Supplementary Figure S1. Chemistry/X-ray. Supplementary Figure S2. Biochemical activity of ALK TKIs. Supplementary Figure S3. Kinome profiling of NVL-655. Supplementary Figure S4. Potency in cell viability assay. Supplementary Figure S5. Maximal effect (Emax) in cell viability assay. Supplementary Figure S6. Cellular activity of NVL-655. Supplementary Figure S7. Comparing NVL-655 and lorlatinib potency. Supplementary Figure S8. Pathway analysis in cell lines. Supplementary Figure S9. Further evidence for on-target activity of NVL-655. Supplementary Figure S10. TRK activity. Supplementary Figure S11. Selectivity for ALK versus TRK using additional assays. Supplementary Figure S12. In vivo studies for ALK fusion with a wild-type kinase domain. Supplementary Figure S13. In vivo studies for ALK fusion with G1202R or I1171N single mutations. Supplementary Figure S14. In vivo studies for ALK fusion with G1202R compound mutations. Supplementary Figure S15. Pharmacodynamic analysis in G1202R compound mutation models. Supplementary Figure S16. Body weight and H&E staining for the YU-1077 intracranial study. Supplementary Figure S17. Estimating TRKB inhibition in humans and mice.

8503 Background: Neladalkib is an investigational ALK TKI designed for inhibition of ALK single and compound resistance mutations, brain penetrance, and sparing TRK. We report the first analyses of phase 2 TKI pre-treated patients (pts) and preliminary data in TKI-naïve pts with ALK + NSCLC . Methods: The global, single arm phase 1/2 ALKOVE-1 trial (NCT05384626) enrolled pts with advanced/metastatic ALK + NSCLC. Key study endpoints are objective response rate (ORR, RECIST v1.1 by BICR), duration of response (DOR), intracranial ORR (IC-ORR) and safety. Efficacy analyses included TKI pre-treated pts who initiated neladalkib 150 mg QD by 30 Sep 2024 or all treated TKI-naïve pts. Data cut: 29 Aug 2025. Results: 656 pts with ALK + NSCLC received neladalkib. Efficacy-evaluable TKI pre-treated pts (n=253) had received a median of 3 prior anticancer therapies (range 1-11, 51% prior chemo). 78% of pts received ≥2 (range 2-5) prior ALK TKIs, of whom 91% had prior lorlatinib. 19% had single or compound ALK G1202R resistance mutations. 40% had CNS disease by BICR. ALK TKI pre-treated results are reported in the Table. In a preliminary analysis of TKI-naïve pts, ORR was 86% (38/44, 2 uPRs); 12-month DOR rate was 91%. IC-ORR was 78% (7/9) with no CNS progression events as of data cutoff. Conclusions: In this ALK TKI pre-treated data set, neladalkib demonstrated clinically meaningful activity, including in pts with CNS disease, ALK G1202R single or compound mutations, and prior lorlatinib. Encouraging preliminary activity was also observed in TKI-naïve pts. Neladalkib’s safety profile was consistent with its ALK-selective, TRK-sparing design. Clinical trial information: NCT05384626 . Efficacy Parameter (RECIST v1.1, BICR) All ALK TKI Pre-treated± chemo ALK TKI Pre-treated,Lorlatinib-naïve ± chemo ORR % (n/N)95% CI 31 (79/253) a, b 26, 37 46 (29/63) c 33, 59 % DOR ≥ 12 m (95% CI) / 18 m (95% CI) d 64 (51, 75) / 53 (34, 68) 80 (58, 91) / 60 (19, 85) G1202R Mutation ORR % (n/N)95% CI 68 (32/47) e,f 53, 81 83 (10/12)52, 98 % DOR ≥ 12 m d (95% CI) 80 (61, 91) 77 (34, 94) Intracranial Activity IC-ORR % (n/N)95% CI 32 (29/92) g, h 22, 42 63 (15/24) g 41, 81 % IC-DOR ≥ 12 m d (95% CI) 71 (48, 85) 92 (57, 99) m, months; NE, not estimable. a Includes 2 unconfirmed partial responses (uPRs). b Pts with prior lorlatinib: ORR 26% (50/190, including 2 uPRs) and mDOR 17.6 m (95% CI: 6.9, NE). c Pts with 1 prior 2 nd generation ALK TKI (alectinib, n=44; brigatinib, n=2) ± chemo: ORR 48% (22/46) and DOR ≥ 12 m of 74% (95% CI: 48, 88). d Estimated by Kaplan-Meier analysis. e Single or compound G1202R resistance mutations may be present. f Includes 1 uPR. g Includes 2 IC-uPRs. h Pts with prior lorlatinib: IC-ORR 21% (14/68) and IC-DOR ≥ 12 m of 55% (95% CI: 26, 77).

