SUMMARY: The FDA on April 5, 2024, granted accelerated approval to ENHERTU® (fam-Trastuzumab Deruxtecan-nxki) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment, and have no satisfactory alternative treatment options. This tumor agnostic indication was approved based on Objective Response Rate and Duration of Response.
The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor growth-promoting protein and is involved in normal cell growth. It is expressed on the surface of various tissue cells throughout the body. In some cancers, HER2 expression is amplified or the cells have activating mutations. HER2 gene amplification can result in HER2 protein overexpression which is often associated with aggressive disease and poor prognosis. Approximately 15-20% of invasive breast cancers as well as advanced Gastric and GastroEsophageal (GE) junction cancers overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody. Additionally, HER2 directed therapies have been used to treat lung and colorectal cancers. HER2 is an emerging biomarker in other solid tumor types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers with HER2 positive expression rates varying from 1-28%. There are currently no approved HER2 directed therapies for these cancers following progression on standard of care therapies. There is an unmet need for effective therapies for these HER2 expressing tumor types.
ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), another ADC targeting HER2, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.
The FDA approval was based on the efficacy of ENHERTU® in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831). All three trials excluded patients with a history of Interstitial Lung Disease /pneumonitis requiring treatment with steroids or Interstitial Lung Disease /pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for active brain metastases or ECOG performance status more than 1. Treatment was administered until disease progression or unacceptable toxicity. The major efficacy outcome measure in all three trials was confirmed Objective Response Rate (ORR), and an additional efficacy outcome was Duration of Response (DOR). All outcomes were assessed by Independent Central Review based on RECIST criteria.
DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label, ongoing Phase II trial evaluating the efficacy and safety of ENHERTU® 5.4 mg/kg IV for the treatment of previously treated HER2 expressing tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumors. DESTINY-PanTumor02 enrolled 267 patients (N=267) at multiple sites in Asia, Europe and North America. Patients had received a median of two prior cancer therapies. In this study, the ORR was 51.4% and median DOR was 19.4 months.
DESTINY-Lung01 is a global, open-label, two-cohort, Phase II trial evaluating the efficacy and safety of ENHERTU® 6.4 mg/kg IV and 5.4 mg/kg IV in patients with HER2 mutant (cohort 2, N=91) or HER2 overexpressing (cohort 1 and 1a, N=90) (defined as IHC 3+ or IHC 2+) unresectable or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC), who had progressed after one or more systemic therapies. In this study, the ORR was 52.9% and the median DOR was 6.9 months.
DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter Phase II trial evaluating the efficacy and safety of two doses, 5.4 mg/kg IV or 6.4 mg/kg IV of ENHERTU® in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumor types, previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (N=80) were randomized 1:1 to receive either 5.4 mg/kg IV or 6.4 mg/kg IV of ENHERTU®. In the second stage, additional patients (N=42) were enrolled in the 5.4 mg/kg IV arm. In DESTINY-CRC02, ORR was 46.9%, and DOR was 5.5 months.
The most common adverse reactions were cytopenias, nausea, vomiting, fatigue, liver function abnormalities and upper respiratory tract infection. The recommended dose of ENHERTU® for this indication is 5.4 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity.
The forementioned trials validate HER2 as an actionable biomarker across a broad range of tumor types, and ENHERTU® has the potential to benefit patients with HER2 expressing advanced disease, who may face a poor prognosis and currently have limited treatment options.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2.