FDA grants breakthrough status to T-DXd for two HER2-positive cancers

Enhertu, AstraZeneca, Breakthrough Therapy Designations, HER2-positive cancers, Daiichi Sankyo, antibody drug conjugate, Trastuzumab Deruxtecan

Daiichi Sankyo and AstraZeneca have garnered FDA Breakthrough Therapy Designations (BTDs) for their Enhertu (T-DXd) therapy to treat two distinct forms of HER2-positive cancer, as per their joint announcement.

The first BTD is for adult patients afflicted with unresectable or metastatic HER2-positive solid tumors who have experienced progression after their previous treatments and have exhausted all other viable therapeutic options. The second BTD pertains to the treatment of patients with HER2-positive metastatic colorectal cancer (mCRC) who have previously undergone at least two regimens of treatment.

“ENHERTU is the first HER2 directed therapy to demonstrate a potential benefit across a series of difficultto-treat cancers and these designations are recognition of the continued potential of this innovative medicine. We remain committed to exploring additional opportunities for ENHERTU in these tumor types with the goal of bringing this treatment to more patients as soon as possible.”

– Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo

The award of both BTDs is underpinned by promising clinical trial results. For the HER2-positive solid tumors group, the BTD is rooted in findings from the phase 2 DESTINY-PanTumor02 study (NCT04482309). Among the 267 patients observed over a median follow-up period of 9.7 months, treatment with T-DXd demonstrated an impressive objective response rate (ORR) of 37.1% and a median duration of response (mDOR) of 11.9 months. In the subset of patients with immunohistochemistry (IHC) 3+, the ORR surged to 61.3%, with a mDOR of 22.1 months. These results were described as encouraging by the study’s investigators, highlighting the therapy’s durable clinical benefits. These findings were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

Safety observations from DESTINY-PanTumor02 indicated that 58.4% of patients encountered grade 3 or higher adverse events (AEs). Additionally, treatment-related interstitial lung disease or pneumonitis occurred in 6.7% of patients, primarily presenting as low-grade cases.

“This is an important step in bringing ENHERTU to patients with a broad range of HER2 expressing solid tumors who currently face a poor prognosis. We are encouraged by the recently reported results from our pantumor 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.” 

– Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca

The DESTINY-PanTumor02 study remains ongoing with a target enrollment of 468 patients bearing HER-expressing solid tumors, including bladder cancer, biliary tract cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, and rare HER2-expressing tumors. The primary endpoint being explored in the trial is ORR, with secondary endpoints encompassing DOR, disease control rate, progression-free survival (PFS), 6- and 1-month PFS rates, overall survival (OS), 6- and 12-month OS rates, the incidence of AEs, pharmacokinetics, and the immunogenicity of T-DXd concerning the presence of anti-drug antibodies.

Eligible participants must be aged 18 years or older, diagnosed with locally advanced, unresectable, or metastatic HER2-expressing solid tumors, and must have progressed on prior therapy. Measurable disease pre-RECSIT v1.1 and adequate cardiac, renal, and hepatic function are also prerequisites for enrollment.

The BTD for the HER2-positive mCRC patient population is founded on data derived from the phase 2 DESTINY-CRC01 study (NCT03384940), with final results published in Nature Communications. In cohort A of the study, encompassing patients with HER-positive mCRC characterized by IH3+ or IHC 2+, the confirmed ORR reached an impressive 45.3%. The mDOR recorded was 7.0 months. Furthermore, T-DXd demonstrated a survival benefit for these patients, with a median PFS of 6.9 months (95% CI, 4.1-8.7 months) and a median OS of 15.5 months (95% CI, 8.8-20.8 months).

Safety outcomes revealed that neutrophil count and anemia represented the most prevalent grade 3 or higher AEs, while treatment-related interstitial lung disease/pneumonitis occurred in 9.3% of patients.

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