TPS8666 Background: Oncogenic ALK gene fusions are detected in ~5% of advanced non-small cell lung cancer (NSCLC) cases. Among these patients, the incidence of brain metastases at diagnosis is ~40%. Prior generations of ALK tyrosine kinase inhibitors (TKIs) present limitations that may influence efficacy and tolerability, such as inadequate control of brain metastases, treatment-emergent drug-resistant ALK mutations, or off-target adverse events, particularly neurological events associated with inhibition of the structurally related TRK kinases. Neladalkib is a potent, brain-penetrant, ALK-selective TKI with preclinical activity against diverse ALK fusions and resistance mutations (Lin et al., Cancer Discovery 2024). In the Phase 1/2 ALKOVE-1 study, neladalkib showed encouraging preliminary efficacy in patients with heavily pretreated ALK+ NSCLC, including in those with ALK single or compound resistance mutations and brain metastases (Drilon et al., ESMO 2024). It also exhibited a favorable safety profile consistent with its ALK-selective, TRK-sparing design. The Phase 3 ALKAZAR study aims to demonstrate the superiority of neladalkib over a current standard of care, alectinib, in TKI-naïve patients with advanced ALK+ NSCLC. Methods: ALKAZAR (NCT06765109) is a global, Phase 3, randomized, controlled, open-label study in adult patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement per local testing of tissue or blood. Prior systemic anticancer treatment for metastatic disease is not allowed. Patients who received prior alectinib in the adjuvant setting are not eligible. Patients are required to have measurable disease by RECIST. Patients with untreated central nervous system (CNS) disease without progressive neurological symptoms or increasing corticosteroid doses are eligible. Patients with non-ALK oncogenic driver alterations are excluded. Approximately 450 patients will be randomized in a 1:1 ratio to receive either oral neladalkib (150 mg once daily) or oral alectinib (600 mg twice daily), stratified by brain metastases, ethnic origin (Asian vs. non-Asian), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) score (0 vs.1 vs. 2). The primary endpoint is progression-free survival by blinded independent central review. Secondary endpoints include intracranial activity, objective response rate, duration of response, overall survival, safety and tolerability, and patient-reported outcomes. Additional analyses will be conducted to investigate candidate biomarkers and molecular mechanisms of response and resistance to neladalkib and alectinib. The study is open to accrual. Clinical trial information: NCT06765109 .

Abstract Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion–positive non–small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested. In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs. In vivo, it induces regression across 12 tumor models, including intracranial and patient-derived xenografts. NVL-655 inhibits ALK over TRK with 22-fold to >874-fold selectivity. These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion–positive non–small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.

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 400mg 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-naive 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-naive 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-naive 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-naive 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

Sunvozertinib (DZD9008) is a rationally designed EGFR Exon20ins inhibitor with wildtype selectivity. Results from the ongoing phase 1/2 studies showed sunvozertinib’s strong anti-tumor activity and encouraging safety profile. Based on these data, sunvozertinib was granted the Breakthrough Therapy Designation by both US FDA and China NMPA. Here we present sunvozertinib’s safety and efficacy results in advanced NSCLC patients with EGFR Exon20ins post platinum-based chemotherapies.

