Cho, B

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.

2598 Background: GI-102 (CD80-IL2v3) is a novel immunocytokine designed to direct IL-2v3 to immune cells and tumor cells. IL-2v3 of GI-102 abolished affinity to IL-2Rα minimizing the impact of IL-2 on Treg cells. Preferential targeting of immune cells and further inhibition of CTLA-4 and PD-L1 via CD80 synergize with potent activity of IL-2v3, resulting in robust proliferation and activation of CD8+ T and NK cells. Here we report preliminary safety and efficacy data of GI-102 from a phase 1/2a trial in patients with metastatic solid tumors. Methods: NCT05824975 is an ongoing, dose escalation (3+3 design) and expansion study to evaluate safety, tolerability, PK, PD and anti-tumor activity of GI-102. Each dose level allows to enroll additional 7 patients to fully inform the safety, PK and PD at that dose level. GI-102 was administered intravenously every 3 weeks until disease progression or unacceptable toxicities. Disease was assessed every 6 weeks using RECIST v1.1. Results: As of 12 Jan 2024, 32 patients were treated in dose escalation: 8 at dose level 0.06 mg/kg, 10 at 0.12 mg/kg, 9 at 0.24 mg/kg and 5 at 0.45 mg/kg. Patients had received median of 3 [1-7] prior lines of therapy, including 25.0% (8/32) who had received ≥ 5 lines and 68.8% (22/32) had experienced immune checkpoint blockade (ICB). No dose-limiting toxicities (DLTs) were observed until the highest dose of 0.45 mg/kg Q3W. The most common treatment-related adverse events (TRAEs, ≥ 10%) were pyrexia [43.8%] and chills [34.4%]. 5 patients [15.6%] had ≥ Grade 3 TRAEs and no patient reported TRAEs leading to discontinuation of GI-102. In 23 patients (7 cutaneous melanoma, 4 non-small cell lung cancer, 3 ovarian cancer and others) who had at least 1 post-treatment tumor assessment, objective responses were observed in 17.4% (4/23). In patients with metastatic melanoma who previously experienced ICB, overall response rate (ORR) and disease control rate (DCR) was 42.9% (3/7) and 85.7% (6/7), respectively, including 3 confirmed partial responses (cPR). The median time to response (TTR) was 6 weeks and duration of response (DoR) was 6.0+, 2.4+ and 1.7+ month, respectively. In patients with metastatic ovarian cancer, ORR and DCR were 33.3% (1/3) and 66.7% (2/3), respectively, including 1 cPR [TTR of 6 weeks; DoR 1.9+ month]. Preliminary PK profile showed target-mediated drug disposition with a half-life of ~48 hours. 0.24 mg/kg of GI-102 resulted in a significant expansion of peripheral lymphocytes, CD8+ T cells (effector & memory) and NK cells, by 4.4 [2.1-9.6], 3.9 [2.0–5.7] and 20.4 [9.5–32.6]-fold change from baseline, respectively. There was no meaningful increase in Treg cells. Conclusions: GI-102 was well tolerated up to dose of 0.45 mg/kg Q3W with meaningful monotherapy activity, regardless of previous ICB experience, in patients who failed on standard of care. The dose-escalation is currently ongoing to identify RP2D. Clinical trial information: NCT05824975 .

Background: Rearranged during transfection ( RET ) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET -altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET -mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET -mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET -mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET -mutant MTC and prior C/V, 62 treatment-naïve patients with RET -mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4–68.5] in patients with RET -mutant MTC and prior C/V, 77.4% [95% CI: 65.0–87.1] in treatment-naïve patients with RET -mutant MTC, and 90.9% [95% CI: 70.8–98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET -mutant MTC and prior C/V, not reached in treatment-naïve patients with RET -mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET -altered thyroid cancer safety population ( N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET- altered thyroid cancer. Clinical Trial Registration: NCT03037385