Source: FDA, National Drug Code (US) Revision Year: 2025
Sevabertinib is a reversible kinase inhibitor of human epidermal growth factor receptor 2 (HER2). It also exhibits activity against epidermal growth factor receptor (EGFR).
In vitro, sevabertinib inhibited the phosphorylation of HER2 and downstream signaling in cancer cells with HER2 alterations and proliferation of cancer cells overexpressing wild-type HER2 or harboring HER2 mutations.
In vivo, sevabertinib demonstrated antitumor activity in subcutaneous mouse xenograft models derived from human NSCLC tumors harboring an activating HER2 exon 20 mutation.
Higher sevabertinib exposure, across the dose range of 10 to 80 mg total daily dose (0.25 to 2 times the recommended dosage), was associated with an increased incidence of diarrhea (all grade and Grade ≥3) and rash.
At 2 times the maximum recommended dose, a mean increase in the QTc interval >20 ms was not observed.
Sevabertinib pharmacokinetics were observed at steady state in patients with advanced NSCLC harboring activating HER2 or EGFR mutations at the approved recommended dosage and are presented as mean (CV%), unless otherwise specified.
Sevabertinib maximum concentration (Cmax) is 902 (45%) ng/mL and total systemic exposure (AUC) is 6,640 (50%) ng*h/mL. Sevabertinib Cmax and AUC increase in a dose-proportional manner across the dose range of 10 mg to 80 mg (0.25 to 2 times the approved recommended total daily dose). Sevabertinib accumulation is approximately 1.7-fold for AUC and 1.3-fold for Cmax at the approved recommended dosage. Steady state is achieved within 3 days.
Sevabertinib median (min, max) time to maximum concentrations (Tmax) is approximately 2 hours (0.5, 8.2 hours) after a single dose.
Sevabertinib Cmax decreases by 56% and AUC decreases by 28% with a high-fat meal (1000 calories, 50% fat) in healthy subjects. No clinically significant differences in sevabertinib pharmacokinetics were observed following administration of a low-fat meal (400 calories, 25% fat).
Sevabertinib apparent volume of distribution is 28 L (42%). Sevabertinib plasma protein binding is 95%. The blood-to-plasma concentration ratio is 0.6.
Sevabertinib effective half-life is approximately 8 hours (33%) with an apparent clearance of 3.1 L/hour (38%).
Sevabertinib is primarily metabolized by CYP3A (major), CYP1A1 (minor), and glucuronidation (minor).
After a single oral dose of radiolabeled sevabertinib 40 mg to healthy subjects, approximately 84% of the dose was recovered in feces (14% unchanged) and approximately 10% in urine (1.3% unchanged).
No clinically significant effects in the pharmacokinetics of sevabertinib were observed based on age (18 to 91 years), race (27% White, 65% Asian, 2.7% Black/African American), sex, body weight (29 to 155 kg), smoking status, eGFR 30 to <90 mL/min, or mild hepatic impairment (AST > ULN and total bilirubin ≤ ULN; or total bilirubin >1 to 1.5× ULN and any AST). The effect of severe renal impairment (eGFR 15 to <30 mL/min), end-stage renal disease (eGFR <15 mL/min), moderate hepatic impairment (total bilirubin >1.5 to 3× ULN and any AST) or severe hepatic impairment (total bilirubin >3× ULN and any AST) on sevabertinib pharmacokinetics is unknown.
Strong CYP3A Inhibitors: Sevabertinib AUC increased 2.3-fold and Cmax 1.6-fold following concomitant use of itraconazole (strong CYP3A inhibitor) 200 mg once daily.
Strong CYP3A Inducers: Sevabertinib AUC decreased by 79% and Cmax by 57% following concomitant use of carbamazepine (strong CYP3A inducer) 600 mg once daily.
CYP3A Substrates: Midazolam (CYP3A substrate) AUC increased 2-fold and Cmax 1.8-fold following concomitant use of HYRNUO 20 mg twice daily.
P-gp Substrates: Dabigatran etexilate (P-gp substrate) AUC increased 1.4-fold following concomitant use of HYRNUO 20 mg twice daily.
BCRP Substrates: Rosuvastatin (BCRP substrate) AUC increased 1.3-fold and Cmax 1.4-fold following concomitant use of HYRNUO 20 mg twice daily.
Other Drugs: No clinically significant differences in sevabertinib pharmacokinetics were observed when used concomitantly with esomeprazole (proton pump inhibitor).
CYP450 Enzymes: Sevabertinib inhibits CYP1A1 and CYP2C8 but does not inhibit CYP2A6, CYP2C9, CYP1A2, CYP2B6, CYP2D6, CYP2C19, or CYP2E1. Sevabertinib does not induce CYP1A2, CYP2B6, or CYP2C19.
