Antibody-Drug Conjugate Receives Two FDA BTDs in HER2+ Solid Malignancies

Investigators of the DESTINY-PanTumor02 study (NCT04482309) evaluated trastuzumab deruxtecan in a population of 268 patients at the 5.4 mg/kg dose level across several disease types with HER2 expression, such as biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic cancer.

The FDA has given breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of HER2-positive unresectable or metastatic solid malignancies that have progressed with no adequate alternative solutions, as well as HER2-positive metastatic colorectal cancer (CRC) following 2 or more previous treatments, according to a press release from Daiichi-Sankyo.¹

The antibody-drug conjugate’s breakthrough therapy designations were supported by 2 studies. The solid tumor indication was backed by data from the phase 2 DESTINY-PanTumor02 study (NCT04482309).² Data from the trial’s interim analysis indicated that patients treated with the agent experienced an overall response rate (ORR) of 37.1% in the overall cohort, as well as 61.3% in the population with an immunohistochemistry (IHC) expression of 3+.

Moreover, patients in the overall population achieved a complete response (CR) rate of 5.6%, a partial response rate of 31.5%, and a stable disease rate of 46.1%; 15.7% had progressive disease. The median duration of response (DOR) in the overall and IHC 3+ populations, respectively, were 11.8 months (95% CI, 9.8-non-estimable [NE]) and 22.1 months (95% CI, 9.3-NE).

It was also reported that trastuzumab deruxtecan’s CRC indication was supported by data from the phase 2 DESTINY-CRC02 study (NCT04744831).³ In a population of patients with HER2-positive locally advanced, unresectable or metastatic CRC who were treated with 5.4 mg/kg and 6.4 mg/kg of the agent, respectively, the ORR was 37.8% (95% CI, 27.3%-49.2%) and 27.5% (95% CI, 14.6%-43.9%). There were no CRs at either dose level.

“[Trastuzumab deruxtecan] is the first HER2 directed therapy to demonstrate a potential benefit across a series of difficult-to-treat cancers and these designations are recognition of the continued potential of this innovative medicine,” Ken Takeshita, MD, global head of Research and Development at Daiichi Sankyo, said in the press release.¹ “We remain committed to exploring additional opportunities for [trastuzumab deruxtecan] in these tumor types with the goal of bringing this treatment to more patients as soon as possible.”

Investigators of the DESTINY-PanTumor02 study evaluated trastuzumab deruxtecan in a population of 268 patients at the 5.4 mg/kg dose level across several disease types with HER2 expression, such as biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic cancer. The trial’s primary end point was ORR by investigator assessment, with key secondary end points including DOR, progression-free survival, overall survival, disease control rate, safety, and tolerability.

Investigators of the DESTINY-CRC02 study indicated that 80 patients were included in the first part of the study who were randomly assigned 1:1 to receive either 5.4mg/kg or 6.4 mg/kg of trastuzumab deruxtecan, while those in the study’s second stage (n = 42) received 5.4 mg/kg.

“This is an important step in bringing [trastuzumab deruxtecan] to patients with a broad range of HER2 expressing solid tumors who currently [have] a poor prognosis,” Susan Galbraith, MBBChir, PhD, executive vice president of Oncology Research and Development at AstraZeneca, concluded.¹ “We are encouraged by the recently reported results from our pan tumor and [CRC] trials that contributed to these designations, and we look forward to working closely with the FDA to provide these patients with a potential new targeted treatment option.”

References

1. ENHERTU® granted two breakthrough therapy designations in U.S. for patients across multiple HER2 expressing cancers. News release. Daiichi-Sankyo. August 31, 2023. Accessed September 6, 2023. https://bit.ly/3sNNP0c
2. Meric-Bernstam F, Makker V, OakninA, 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. doi:10.1200/JCO.2023.41.17_suppl.LBA3000
3. Raghav K, 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