China’s NMPA approves Enhertu for previously treated HER2-positive metastatic solid tumours – Daiichi Sankyo

Enhertu (trastuzumab deruxtecan) has been approved in China as a monotherapy for the treatment of adult patients with unresectable or metastatic solid tumors with HER2 expression (immunohistochemistry [IHC] 3+) who have received prior treatment or have no satisfactory alternative treatment options.

This indication was granted as a conditional approval based on the results of single-arm studies. Full approval of this indication will depend on the clinical benefit of a confirmatory trial.

Enhertu is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.

The approval by China’s National Medical Products Administration (NMPA) is based on results from four phase 2 trials, including DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-CRC02 and DESTINY-PanTumor03 where Enhertu demonstrated clinically meaningful responses across a broad range of tumors.

In DESTINY-PanTumor02, Enhertu demonstrated a confirmed objective response rate (ORR) of 51.4% (95% confidence interval [CI]: 41.7-61.0) with four complete responses (CRs) and 53 partial responses (PRs) in a subgroup of previously treated patients (n=111) with centrally or locally confirmed HER2 positive (IHC 3+) solid tumors. Median duration of response (DOR) was 19.4 months (95% CI: 10.0-29.9). Median progression-free survival (PFS) was 10.1 months (95% CI: 7.0-14.2) and median overall survival (OS) was 17.7 months (95% CI: 12.8-23.4).

In DESTINY-Lung01, Enhertu demonstrated a confirmed ORR of 52.9% (95% CI: 27.8-77.0) with one CR and eight PRs in a subgroup of previously treated patients (n=17) with centrally confirmed HER2 positive (IHC 3+) non small cell lung cancer (NSCLC). Median DOR was 6.9 months (95% CI: 4.0-9.8). Median PFS was 7.5 months (95% CI: 3.1-11.0) and median OS was 12.5 months (95% CI: 9.3-not evaluable [NE]).

In DESTINY-CRC02, Enhertu demonstrated a confirmed ORR of 46.9% (95% CI: 34.3-59.8) with zero CRs and 30 PRs in a subgroup of previously treated patients (n=64) with centrally confirmed HER2 positive (IHC 3+) colorectal cancer. Median DOR was 5.5 months (95% CI: 4.2-8.1). Median PFS was 7.0 months (95% CI: 5.7-8.2) and median OS was 15.1 months (95% CI: 12.6-NE).

In DESTINY-PanTumor03, Enhertu demonstrated a confirmed ORR of 58.0% (95% CI: 43.2-71.8) with one CR and 28 PRs in previously treated patients in China (n=50) with centrally confirmed HER2 positive (IHC 3+) solid tumors, including biliary tract, bladder, cervical, colorectal, endometrial, NSCLC, ovarian and parotid gland cancer. Median DOR was 15.4 months (95% CI: 12.5- not calculable [NC]). Median PFS was 15.7 months (95% CI: 7.2 NC) and median OS was not reached (95% CI: 11.0-NC).

“HER2 overexpression occurs across multiple tumor types and is associated with aggressive disease and a poor prognosis,” said Xiaohua Wu, MD, Supervisor of Oncology of Fudan University Shanghai Cancer Center, Chairman and Chief Expert of the Multidisciplinary Team in Gynecologic Oncology, Principal Investigator in China of the DESTINY-PanTumor03 trial. “Until now, HER2 directed therapies were only available for specific tumor types. The approval of trastuzumab deruxtecan as a tumor agnostic HER2 directed therapy, supported by clinically meaningful responses observed across a broad range of HER2 positive solid tumors, offers a new treatment for patients who have historically had limited options.”

The safety profile of Enhertu in DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-CRC02 and DESTINY PanTumor03 was consistent with previous clinical trials with no new safety concerns identified. Grade 3 or grade 4 adverse reactions from a pooled safety analysis of 4,146 patients treated with Enhertu (5.4 mg/kg) across multiple tumor types in clinical studies included neutropenia (18.7%), anemia (8.2%), fatigue (7.4%), leukopenia (6.6%), thrombocytopenia (5.4%), lymphopenia (5.0%), nausea (4.5%), increased transaminases (3.3%), hypokalemia (3.1%), diarrhea (2.1%), vomiting (2.0%), decreased appetite (1.4%) and pneumonia (1.2%). Grade 5 adverse reactions occurred in 0.9% of patients, including interstitial lung disease (ILD) (0.7%). Discontinuation of treatment due to an adverse reaction occurred in 10.1% of patients treated with Enhertu. The most frequent adverse reaction associated with permanent discontinuation was ILD (7.6%).