Transporter Systems: Sevabertinib is a substrate of P-gp, and BCRP. Sevabertinib inhibits MATE1 and MATE2-K but does not inhibit OATP1B1, OATP1B3, MRP2, OAT1, OAT3, OCT1, or OCT2.
Carcinogenicity studies have not been conducted with sevabertinib.
Sevabertinib was not genotoxic in a bacterial reverse mutation (Ames) and an in vitro micronucleus assay, or an in vivo micronucleus assay in rats.
Fertility studies have not been conducted with sevabertinib.
The efficacy of HYRNUO was evaluated in SOHO-01 (NCT05099172), an open-label, single-arm, multicenter, multi-cohort clinical study. Eligible patients (Groups D and E) were required to have previously treated locally advanced or metastatic NSCLC with HER2 (ERBB2) activating mutations and have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. HER2 (ERBB2) activating mutations were determined in tumor tissue or plasma by local laboratories prior to enrollment. Patients with treated, stable and asymptomatic brain metastases were eligible. Patients with symptomatic CNS metastases, clinically significant cardiac disease, and history of steroid dependent interstitial lung disease (ILD)/pneumonitis were excluded.
Patients received HYRNUO 20 mg orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcomes were confirmed objective response rate (ORR) and duration of response (DOR), as assessed by Blinded Independent Central Review (BICR) using RECIST v1.1.
The efficacy population included 70 patients from Group D, and 52 patients from Group E, with advanced non-squamous NSCLC with HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations based on prospective local testing. Of the 122 patients in these combined cohorts, tumor tissue samples from 67.2% (82/122) of patients were retrospectively tested using Oncomine Dx Target Test (Life Technologies Corporation). While 92.7% (76/82) of samples were positive for HER2 (ERBB2) TKD activating mutations, 7.3% (6/82) were unevaluable, and there were no samples with negative status for HER2 (ERBB2) TKD activating mutations.
Efficacy was evaluated in 70 patients with locally advanced or metastatic non-squamous NSCLC with HER2 (ERBB2) TKD activating mutations who had received prior systemic therapy but were naïve to therapy targeting HER2 mutations. Baseline demographic and disease characteristics of the efficacy population were: median age 59 years (range 29 to 77 years); 67% female; 70% Asian, 23% White, 1.4% Black or African American, 6% race not reported; 2.9% were of Hispanic or Latino ethnicity. Patients had an ECOG performance status of either 0 (39%) or 1 (61%); 69% were never-smokers, 29% were former smokers and 2.9% were current smokers. All patients had adenocarcinoma histology. Ninety-one percent (91%) of patients had stage IV disease and 20% had stable brain metastases. The median number of prior therapies was 1 (range 1 to 8); 94% of patients received prior platinum-based chemotherapy, 71% received prior immunotherapy, and 69% received both in combination. Among the patients, 70% of patients had a Y772_A775dup (YVMA) exon 20 insertion.
Efficacy results for SOHO-01 Group D are presented in Table 8.
Table 8. Efficacy Results for SOHO-01: Group D*:
| Efficacy Parameter | HYRNUO N=70 |
|---|---|
| Objective Response Rate (ORR)*, (95% CI) | 71% (59, 82) |
| Complete Response | 2.9% |
| Partial Response | 69% |
| Duration of Response (DOR)† | N=50 |
| Median, months (95% CI)‡ | 9.2 (6.3, 15.0) |
| DOR ≥6 months† | 54% |
| DOR ≥12 months† | 18% |
CI – Confidence Interval
* ORR 95% CI calculated using Clopper-Pearson method.
† Observed proportion of responding patients with duration of response beyond landmark time.
‡ Kaplan-Meier estimate.
Efficacy was evaluated in 52 patients with locally advanced or metastatic non-squamous NSCLC with HER2 (ERBB2) TKD activating mutations who had received prior systemic therapy including HER2-targeted ADCs.
Baseline demographic and disease characteristics of this efficacy population were: median age 65 years (range 35 to 91 years); 67% female; 62% Asian, 27% White, 6% Black or African American, 6% race not reported; 1.9% were of Hispanic or Latino ethnicity. Patients had an ECOG performance status of either 0 (29%) or 1 (71%); 65% were never-smokers, and 35% were former smokers. All patients had adenocarcinoma histology. Eighty-five percent (85%) of patients had stage IV disease and 29% had stable brain metastases. The median number of prior therapies was 2 (range 1 to 8), 77% of patients received prior platinum-based chemotherapy, 56% received prior immunotherapy, and 56% received both in combination. Among the patients, 77% of patients had a Y772_A775dup (YVMA) exon 20 insertion.
The ORR was 38% (95% CI 25, 53), with 6% of patients having a complete response and 33% of patients having a partial response. The median DOR was 7 months (95% CI 5.6, NE); ranging from 1+ to 17.2+ months based on the observed DOR. The observed proportion of responding patients with DOR of ≥6 months and ≥12 months was 60% and 10%, respectively.
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