Aberrations of the ALK oncogene drive tumor cell proliferation, survival, and metastasis in multiple adult and pediatric cancers. ALK gene fusions are detected in ~5% of advanced non-small cell lung cancers (NSCLC); among these patients, the incidence of central nervous system (CNS) metastases at diagnosis is ~40%. Although 5 tyrosine kinase inhibitors (TKIs) are approved by the FDA and EMA for ALK-positive NSCLC, therapeutic limitations remain, such as acquired resistance due to secondary and compound ALK mutations and/or neurologic adverse events attributed to off-target inhibition of TRK. NVL-655 is a novel, brain-penetrant ALK-selective TKI that exhibits preclinical activity against diverse ALK fusions and mutations, including G1202R and G1202R compound mutations, while sparing inhibition of TRK. The ALKOVE-1 study is evaluating the safety and preliminary activity of NVL-655 in patients with solid tumors harboring oncogenic ALK alterations, including those with acquired ALK resistance mutations and CNS metastases. ALKOVE-1 consists of a phase I dose escalation followed by a phase II expansion in cohorts defined by tumor type and prior therapies. Phase I includes adult patients with any solid tumor type harboring an oncogenic ALK gene fusion or activating mutation (by local testing), including ALK fusion-positive NSCLC after ≥ 1 prior 2nd or 3rd generation ALK TKI. Prior platinum-based chemotherapy and/or immunotherapy, CNS disease without progressive neurological symptoms or increasing corticosteroid doses, and evaluable but non-measurable disease are allowed. Patients will receive NVL-655 by daily oral administration. Primary phase I objectives are to determine the NVL-655 recommended phase II dose and, if applicable, maximum tolerated dose. Additional objectives include evaluation of safety/ tolerability, preliminary activity, and characterization of the pharmacokinetic and pharmacodynamic profiles of NVL-655. Longitudinal analysis of circulating tumor DNA will be performed, including ALK mutation profiling and other relevant biomarkers. The phase I portion of the study is ongoing. NCT05384626 (May 20, 2022). Nuvalent, Inc. Nuvalent. Inc.

Background: Oncogenic ALK alterations drive diverse tumor types, including ALK fusions in 3-5% of non-small cell lung cancers (NSCLCs). While 3 generations (1G, 2G, 3G) of ALK tyrosine kinase inhibitors (TKIs) are approved globally for ALK fusion-positive (ALK+) NSCLC, they are limited by acquired ALK resistance mutations, CNS relapses, and for the 3G TKI lorlatinib, neurologic adverse events attributed to off-target TRK inhibition. A rationally designed ALK TKI that overcomes these limitations is needed. Preclinically, NVL-655 is a brain-penetrant, ALK-selective, and TRK-sparing TKI that exhibits activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations. Materials and Methods: ALKOVE-1 (NCT05384626) is a global phase 1/2 trial of NVL-655. The ongoing phase 1 dose escalation enrolls patients (pts) with a previously treated ALK+ solid tumor, including NSCLC treated with ≥1 prior 2G or 3G ALK TKI. Primary objectives are to determine the safety/tolerability, recommended phase 2 dose (RP2D), and if applicable, the maximum tolerated dose (MTD). Additional objectives include assessments of pharmacokinetics (PK), pharmacodynamics, and preliminary activity by investigator-assessed tumor response (RECIST v1.1). Data cut: June 12, 2023. Results: 57 pts (54 NSCLC, 3 other solid tumors) received NVL-655 orally at 15-200 mg once daily (QD). Pts previously received a median of 4 (range: 1-8) prior anticancer therapies, including a 2G or 3G ALK TKI (100%); ≥1 2G ALK TKI + lorlatinib (77%); ≥3 ALK TKIs (53%); and chemotherapy (60%). At baseline, 51% had a history of CNS metastases. 47% had known ALK resistance mutations and 32% had compound ALK mutations, as per available local testing or central analyses of baseline circulating tumor DNA (ctDNA). Treatment-related adverse events (TRAEs) were generally mild; most frequent were nausea (12%), transaminase elevation (12%), fatigue (9%), and constipation (7%). Grade ≥3 TRAEs were transaminase elevation (n=2), CPK elevation (n=1), and fatigue (n=1). NVL-655 PK analyses demonstrated dose-proportional exposure. Partial responses (PR) were observed in 45% (15/33; 8 pending confirmation) of efficacy-evaluable pts with ALK+ NSCLC (15-150 mg QD), in 65% (11/17) with baseline ALK resistance mutations, and in 41% (12/29) post-lorlatinib, including cases with compound resistance mutations. CNS activity, including complete resolution of CNS metastases, has been observed. ctDNA analyses showed reductions, including clearance, of ALK fusion and mutation variants. Neither the MTD nor RP2D has been identified; phase 1 continues. Conclusions: NVL-655 has been well-tolerated up to 200 mg daily with favorable PK. Preliminary activity has been demonstrated in heavily pretreated pts with ALK+ NSCLC, including those who previously received 2G ALK TKI(s) + lorlatinib, with brain metastases, or with single/compound ALK resistance mutations. Citation Format: Jessica J Lin, Melissa Johnson, Enriqueta Felip, Sai-Hong Ignatius Ou, Benjamin Besse, Christina Baik, Julien Mazieres, Yasir Elamin, Joshua E. Reuss, Anna Minchom, Aurelie Swalduz, Nick Pavlakis, Geoffrey Liu, Shirish Gadgeel, D. Ross Camidge, Jennifer A Green, Junwu Shen, John Soglia, Yuting Sun, Viola W Zhu, Alexander Drilon. Safety and preliminary activity of the selective ALK inhibitor NVL-655 in patients with ALK fusion-positive solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B154.

