Source: FDA, National Drug Code (US) Revision Year: 2026
Zidesamtinib is an inhibitor of tyrosine kinase ROS1, including ROS1 resistance mutations. In a biochemical assay, zidesamtinib inhibited ROS1 (IC50 = 0.7 nM) and also showed inhibitory effects on ALK (IC50 = 3 nM) and tropomyosin receptor kinases (TRKs), TRKB (IC50 = 54 nM), TRKC (IC50 = 193 nM) and TRKA (IC50 = 258 nM).
In vitro, zidesamtinib inhibited the viability of cultured cells expressing ROS1 fusion genes and resistance mutations (G2032R, S1986F, F2004C/V, L2026M, D2033N, and G2101A). In mice subcutaneously implanted with tumors harboring ROS1 fusions, including the G2032R mutation, administration of zidesamtinib resulted in tumor growth inhibition. Zidesamtinib had antitumor activity in an intracranial NSCLC xenograft model harboring a ROS1 fusion.
An increased incidence of dysgeusia was observed with higher metabolite M9 exposure.
The largest mean increase in QTc interval was 13 ms (upper confidence interval = 19 ms) after administration of JIDEYTRO 100 mg once daily (the maximum recommended dosage) in patients with advanced ROS1-positive NSCLC and other advanced ROS1-positive solid tumors [see Warnings and Precautions (5.2)].
Zidesamtinib pharmacokinetics were observed at steady-state in patients with advanced ROS1-positive NSCLC and other solid tumors at the approved recommended dosage and are presented as mean (coefficient of variation [CV]%) unless otherwise specified. Zidesamtinib maximum plasma concentration (Cmax) is 934 ng/mL (44%) and total systemic exposure (AUC) is 8,310 ng.h/mL (37%). Zidesamtinib Cmax and AUC increase in a dose proportional manner over the dose range of 25 mg to 100 mg orally once daily (0.25 to 1 times the maximum recommended dosage). Zidesamtinib accumulation is approximately 1.5-fold and steady-state is reached in approximately 4 days.
Zidesamtinib median (min, max) time to maximum plasma concentration (Tmax) is 1 hour (0.3, 6 hours). Zidesamtinib absolute bioavailability is 83%.
No clinically significant differences in zidesamtinib exposure were observed in healthy participants following administration of a high fat meal (approximately 1,000 calories with 60% fat).
Zidesamtinib apparent (oral) volume of distribution (Vss) is 326 L (18%).
Zidesamtinib plasma protein binding is 79% and is not concentration-dependent in vitro. Zidesamtinib blood-to-plasma ratio was 0.9 in vitro.
Zidesamtinib elimination half-life is 18 (51%) hours with an apparent (oral) clearance of 12 (37%) L/h.
Zidesamtinib is primarily metabolized by CYP3A with minor contributions from CYP1A2 and CYP2C8. An active metabolite, a des-ethyl metabolite (M9), with activity one-third that of the parent, was identified in plasma and its AUC represents 48% of the parent AUC.
Following oral administration of a single 100 mg radiolabeled dose to healthy participants, approximately 47% of the dose was recovered in the urine (<1% unchanged) and 33% in the feces (<2% as unchanged).
No clinically meaningful differences in the pharmacokinetics of zidesamtinib were observed based on age (26 to 87 years), sex, race (White 44%, Asian 38%, or Black 4%), body weight (36 to 162 kg), eGFR 30 to 90 mL/min [estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)], or mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) to moderate (total bilirubin >1.5 to 3 times ULN with any AST) hepatic impairment. The effect of severe (total bilirubin >3 x ULN with any AST) hepatic impairment, severe renal impairment (eGFR < 30 mL/min), or dialysis on zidesamtinib pharmacokinetics is unknown.
Strong CYP3A Inhibitors: Zidesamtinib AUC increased 2.6-fold and Cmax increased 1.8-fold following concomitant use of itraconazole (strong CYP3A inhibitor) 200 mg twice daily followed by 200 mg once daily for 6 days.
CYP3A Substrates: No clinically significant differences on midazolam (a sensitive CYP3A substrate) pharmacokinetics were observed when used concomitantly with JIDEYTRO.
Acid-Reducing Agents: No clinically significant difference in steady-state zidesamtinib pharmacokinetics were observed when used concomitantly with lansoprazole (proton pump inhibitor).
CYP450 Enzymes: Zidesamtinib and M9 do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6.
