FDA Grants Breakthrough Therapy Designations to Trastuzumab Deruxtecan for HER2+ Solid Tumors, Including mCRC

The FDA has granted 2 breakthrough therapy designations to fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with unresectable or metastatic HER2-positive solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, and for those with HER2-positive metastatic colorectal cancer (mCRC) who have received at least 2 prior lines of therapy. Both designations require HER2 positivity of immunohistochemistry (IHC) 3+.¹

Results from the phase 2 DESTINY-PanTumor02 (NCT04482309), as well as the DESTINY-CRC01 (NCT03384940) and DESTINY-CRC02 (NCT04744831) trials, served as the basis for the solid tumor and CRC designations, respectively.

“[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, R&D, Daiichi Sankyo, stated in a news release. “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.”

DESTINY-PanTumor02 is a global, multicenter, multicohort, open-label phase 2 trial evaluating the efficacy and safety of 5.4 mg/kg of trastuzumab deruxtecan in patients with HER2-expressing tumors (IHC 3+ or IHC 2+), including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, and other tumors.

The primary end point of the trial is confirmed, investigator-assessed objective response rate (ORR). Secondary end points include duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety, tolerability, and pharmacokinetics.

Primary results, which were presented during the 2023 ASCO Annual Meeting, demonstrated that 37.1% of patients (n = 267) achieved an objective response; complete response (CR) occurred in 5.6% (n = 15) of patients, 31.5% (n = 84) experienced partial response (PR), and 46.1% (n = 123) had stable disease. The DCR was 68.2%, and median DOR was 11.8 months (95% CI, 9.8-not estimable [NE]). The highest activity was seen in patients with HER2 IHC 3+, with an ORR of 61.3% and median DOR of 22.1 months (95% CI, 9.3-NE).²

DESTINY-CRC01 is a global, phase 2, open-label, multicenter trial, which evaluated the efficacy and safety of 6.4 mg/kg of trastuzumab deruxtecan in patients with HER2-expressing unresectable and/or mCRC.

The primary end point of the main cohort of DESTINY-CRC01, which enrolled 53 patients with HER2-positive (IHC 3+ or IHC 2+/in-situ hybridization [ISH]+) mCRC, was confirmed ORR as assessed by independent central review. Secondary end points included DCR, DOR, PFS, OS and safety.

Final results from the trial, which were presented at the 2022 Gastrointestinal Cancers Symposium with median follow-up of 62.4 weeks, demonstrated that the confirmed ORR was 45.3% (95% CI, 31.6%-59.6%) and the DCR was 83.0% (95% CI, 70.2%-91.9%). Median DOR was 7.0 months (95% CI, 5.8-9.5), median PFS was 6.9 months (95% CI, 4.1-8.7), and median OS was 15.5 months (95% CI, 8.8-20.8). Additional results demonstrated confirmed ORRs of 43.8% (95% CI, 19.8%-70.1%) in patients with prior anti-HER2 therapy, 57.5% (95% CI, 40.9%-73.0%) in patients with HER2 IHC 3+, and 7.7% (95% CI, 0.2%-36.0%) in patients with HER2 IHC 2+/ISH+ disease.³

DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter phase 2 trial evaluating the efficacy and safety of both 5.4 mg/kg and 6.4 mg/kg of trastuzumab deruxtecan in patients with locally advanced, unresectable or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH+) CRC. Eligible patients must have had BRAF wild-type, RAS wild-type, or RAS-mutant tumors previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (n = 80) were randomly assigned to receive 5.4 mg/kg or 6.4 mg/kg of trastuzumab deruxtecan. In the second stage, 42 additional patients were enrolled in the 5.4 mg/kg arm.

The primary end point of the trial is confirmed ORR as assessed by blinded independent central review. Secondary end points include DOR, DCR, investigator-assessed confirmed ORR, clinical benefit rate, PFS, OS, and safety.

Data presented at the 2023 ASCO Annual Meeting indicated that the confirmed ORR 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. At median follow-up of 8.9 months (range, 0.5-17.1) in the 5.4 mg/kg arm and 10.3 months (range, 0.7-16.4) in the 6.4 mg/kg arm, median DOR was 5.5 months (95% CI, 4.2-8.1) and 5.5 months (95% CI, 3.7-NE). Median PFS was 5.8 months (95% CI, 4.6-7.0) and 5.5 months (95% CI, 4.2-7.0) in the lower and higher dose arms, respectively.

In the 5.4-mg/kg arm, the ORR was 46.9% (95% CI, 34.3%-59.8%) in the HER2 IHC 3+ population vs 5.6% (95% CI, 0.1%-27.3%) in the IHC 2+/ISH+ population. In the 6.4 mg/kg arm, the ORR was 29.4% (95% CI, 15.1%-47.5%) in the IHC 3+ population vs 16.7% in the IHC 2+/ISH+ population. Responses were also seen in patients who had received prior anti-HER2 therapy, at 41.2% (95% CI, 18.4%-67.1%) and 40.0% (95% CI, 12.2%-73.8%) in the lower and higher dose cohorts, respectively.⁴

“This is an important step in bringing [trastuzumab deruxtecan] to patients with a broad range of HER2 expressing solid tumors who currently face a poor prognosis,” Susan Galbraith, MBBChir, PhD, executive vice president, Oncology R&D, AstraZeneca, added in the press release. “We are encouraged by the recently reported results from our pan tumor and colorectal cancer 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.”¹

References

1. Enhertu granted two breakthrough therapy designations in US for patients across multiple HER2 expressing cancers. News release. Daiichi Sankyo. August 31, 2023. Accessed August 31, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202308/20230831_E2.pdf
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. doi:10.1200/JCO.2023.41.17_suppl.LBA3000
3. Yoshino T, Di Bartolomeo M, Raghav KPS, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2022;40(suppl 4):119. doi:10.1200/JCO.2022.40.4_suppl.119
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