SUMMARY: The FDA on August 11, 2022, granted accelerated approval to ENHERTU® (fam-trastuzumab deruxtecan-nxki), for adult patients with unresectable or metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have activating human Epidermal Growth Factor Receptor 2 or HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC. FDA also approved Oncomine™ Dx Target Test (tissue) and Guardant360® CDx (plasma) as companion diagnostics for ENHERTU®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.
The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including Breast, Gastric, Lung and Colorectal cancers. It is a growth-promoting protein, and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types. However, HER2 overexpression and gene amplification are associated with distinct molecular entities and have limited therapeutic value in lung cancer.
HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers and are detected in 2 to 4% of NSCLCs. They are more often detected in younger, female and never-smokers, and almost exclusively in Adenocarcinomas. Next-generation sequencing is used to identify HER2 mutations. Majority of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth, aggressive form of disease and poor prognosis, and with an increased incidence of brain metastases. There are currently no therapies approved specifically for the treatment HER2 mutant NSCLC and is therefore an unmet need.
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 HERCEPTIN® (Trastuzumab), attached to a potent cytotoxic Topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker. 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), which is also an Antibody-Drug Conjugate, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), the 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, minimizing systemic exposure. ENHERTU® is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-positive or HER2-Low breast cancer and locally advanced or metastatic HER2-positive Gastric or GastroEsophageal Junction adenocarcinoma who have received a prior Trastuzumab based regimen. Translational research demonstrated that HER2-mutant NSCLC may preferentially internalize the HER2 receptor Antibody-Drug Conjugate complex regardless of HER2 protein expression and overcome resistance to other HER2-targeted agents.
In the DESTINY-Lung01 Phase II, open-label, two-cohort trial of heavily pretreated population of patients with HER2-mutated advanced NSCLC, treatment with ENHERTU® 6.4 mg/kg given by IV infusion every 3 weeks resulted in an Objective Response Rate (ORR) of 55%, with a median Duration of Response was 9.3 months. Responses were observed across different HER2 mutation subtypes. The median PFS was 8.2 months, and the median OS was 17.8 months (NEJM 2022;386:241-251).
The present FDA approval was based on DESTINY-Lung02, which is a global, multicenter, multi-cohort, randomized, blinded, dose-optimization, Phase II trial, in which the safety and efficacy of two doses ENHERTU® (5.4mg/kg or 6.4mg/kg) was evaluated, in patients with HER2 mutated metastatic NSCLC, with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. This study enrolled 152 patients (N=152) and patients were selected for treatment with ENHERTU® based on the presence of activating HER2 (ERBB2) mutations in a tumor specimen. Patients were randomized to receive ENHERTU® 6.4 mg/kg or 5.4 mg/kg by IV infusion every 3 weeks, until unacceptable toxicity or disease progression. The Primary endpoint of the trial was Objective Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DoR), Progression Free Survival (PFS), Overall Survival (OS) and Safety. The primary/interim efficacy analysis included a pre-specified cohort of 52 patients (N=52). The median age in this cohort was 58 years, 69% were female; 79% were Asian, 12% were White, and 10% were of other races.
ENHERTU® 5.4mg/kg IV demonstrated a confirmed Objective Response Rate of 57.7%, with a Complete Response Rate of 1.9%, Partial Response Rate of 55.8%, and median Duration of Response of 8.7 months. The most common adverse effects included nausea, alopecia, increased AST and ALT, cytopenias, and was consistent with previous clinical trials, with no new safety concerns identified.
It was concluded that ENHERTU® is the first HER2-directed treatment option for patients with HER2 mutated NSCLC, and fulfills an unmet medical need in this patient population.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