UDP-glucuronosyltransferase (UGT): Zidesamtinib does not inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 or UGT2B15.
Transporter Systems: Zidesamtinib inhibits P-glycoprotein (P-gp), BCRP, and MATE1. Zidesamtinib does not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2 or MATE2K.
M9 does not inhibit P-gp, BCRP, MATE1, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2 or MATE2K.
Carcinogenicity studies with zidesamtinib were not conducted.
Zidesamtinib was genotoxic in the in vivo rat micronucleus assays. Zidesamtinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro assay in human lymphoblastoid TK6 cells. Zidesamtinib did not induce DNA strand breaks in the comet assay in liver.
Dedicated fertility studies were not conducted with zidesamtinib. In a 13-week repeat dose toxicity study with oral administration of zidesamtinib in rats, adverse effects in reproductive organs included hemorrhage and inflammation of the ovaries with dilation and inflammation of the oviduct in females at doses ≥3 mg/kg/day (≥1.7 times the human exposure at the recommended dose based on AUC) and spermatid retention and tubular degeneration in the testis in males at doses ≥6 mg/kg/day (approximately equivalent to the human exposure at the recommended dose based on AUC). Findings in males were reversible, whereas the reversibility in females was not assessed.
The efficacy of JIDEYTRO was evaluated in 117 patients with previously treated locally advanced or metastatic ROS1-positive NSCLC who received JIDEYTRO at a dose of 100 mg orally once daily in ARROS- 1, a multicenter, single-arm, open-label, multi-cohort clinical trial (NCT05118789). Eligible patients were required to have ROS1-positive locally advanced or metastatic NSCLC, ECOG performance status ≤1, and measurable disease per RECIST v1.1. Patients with asymptomatic, stable intracranial metastases were eligible. Identification of ROS1 gene fusions was determined in local laboratories using next-generation sequencing (NGS), polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) tests.
The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 as assessed by blinded independent central review (BICR). Intracranial response according to modified RECIST v1.1 was assessed by BICR. Tumor assessments with imaging were performed every 8 weeks for the first 18 months and every 12 weeks thereafter. The efficacy population included 117 patients who received at least 1 prior ROS1 TKI with or without prior platinum-based chemotherapy or immunotherapy.
Among the 117 patients with ROS1 TKI-pretreated NSCLC, the median age was 57 years (range 31 to 83); 56% were female; 47% were White; 36% were Asian; 4% were Black or African American and 13% were unknown or other races; 68% never smoked; and 62% had ECOG performance status of 1 at baseline. At baseline, 100% had metastatic disease; 49% had CNS metastases by BICR; 97% had adenocarcinoma; 52% patients had received prior platinum-based chemotherapy for advanced disease; 50% received 1 prior ROS1 TKI (including crizotinib [47%], entrectinib [46%] and repotrectinib and/or taletrectinib [7%]), and 50% received 2 or more prior ROS1 TKIs (including lorlatinib, repotrectinib and/or taletrectinib [93%]).
Efficacy results are summarized in Table 5.
Table 5. Efficacy Results for Patients with ROS1-Positive TKI-Pretreated NSCLC in ARROS-1 per BICR Assessment:
| Efficacy Parameters | ROS1 TKI-Pretreated (N=117) |
| Confirmed Response Rate, % (95% CI) | 44% (34, 53) |
| Complete Response | 0.9% |
| Duration of Response (DOR) | |
| Range (months) | 1.9, 28.5+ |
| Response Duration ≥6 monthsa | 82% |
| Response Duration ≥12 monthsa | 69% |
Abbreviations: CI = confidence interval; NE = not evaluable
a Based on observed DOR rate
+ Ongoing response
In patients who received one prior ROS1 TKI (N=59), the overall response rate was 49% (95% CI: 36, 63). In patients who received two or more prior ROS1 TKIs (N=58), including lorlatinib, repotrectinib and/or taletrectinib, the overall response rate was 38% (95% CI: 26, 52). Fifty patients had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months prior to study entry; responses were observed in 48% (95% CI: 34, 63) of patients including 22% of patients with a complete response. Responses were observed in 21 of the 42 (50%) patients who had ROS1 resistance mutations. Of the 26 patients with the solvent front G2032R resistance mutation, responses were observed in 14 patients (54%). Responses were also observed in patients with other mutations (ROS1G2032K, ROS1D2033N, ROS1F2004C/V, ROS1G1957A).
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.