FDA Grants Priority Review to Trastuzumab Deruxtecan for HER2-Positive Solid Tumors

US FDA

The FDA has granted priority review to a supplemental biologics license application (sBLA) seeking the approval of the HER2-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior treatment or for whom no satisfactory treatment alternatives exist.¹

The sBLA is based on findings from the phase 2 DESTINY-PanTumor02 trial (NCT04482309), in which T-DXd elicited durable and clinically meaningful responses in previously treated patients with a range of HER2-expressing (IHC 3+/2+) metastatic solid tumors, including bladder, biliary tract, endometrial, cervical, and ovarian cancers.

At a median follow-up of 12.75 months, the overall response rate (ORR) in all patients (n = 267) was 37.1% (95% CI, 31.3%-43.2%), and responses were observed in all cohorts.² The median duration of response (DOR) was 11.3 months (95% CI, 9.6-17.8), the median progression-free survival (PFS) was 6.9 month (95% CI, 5.6-8.0), and the median overall survival (OS) was 13.4 months (95% CI, 11.9-15.5). In patients with IHC 3+ HER2 expression per central review (n = 75), the ORR was 61.3% (95% CI, 49.4%-72.4%), the median DOR was 22.1 months (95% CI, 9.6-NR), the median PFS was 11.9 months (95% CI, 8.2-13.0), and the median OS was 21.1 months (95% CI, 15.3-29.6).

The priority review was also supported by data with T-DXd from the phase 2 DESTINY-Lung01 (NCT03505710) and DESTINY-CRC02 (NCT04744831) trials.¹

“The clinical benefit seen across HER2-expressing metastatic solid tumors in the DESTINY-PanTumor02 trial and ongoing data from the [T-DXd] clinical development program continues to demonstrate the potential of this medicine beyond its approved indications,” Ken Takeshita, MD, global head of Research and Development at Daiichi Sankyo, stated in a news release. “If approved, [T-DXd] could become the first HER2-directed therapy and ADC with a tumor-agnostic indication, providing patients with a potential new treatment option.”

Under the Prescription Drug User Fee Act, the FDA will decide on the sBLA by the second quarter of 2024. The sBLA is being reviewed under the Real-Time Oncology Review program and Project Orbis.

“Today’s priority review for the first tumor-agnostic submission for [T-DXd] reflects the potential of this medicine to redefine the treatment of HER2-expressing cancers,” Susan Galbraith, executive vice president of Oncology Research and Development at AstraZeneca, added in the news release. “Biomarkers for HER2 expression are already established in breast and gastric cancers, but we must now define them across tumor types. We will continue working closely with the FDA to bring this potential first tumor-agnostic HER2-targeted medicine and biomarker to patients as quickly as possible.”

Findings from the global, multicenter, multicohort, open-label DESTINY-PanTumor02 were presented at the 2023 ESMO Congress and simultaneously published in the Journal of Clinical Oncology. This trial assessed the efficacy and safety of T-DXd at 5.4 mg/kg in patients across multiple sites in Asia, Europe, and North America with HER2-expressing solid tumors, including bladder, biliary tract, cervical, ovarian, endometrial, and pancreatic cancers.

Investigator-assessed confirmed ORR (cORR) served as the primary end point of DESTINY-PanTumor02, with DOR, disease control rate (DCR), PFS, OS, safety, tolerability, and pharmacokinetics serving as key secondary end points.

The global, open-label, 2-cohort DESTINY-Lung01 trial investigated the efficacy and safety of T-DXd at 5.4 mg/kg and 6.4 mg/kg in 181 patients across multiple sites in Asia, Europe, and North America with HER2-overexpressing (cohorts 1 and 1a; n = 90) and HER2-mutant (cohort 2; n = 91) metastatic non–small cell lung cancer who had progressed after at least 1 systemic therapy. ORR by blinded independent central review (BICR) served as the primary end point, with key secondary end points of DCR, DOR, PFS, OS, and safety. At a median follow-up of 13.1 months (range, 0.7-29.1), the cORR in cohort 2 with T-DXd administered at 6.4 mg/kg was 55% (95% CI, 44%-65%).³ The median DOR, PFS, and OS was 9.3 months (95% CI, 5.7-14.7), 8.2 months (95% CI, 6.0-11.9), and 17.8 months (95% CI, 13.8-22.1), respectively.

The global, randomized, 2-arm, multicenter, parallel, 2-stage DESTINY-CRC02 trial assessed the efficacy and safety of T-DXd in 122 patients across Asia, Europe, and North America with locally advanced, metastatic or unresectable HER2-positive, BRAF wild-type CRC or RAS wild-type/RAS-mutant tumors previously treated with standard therapy. In stage 1, patients (n = 80) were randomly assigned 1:1 to receive T-DXd at 5.4 mg/kg or 6.4 mg/kg. In stage 2, additional patients (n = 42) were enrolled in the 5.4 mg/kg arm. cORR by BICR served as the primary end point of this trial, with DCR, DOR, investigator-assessed cORR, PFS, OS, clinical benefit rate, and safety as key secondary end points.

At respective median follow-ups of 8.9 months (range, 0.5-17.1) and 10.3 months (range, 0.7-16.4), the cORR was 37.8% (95% CI, 27.3%-49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6%-43.9%) in the 6.4 mg/kg arm.⁴ All responses were PRs in both arms. In the 5.4 mg/kg arm, the median DOR and PFS were 5.5 months (95% CI, 4.3-8.1) and 5.8 months (95% CI, 4.6-7.0), respectively. In the 6.4 mg/kg arm, the median DOR and PFS were 5.5 months (95% CI, 3.7-NE) and 5.5 months (95% CI, 4.2-7.0), respectively.

The safety profile of T-DXd observed across DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 was consistent with that seen in previous trials with this agent, and no new safety signals were identified.¹ In DESTINY-PanTumor02, 40.8% of patients experienced grade 3 or higher treatment-related adverse effects (TRAEs), and 10.5% of patients had adjudicated drug-related interstitial lung disease (ILD).² These respective values were 46% and 26% in DESTINY-Lung01.³ In DESTINY-CRC02, the rates of grade 3 or higher TRAEs were 49.4% and 59.0% in the 5.4 mg/kg and 6.4 mg/kg arms, respectively, and the respective rates of adjudicated drug-related ILD were 8.4% and 12.8%.⁴

This priority review designation follows the August 2023 FDA breakthrough therapy designation for T-DXd in patients with metastatic HER2-positive solid tumors.¹

References

1. Enhertu granted priority review in the US for patients with metastatic HER2-positive solid tumors. News Release. AstraZeneca. January 29, 2023. Accessed January 29, 2023. https://www.astrazeneca.com/media-centre/press-releases/2024/enhertu-granted-priority-review-in-the-us-for-patients-with-metastatic-her2-positive-solid-tumours.html#
2. 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
3. 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
4. Raghav KPS, Siena S, Takashima A, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study. J Clin Oncol. 2023;41(suppl 16):3501. doi:10.1200/JCO.2023.41.16_suppl.3501