment. RET + NSCLC patients treated in the 1L setting with PRAL had an overall response rate (ORR) of 73.8% (14 CR; 17 PR). For 2L line PRAL, the ORR was 61.5% (1 CR; 15 PR). Anemia (17.1%), diarrhea (13.4%), and constipation (13.4%) were the most frequently reported adverse events (AE). Discontinuation was mainly due to loss of/no response (80.6%), insurance (16.1%), and AEs (3.2%). The single PRAL patient that discontinued due to an AE had edema. There were an additional 7 patients that switched to PRAL due to an AE on a different RETi. The post-switch ORR was 57.1% (4/7); of these patients, 3 maintained their previous response and 1 improved their response. Conclusions: In this retrospective chart review, pralsetinib was used across treatment lines with high real-world response rates, consistent with results from the ARROW trial. Treatment selection was influenced by specific clinical factors including patient comorbidities, ECOG performance status, and safety concerns, with AE-driven switching uncommon yet associated with continued responses.

6028 Background: RET alterations are targetable oncogenic drivers in multiple solid tumors and TCs. Pralsetinib is an oral, potent, selective RET inhibitor granted accelerated approval by the FDA for adults and children aged ≥12 y with advanced/metastatic RET fusion-positive TC who require systemic therapy and are radioactive iodine-refractory, based on ARROW trial (NCT03037385) results. Accelerated approval for medullary TC (MTC) was withdrawn by the sponsor in 2023 due to recruitment challenges in the confirmatory trial. We report final efficacy and safety in ARROW patients with RET -altered TC and MTC. Methods: Phase 2 ARROW patients were enrolled from 84 sites in 13 countries. Primary end points were overall response rate (ORR; per RECIST v1.1) and safety. Progression-free survival (PFS), overall survival (OS), and safety were assessed in patients with advanced/metastatic TC and MTC who received ≥1 dose of pralsetinib (Efficacy Population [EP]). ORR and duration of response (DOR) were assessed in the Measurable Disease Population (MDP). Results: At the May 20, 2024, data lock, 28 patients with RET -altered TC and prior systemic treatment and 145 patients with RET -altered MTC received pralsetinib 400 mg/d (median treatment duration: 24.7 mo [TC]; and 35.4 mo [MTC]). In the TC and MTC groups, median age was 58 and 57 y; 39% and 64% were male; median (range) prior lines of treatment was 2 (1, 9) and 1 (1, 6). 53.8% of MTC patients had prior systemic treatment. In TC and MTC patients, ORRs (95% CI) were 91.7% (73.0, 99.0) and 68.2% (59.5, 76.0) (Table). Treatment-related adverse events (TRAEs) occurred in 27 (96%) TC and 142 (98%) MTC patients; 68% and 67% had grade ≥3. TRAEs in ≥35% of TC and MTC patients were increased AST (50% and 38%) and ALT (43% and 30%), decreased white blood cell count (39% and 30%), and anemia (39% each). Death due to a TRAE occurred in 1 TC patient (liver injury) and 1 MTC patient (pneumonia). Safety was consistent with prior reports. Conclusions: The final analysis of ARROW confirms that pralsetinib yields clinically meaningful and durable responses in patients with RET -altered TC and MTC with a manageable safety profile consistent with prior reports. Clinical trial information: NCT03037385 . Efficacy summary. All MTC MTCPrior Cabozantinib/Vandetanib MTC Treatment-Naïve TCPrior Systemic Treatment MDP, n 132 60 62 24 ORR, % (95% CI) 68.2(59.5, 76.0) 56.7(43.2, 69.4) 79.0(66.8, 88.3) 91.7(73.0, 99.0) Complete response, n (%) 12 (9.1) 2 (3.3) 7 (11.3) 4 (16.7) Partial response, n (%) 78 (59.1) 32 (53.3) 42 (67.7) 18 (75.0) DOR, median, mo (95% CI) 39.6(29.4, NE) 21.7(15.1, 34.8) NR(36.8, NE) NR(16.0, NE) DOR follow-up, median, mo (95% CI) 45.7(41.0, 48.4) 48.9(36.9, 58.7) 45.1(40.4, 47.8) 35.4(26.9, 40.0) EP, n 145 67 67 28 OS, median, mo (95% CI) NR(54.6, NE) 42.2(31.2, NE) NR(NE, NE) NR(25.4, NE) PFS, median, mo (95% CI) 37.2(27.5, 55.5) 24.9(19.9, 35.0) 55.3(36.8, NE) NR(14.7, NE) NE, not evaluable; NR, not reached.