Enhertu (trastuzumab deruxtecan) supplemental New Drug Application submitted in Japan for patients with HER2 positive metastatic solid tumors- Daiichi Sankyo

Daiichi Sankyo  has submitted a supplemental New Drug  Application (sNDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for Enhertu (trastuzumab deruxtecan) for the treatment of adult patients with HER2 positive advanced or recurrent solid tumors refractory or intolerant to standard treatments. HER2 directed therapies currently are approved to treat breast, colorectal, gastric, lung and salivary gland cancer in Japan. However, there are no HER2 directed therapies approved for other cancers that are HER2 overexpressed (IHC 3+) or amplified (ERBB2).The sNDA is based on data from four phase II  trials including HERALD, an investigator-initiated trial conducted in Japan, DESTINY-PanTumor02, DESTINY-CRC02 and DESTINY-Lung01 where Enhertu demonstrated clinically meaningful responses across a broad range of tumors.  “The clinical benefit seen across several studies supports the potential of ENHERTU to treat any type of HER2 positive metastatic solid cancer,” said Dr. Yuki Abe,  Head of R&D Division in Japan and Head of Research, Daiichi Sankyo. “We look forward to working with the Japan health authority to bring the first antibody drug conjugate with a tumor agnostic indication to patients.”

HERALD is a multicenter, open-label, single-arm phase II trial evaluating the efficacy and safety of  Enhertu (5.4 mg/kg) in patients with unresectable, advanced or recurrent solid tumors refractory or intolerant to standard treatments and have HER2 gene amplification in circulating tumor DNA, including biliary tract, cervical, colorectal, endometrial, esophageal, gastric, melanoma, non-small cell lung, ovarian, pancreatic, prostate, salivary gland, small intestine, urothelial cancer or other tumors  The primary endpoint of HERALD is confirmed objective response rate (ORR) as assessed by investigator. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), time to treatment failure, overall survival (OS), ORR by independent central review and safety. Results from HERALD were published in the Journal of Clinical Oncology. HERALD enrolled 62 patients at seven sites in Japan. 

DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label phase II 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 efficacy endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DOR, DCR, PFS, OS, safety, tolerability and pharmacokinetics. Results from DESTINY-PanTumor02 were published in the Journal of Clinical Oncology. DESTINY-PanTumor02 enrolled 267 patients, including 75 HER2 positive (IHC 3+) adult patients, at multiple sites in Asia, Europe and North America.

DESTINY-Lung01 is a global phase 2, open-label, two-cohort trial evaluating the efficacy and safety of  Enhertu (6.4 mg/kg and 5.4 mg/kg) in patients with HER2 mutant (cohort 2, n=91) or HER2 overexpressing (defined as IHC 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 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  (see 3rd citation). Full results from the HER2 overexpressing cohort were published in The Lancet Oncology. 

DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter phase 2 trial evaluating the efficacy and safety of two doses (5.4 mg/kg or 6.4 mg/kg) of Enhertu in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, RAS wild-type or RAS mutant tumor types previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (n=80) were randomized 1:1 to receive either 5.4 mg/kg or 6.4 mg/kg of Enhertu. In the second stage, additional patients (n=42) were enrolled in the 5.4 mg/kg arm. The primary endpoint is confirmed ORR as assessed by blinded independent central review. Secondary endpoints include DOR, DCR, investigator-assessed confirmed ORR, clinical benefit ratio, PFS, OS and safety. Results from DESTINY-CRC02 were published in The Lancet Oncology.  DESTINY-CRC02 enrolled 122 patients, including 64 HER2 positive (IHC 3+) adult patients, at multiple sites in Asia, Europe and North America.

See citations: Yagisawa M, Taniguchi H, Satoh T et al. Trastuzumab Deruxtecan in Advanced Solid Tumors With Human Epidermal Growth Factor Receptor 2 Amplification Identified by Plasma Cell-Free DNA Testing: A Multicenter, Single-Arm, Phase II Basket Trial.  J Clin Oncol . 2024, 42:3817 .doi: 10.1200/JCO.23.02626. 

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

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.