“This approval of Enhertu reflects the continued evolution of cancer care toward treatment regimens focused on the underlying biology of the disease rather than where a tumor originates in the body,” said Michio Hayashi, China President, Daiichi Sankyo. “As the first tumor agnostic HER2 directed medicine approved in China, Enhertu has the potential to expand treatment for eligible patients across a broad range of HER2 positive metastatic cancers.”

“Precision medicine is playing an increasingly important role in guiding treatment decisions based on the molecular and biological characteristics of a patient’s disease,” said Mary Guan, General Manager, China Oncology Business, AstraZeneca. “This approval marks the tenth indication for Enhertu in China and provides clinicians with a targeted option for patients with HER2 positive metastatic cancer across tumor types. It also reinforces the importance of biomarker testing to identify patients who may be eligible for HER2 directed treatment, supporting more personalized treatment decisions.”

Enhertu (5.4 mg/kg) is approved in more than 50 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior treatment and/or have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-CRC02, DESTINY-PanTumor03 and/or HERALD trials.

DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label, phase 2 trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) for the treatment of previously treated HER2 expressing tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumors. The primary endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DOR, disease control rate (DCR), PFS, OS, safety, tolerability and pharmacokinetics. Results from DESTINY-PanTumor02 were published in the Journal of Clinical Oncology. Results from patients with HER2 positive (IHC 3+) disease identified by local or central testing (n=111) were published in Advances in Therapy. DESTINY-PanTumor02 enrolled 267 patients, including 111 HER2 positive (IHC 3+) adult patients at multiple sites in Asia, Europe, North America, South America and Oceania.

DESTINY-Lung01 is a global, open-label, two-cohort, phase 2 trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg or 6.4 mg/kg) in patients with HER2 mutant (Cohort 2, n=91) or HER2 overexpressing (defined as IHC 2 3+ or IHC 2+) (Cohort 1 and 1a, n=90) unresectable or metastatic NSCLC who had progressed after one or more systemic therapies. The primary endpoint of DESTINY-Lung01 is confirmed ORR by independent central review. Key secondary endpoints include DOR, DCR, PFS, OS and safety. Results from the HER2 mutant cohort were published in The New England Journal of Medicine and results from the HER2 overexpressing cohort were published in The Lancet Oncology. DESTINY-Lung01 enrolled 181 patients, including 17 HER2 positive (IHC 3+) adult patients at multiple sites in Asia, Europe and North America.

DESTINY-PanTumor03 is a multicenter, open-label, phase 2 trial in China evaluating the efficacy and safety of Enhertu (5.4 mg/kg) as a monotherapy or in combination with anti-cancer agents for the treatment of patients with HER2 expressing (IHC 3+) locally advanced, unresectable or metastatic solid tumors that have progressed following at least one prior systemic regimen or have no satisfactory alternative treatment options. The primary endpoint of DESTINY-PanTumor03 is confirmed ORR as assessed by independent central review. Secondary endpoints include DOR, PFS, OS, DCR, best objective response and safety. Results from DESTINY PanTumor03 were published in the Journal of Clinical Oncology. DESTINY-PanTumor03 enrolled 50 patients at multiple sites in China.

Citations: Meric-Bernstam F, Makker V, Oaknin A et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial.  J Clin Oncol  . 2024, 42:47 doi: 10.1200/JCO.23.02005

Oaknin, A., Lee, JY., Makker, V. et al. Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02. Adv Ther 41, 4125–4139 (2024). https://doi.org/10.1007/s12325-024-02975-x

Li BT, Smit EF, Goto Y et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer.  N Engl J Med  2022  386:241 doi: 10.1056/NEJMoa2112431.

Smit EF, Felip E, Uprety D et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.  Lancet Oncol  2024, 25:439 doi: 10.1016/S1470-2045(24)00064-0

Raghav K, Siena S, Takashima A, et al. Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial. Lancet Oncol . 2024, 25:1147 doi: 10.1016/S1470-2045(24)00380-2.

Yanqiao Zhang, Bin Jiang, Jingdong Zhang, et al. Trastuzumab deruxtecan (T-DXd) for pretreated patients in China with HER2 IHC 3+ solid tumors: DESTINY-PanTumor03 Part 1 primary analysis. J Clin Oncol 44, 3026(2026) Volume 44, Number 16_suppl DOI: 10.1200/JCO.2026.44.16_suppl.3026