Nagasaka, Misako

e23419 Background: Current risk assessment for cancer-associated thrombosis remain suboptimal in NSCLC, likely due to unaccounted tumor-specific biology. Although ALK and ROS1-positive NSCLC share closely related structure and elevated thrombotic risk, real-world data on thromboembolic outcomes remain limited. Methods: This multicenter retrospective study was conducted using TriNetX, a global federated health research network;14 of 113 healthcare organizations contributed to analysis. Adults (≥18 years) with NSCLC ROS1 or ALK from 2012-2025 were included. Index event was defined as the first documented NSCLC diagnosis. Outcomes included cumulative incidence, Kaplan–Meier survival analysis (KMS), and event recurrence for arterial thromboembolism (ATE), deep vein thrombosis (DVT), and pulmonary embolism (PE). Analyses were conducted pre and post-propensity score matching (PSM) adjusted for age and sex. Subgroup analyses evaluated outcomes at 1, 3, 6, and ≥12 months. Results: 3,310 NSCLC patients were identified (ALK n=3,155; ROS1 n=155). Mean age was 73 years, with 52.8% female and 46.2% male; 72.5% White, 12.7% Black, 9.5% Asian; South (49%), Northeast (29%). ALK NSCLC were older than those with ROS1 (mean 68.9 vs 64.6 years, p<0.0001), with similar sex distribution. ROS1 had higher proportion of White (85% vs 72%), while ALK included more Asian and Black. Median follow-up prior to matching was 482 days for ROS1 (post-PSM:482) and 546 days for ALK (post-PSM:601) Incidence proportions in ROS1 NSCLC were 12.3% for ATE, 9.7% for DVT, and 12.9% for PE (vs. ALK: 22.6% for ATE, 12.5% for DVT, 11.8% for PE) For ATE, prior to PSM, ROS1 NSCLC demonstrated a significantly lower risk compared with ALK (16.6% vs 25.0%), with an absolute risk difference of −8.4% (95% CI −14.7 to −2.2; p=0.02) and relative risk of 0.66 (95% CI 0.46–0.96). KMS showed longer ATE-free survival in ROS1 compared to ALK (48.2% vs 44.5%, p=0.01; HR 0.60, 95% CI 0.40–0.91, p=0.04). After PSM, overall ATE risk difference did not reach statistical significance, although ROS1 continued to demonstrate lower risk (16.6% vs 25.8%; risk difference −9.2%, p=0.06). Notably, in the subgroup analyses, this significant risk difference emerged ≥12 months, with improved late ATE-free survival in ROS1(91.1% vs 80.3%, p=0.01). For VTE and PE, no significant differences in risk, survival analyses or recurrence, were observed between ROS1 and ALK before or after PSM (DVT risk: 9.2% vs 9.7% pre-PSM; 9.2% vs 10.1% post-PSM; PE: 11.2% vs 9.9% pre-PSM; 11.2% vs 8.6% post-PSM; all p>0.05). Conclusions: Arterial thromboembolism differed by oncogenic subtype, with higher ATE risk in ALK compared with ROS1-positive NSCLC, particularly ≥12-months. In contrast, no significant difference in venous thromboembolism and pulmonary embolism were observed; further validation in prospective studies is warranted.

Abstract Background Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety management strategies require further characterization. Patients and Methods The safety profile of repotrectinib (treatment-emergent/related adverse events [TEAEs/TRAEs]) was established in patients who initiated treatment at the recommended dose (160 mg daily [QD] for 14 days, then 160 mg twice daily [BID]) across all cohorts of the global, multicenter phase 1/2 TRIDENT-1 study. AE management strategies were outlined. Results In 472 patients, the most common TRAEs (dizziness [58%] and dysgeusia [50%]) were likely TRK inhibition-related. Median relative dose intensity was 90%; 14% (n = 66/472) of patients did not increase their initial QD dose to BID (mostly due to CNS AEs). Rates of dizziness (median onset, 7 days) were similar in patients with/without baseline brain metastases. Dose modifications downgraded severity or resolved dizziness in 78% of patients; 58% of patients had pharmacologic intervention without dose modification. Dizziness was downgraded/resolved in 62% (n = 120/195) of patients who did not receive dose modification or pharmacologic intervention. Treatment-related cognitive impairment and weight gain occurred in 19% and 12% of patients, respectively. Treatment-emergent withdrawal pain occurred in 14% of patients (median resolution time, 2.1 weeks). Dose interruption and reduction from TRAEs occurred in 39% and 38% of patients, respectively; 10% reported later re-escalation back to 160 mg BID. Conclusion Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.

Abstract Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI. Experimental Design: We established “RETgistry,” a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan–Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1–16.6] and 17.3 months (95% CI, 14–20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022). Conclusions: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.