Japanese Approval Is Sought for T-DXd in HER2+ Advanced Solid Tumors

sNDA for T-DXd in HER2+ Solid Tumors

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A supplemental new drug application (sNDA) seeking the approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of adult patients with HER2-positive advanced or recurrent solid tumors that are refractory or intolerant to standard therapies was submitted to Japan’s Ministry of Health, Labor and Welfare.1

The sDNA was submitted based on data from 4 phase 2 trials in which T-DXd revealed clinically meaningful responses across multiple solid tumors: HERALD (UMIN000029315), DESTINY-PanTumor02 (NCT04482309), DESTINY-CRC02 (NCT04744831), and DESTINY-Lung01 (NCT03505710).

“The clinical benefit seen across several studies supports the potential of [T-DXd] to treat [patients with] any type of HER2-positive metastatic solid cancer,” said Yuki Abe, PhD, head of R&D Division in Japan and head of research at Daiichi Sankyo, in a news release. “We look forward to working with the Japanese health authority to bring the first antibody-drug conjugate [ADC] with a tumor-agnostic indication to patients.”

HERALD Trial Overview

The phase 2, open-label, multicenter, single-arm study evaluated the efficacy and safety of T-DXd at 5.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity in patients with unresectable, advanced or recurrent solid tumors refractory or intolerant to standard treatments. Patients were also required to have HER2 gene amplification in circulating tumor DNA (ctDNA; n = 62), which includes biliary tract, cervical, endometrial, ovarian, colorectal (CRC), esophageal, salivary gland, gastric, non–small cell lung cancer (NSCLC), pancreatic, prostate, small intestine, urothelial cancer or other tumors.1,2

The confirmed objective response rate (ORR) by investigator assessment was 56.5% (95% CI, 43.3%-69.0%), which demonstrated a value beyond the 5% threshold.2 Notably, the best overall responses included partial response (PR; 56.5%), stable disease (SD; 33.9%), and progressive disease (PD; 9.7%). The median progression-free survival (PFS) per investigator assessment was 7.0 months (95% CI, 4.9-9.7), and 71% of patients experienced disease progression.

The study’s primary end point was confirmed ORR per investigator assessment; secondary end points included duration of response (DOR), disease control rate (DCR), PFS, time to treatment failure, overall survival (OS), ORR by ICR, and safety.1

DESTINY-PanTumor02 Overview

The phase 2, open-label, global, multicenter study investigated the efficacy and safety of T-DXd for patients with previously treated HER2-expressing tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, or other tumors.

Across 7 tumor cohorts, patients (n = 267) were treated with intravenous T-DXd at 5.4 mg/kg once every 3 weeks.3 At a median follow-up of 12.75 months, the ORR in all patients (n = 267) was 37.1% (95% CI, 31.3%-43.2%). The median DOR was 11.3 months (95% CI, 9.6-17.8); the median PFS was 6.9 months (95% CI, 5.6-8.0); and the median OS was 13.4 months (95% CI, 11.9-15.5). Specifically, patients with HER2 immunohistochemistry (IHC) 3+ expression (n = 75) had an ORR of 61.3% (95% CI, 49.4%-72.4%), a median DOR of 22.1 months (95% CI, 9.6-not reached), a median PFS of 11.9 months (95% CI, 8.2-13.0), and a media OS of 21.1 months (95% CI, 15.3-29.6).

The primary end point of the study was is confirmed ORR per investigator assessment; secondary end points include DOR, DCR, PFS, OS, safety, and pharmacokinetics.

DESTINY-CRC02 Overview

The phase 2 global, multicenter, two-arm, randomized study assessed the efficacy and safety of 2 doses of T-DXd at 5.4 mg/kg and 6.4 mg/kg in patients with unresectable or metastatic HER2-positive CRC who harbored BRAF wild-type, RAS wild-type, or RAS-mutant tumor types and had previously received standard therapy.1 The study was conducted in 2 stages, in which patients in the stage 1 portion (n = 80) were randomly assigned 1:1 to receive either 5.4 mg/kg or 6.4 mg/kg of T-DXd. Additional patients (n = 42) were enrolled in the 5.4 mg/kg arm in the stage 2 portion of the study.

The median duration of follow-up was 8.9 months (IQR, 6.7-10.5) in the 5.4 mg/kg arm and 10.3 months (IQR, 5.9-12.7) in the 6.4 mg/kg arm.4 The confirmed ORR per blinded independent central review (BICR) was 37.8% (95% CI, 27.3%-49.2%) and 27.5% (95% CI, 14.6%-43.9%) in the 5.4 mg/kg and 6.4 mg/kg arms, respectively.

Confirmed ORR per BICR was the study’s primary end point, and DOR, DCR, investigator-assessed confirmed ORR, clinical benefit ratio, PFS, OS, and safety were the secondary end points.1

DESTINY-Lung01 Overview

The phase 2, global, multicenter, two-arm, randomized study evaluated the efficacy and safety of T-DXd at the same 2 doses of 5.4 mg/kg and 6.4 mg/kg in patients with HER2-mutant (cohort 2, n = 91) or HER2 overexpressing (IHC 3+ or IHC 2+; cohort 1 and 1a, n = 90) unresectable or metastatic NSCLC who experienced disease progression after 1 or more systemic therapy.

In cohorts 1 and 1a, the median treatment duration was 4.1 months (IQR, 1.4-7.1) and 5.5 months (IQR, 1.4-8.7) in cohorts 1 and 1a, respectively.5 The confirmed ORR per ICR was 26.5% (95%, 15.0%-41.1%), all being PRs in cohort 1, and 34.1% (95% CI, 20.1%-50.6%), with 2 complete responses and 12 PRs. In cohort 2, the median follow-up was 13.1 months (range, 0.7-29.1).6 The centrally confirmed ORR was 55% (95% CI, 44%-65%), and the median DOR was 9.3 months (95% CI, 5.7-14.7).

The primary end point of the study was confirmed ORR per ICR; secondary end points included DOR, DCR, PFS, OS, and safety.1

References

1. Enhertu supplemental new drug application submitted in Japan for patients with HER2 positive metastatic solid tumors. News release. Daiichi Sankyo. April 24, 2025. Accessed April 24, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202504/20250424_E.pdf
2. 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(32):3817-3825. doi:10.1200/JCO.23.02626
3. 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(1):47-58. doi:10.1200/JCO.23.02005
4. 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(9):1147-1162. doi:10.1016/S1470-2045(24)00380-2
5. 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(4):439-454. doi:10.1016/S1470-2045(24)00064-0
6. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431