FDA fast tracks trastuzumab deruxtecan for HER2+ tumors, including bladder cancer


The application is based on findings from the phase 2 DESTINY-PanTumor02 trial.

The FDA has granted a priority review designation to a supplemental Biologics License Application (sBLA) for trastuzumab deruxtecan (Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-positive solid tumors—including bladder cancer—who have received prior treatment or who have no satisfactory alternative treatment options.1



The sBLA is based on findings from the phase 2 DESTINY-PanTumor02 trial (NCT04482309), which showed that trastuzumab deruxtecan elicited clinically meaningful activity in this patient population.2

Specifically, the study results showed that at the November 16, 2022, data cutoff, patients with cervical (n = 40), endometrial (n = 40), ovarian (n = 40), biliary tract (n = 41) pancreatic (n = 25), bladder (n = 41), and other cancers (n = 40) experienced investigator-assessed overall response rates (ORRs) of 50.0%, 57.5%, 45.0%, 22.0%, 4.0%, 39.0%, and 30.0%, respectively. The complete response (CR) rates were 5.0%, 17.5%, 10.0%, 2.4%, 0%, 2.4%, and 0% respectively.2

The objective response rate (ORR) in the total population (N = 267) was 37.1%, including a 5.6% CR rate. The median progression-free survival (PFS) in the total population was 6.9 months and the median overall survival (OS) was 13.4 months.

In a subgroup of patients with HER2 IHC 3+ expression per central testing (n = 75), trastuzumab deruxtecan elicited an ORR of 61.3%, with a 22.1-month median duration of response (DOR). The median PFS and OS were 11.9 and 21.1 months, respectively, in this subgroup.3

The FDA is scheduled to make a decision on the sBLA during the second quarter of this year.

“Today’s priority review for the first tumor-agnostic submission for Enhertu reflects the potential of this medicine to redefine the treatment of HER2-expressing cancers. 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,” Susan Galbraith stated in a news release.1 Galbraith is executive vice president, Oncology R&D, AstraZeneca, which codevelops trastuzumab deruxtecan with Daiichi Sankyo.

DESTINY-PanTumor02 was an open-label, multicenter study of patients with advanced solid tumors who were not eligible for curative therapy. Patients needed to be in their second line or later of therapy, have a HER2 expression by immunohistochemistry (IHC) of 3+ or 2+, and an ECOG performance status of 1 or 0. Prior HER2-directed therapy was permitted. Trastuzumab deruxtecan was administered at a dose of 5.4 mg/kg every 3 weeks in all cohorts.2

The primary end point was confirmed ORR by investigator. Secondary end points included disease control rate (DCR), DOR, PFS, OS, and safety.

The safety profile of trastuzumab deruxtecan was found to be consistent with the known profile of the agent. In the overall population, common any-grade treatment-emergent adverse events (TEAEs) included nausea (54.3%), fatigue (37.8%), neutropenia (32.6%), anemia (25.8%), diarrhea (25.5%), vomiting (24.3%), decreased appetite (16.5%), thrombocytopenia (16.5%), alopecia (16.1%), and leukopenia (10.1%). These AEs occurred at a grade 3 or higher severity in 3.4%, 6.0%, 19.1%, 8.6%, 3.7%, 1.5%, 1.5%, 5.2%, 0.0%, and 2.6% of patients, respectively.

Regarding interstitial lung disease and pneumonitis related to treatment with trastuzumab deruxtecan, any-grade events were reported in 7.5% of patients. Most instances were grade 2 (4.5%), although grade 1 (2.2%), grade 3 (0.4%), and grade 5 (0.4%) events were also reported.

Additional findings from the study revealed that the median DORs were 9.8 months (95% CI, 4.2-not evaluable [NE]), not reached (NR; 95% CI, 9.9-NE), 11.3 months (95% CI, 4.1-NE), 8.6 months (95% CI, 2.1-NE), not reached, 8.7 months (95% CI, 4.3-11.8), and not reached (95% CI, 4.1-NE) in the cervical, endometrial, ovarian, biliary tract, pancreatic, bladder, and other cohorts, respectively. The 12-week DCR rates were 67.5%, 80.0%, 70.0%, 65.9%, 36.0%, 70.7%, and 75.0%, respectively.

Notably, patients with a HER2 status of IHC 3+ generally experienced heightened response rates. The ORRs among patients with an IHC of 3+ were 75.0%, 84.6%, 63.6%, 56.3%, 0.0%, 56.3%, and 44.4%, in the cervical (n = 8), endometrial (n = 13), ovarian (n = 11), biliary tract (n = 16), pancreatic (n = 2), bladder (n = 16), and other (n = 9) cohorts, respectively. Comparatively, the ORRs for patients with a HER2 of IHC 2+ were 40.0%, 47.1%, 36.8%, 0.0%, 5.3%, 35.0%, and 18.8 % in the cervical (n =20), endometrial (n = 17), ovarian (n = 19), biliary tract (n = 14), pancreatic (n = 19), bladder (n = 20), and other (n = 16) cohorts, respectively.

The median DOR for all patients with an IHC of 3+ was 22.1 months (95% CI, 9.3-NE) and was 9.8 months (95% CI, 4.2-12.6) among those with an IHC of 2+.

“The clinical benefit seen across HER2-expressing metastatic solid tumors in the DESTINY-PanTumor02 trial and ongoing data from the Enhertu clinical development program continues to demonstrate the potential of this medicine beyond its approved indications. If approved, Enhertu could become the first HER2-directed therapy and antibody drug conjugate with a tumor-agnostic indication, providing patients with a potential new treatment option,” Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, stated in a news release.1


1. Enhertu granted Priority Review in the US for patients with metastatic HER2-positive solid tumors. Published online and accessed January 29, 2024. 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 (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41(suppl 17):LBA3000

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

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