BACKGROUND 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 400mg 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; 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 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% (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 months 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 following 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.

Supplementary methods, figure legends

Abstract Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non–small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached. Significance: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599

6080 Background: Alterations in RET are targetable oncogenic drivers in TC. Pralsetinib is a highly potent, selective RET inhibitor, with demonstrated efficacy in pts with RET-altered TC. In a previous analysis of the Phase I/II ARROW trial (NCT03037385; data cutoff: 22 May 2020), overall response rates [ORR; measurable-disease population] with pralsetinib at 400 mg once daily (QD) were 60% (33/55) and 71% (15/21) in pts with RET-mutant medullary TC ( RET-mutant MTC) who had received prior multikinase inhibitors cabozantinib and/or vandetanib (C/V), and those who were treatment naïve, respectively, and 89% (8/9) in pts with previously treated RET fusion-positive TC ( RET-fp TC). Here we report an updated analysis of these cohorts in the intention-to-treat (ITT) population. Methods: Adult pts with RET-altered locally advanced/metastatic TC who had enrolled in ARROW and initiated pralsetinib at 400 mg QD, were included. Phase II primary endpoints: ORR (by blinded independent central review, per RECIST v1.1) and safety. Efficacy endpoints for this analysis were assessed in the ITT population. Safety was assessed in all pts with RET-altered TC who initiated pralsetinib at 400 mg QD. Enrolment cutoff: 23 August 2020 for the ITT population; data cutoff: 12 April 2021. Results: The ITT population comprised 145 pts with RET-mutant MTC (with or without prior systemic therapy, including C/V) and 22 pts with RET-fp TC, 21 of whom had received prior systemic therapy (including multikinase inhibitor[s] and/or radioactive iodine). In pts with RET-mutant MTC who had received prior C/V (n = 67), ORR was 51% (34/67; 95% CI 38–63; 2 complete responses [CR]; 32 partial responses [PR]), median duration of response (DoR) was 25.8 months (95% CI 18.0–not reached [NR]) and median progression-free survival (PFS) was 24.9 months (95% CI 19.7–31.2). In treatment-naïve pts with RET-mutant MTC, ORR was 72% (48/67; 95% CI 59–82; 4 CR; 44 PR), and median DoR and median PFS were not reached. In pts with previously treated RET-fp TC, ORR was 86% (18/21; 95% CI 64–97; 3 CR; 15 PR), median DoR was 17.5 months (95% CI 16.0–NR) and median PFS was 19.4 months (95% CI 13.0–NR). Median overall survival (OS) was not reached in any of the cohorts. The safety population comprised 172 pts with RET-altered TC treated at 400 mg QD. The most common treatment-related adverse events (TRAEs) were increased aspartate aminotransferase (n = 67; 39%), anemia (n = 60; 35%), hypertension (n = 57; 33%) and decreased white blood cell count (n = 52; 30%). Serious TRAEs were reported in 27 pts (16%); the most frequent was pneumonitis (n = 5; 3%). Nine pts (5%) discontinued pralsetinib due to a TRAE and one patient ( < 1%) died due to a TRAE ( pneumocystis jirovecii pneumonia) following 44 days ( < 3 cycles) on pralsetinib. Conclusions: In this updated analysis including more pts, pralsetinib continues to be efficacious with a manageable safety profile in pts with RET-altered TC. Clinical trial information: NCT03037385.

Introduction: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts. Methods: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine. Results: Of 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4). Conclusions: Rates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible. (C) 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

Oncogenic ROS1 gene fusions are implicated in the pathogenesis of various adult and pediatric cancers, including up to 3% of non-small cell lung cancers (NSCLC), where up to 40% of patients present with central nervous system (CNS) metastases. Tyrosine kinase inhibitors (TKIs) approved by the FDA and EMA for ROS1-positive NSCLC (crizotinib and entrectinib) are limited by acquired resistance, frequently mediated by secondary ROS1 kinase domain mutations. In addition, dual TRK/ROS1 kinase inhibitors such as entrectinib are associated with neurologic adverse events.