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Accelerated Approval of Tucatinib With Trastuzumab for Colorectal Cancer

The FDA granted accelerated approval to tucatinib in combination with trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

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Efficacy was evaluated in 84 patients in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. Patients were required to have HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, and an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb). Patients whose tumors were deficient in mismatch repair (dMMR) proteins or were microsatellite instability-high (MSI-H) must also have received an anti-programmed cell death protein-1 mAb. Patients who received prior anti-HER2 targeting therapy were excluded.


Patients received tucatinib 300 mg orally twice daily with trastuzumab (or a non-U.S. approved trastuzumab product) administered at a loading dose of 8 mg/kg intravenously on Day 1 of Cycle 1 followed by a maintenance dose of trastuzumab 6 mg/kg on Day 1 of each subsequent 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.


The major efficacy measures were overall response rate (ORR) and duration of response (DOR) as assessed by a blinded independent central review (RECIST version 1.1.). ORR was 38 percent (95% CI: 28, 49) and median DOR was 12.4 months (95% CI: 8.5, 20.5).


The most common adverse events (>=20%) were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. The most common laboratory abnormalities (>=20%) were increased creatinine, increased glucose, increased ALT, decreased hemoglobin, increased AST, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.


The recommended tucatinib dose is 300 mg taken orally twice daily in combination with trastuzumab until disease progression or unacceptable toxicity.


This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration. The application review is ongoing at the other regulatory agency.


Rare Pediatric Disease Designation for OR-449 for Pediatric Adrenocortical Carcinoma

The FDA has granted Rare Pediatric Disease Designation of OR-449 for the treatment of pediatric adrenocortical carcinoma (ACC). OR-449 is a selective, first-in-class, potent, and orally bioavailable small molecule antagonist to steroidogenic factor-1 (SF-1 or NR5A1), an orphan nuclear receptor and transcription factor that is essential for the growth and development of the adrenal gland. Researchers are developing OR-449 for both the adult and pediatric forms of ACC, as well as other cancers known to express a high level of SF-1.


ACC is a rare and aggressive cancer of the adrenal gland. Surgical removal of an affected adrenal gland is an effective treatment if the tumor has not metastasized. Once an ACC tumor becomes metastatic, as it does for most patients, it is difficult to control and 5-year survival in both adult and pediatric patients with metastatic disease is low, about 10-20 percent. The estimated annual incidence of ACC in the U.S. is 600 patients/year. In clinical practice, SF-1 is widely used as a marker for ACC, and it is recognized as a potential therapeutic target for both adult and pediatric ACC. SF-1 is commonly amplified at the gene level in pediatric ACC, and SF-1 is recognized as a cell lineage marker in the FDA's Pediatric Cancer Target List.


IND Application for a Next-Generation Farnesyl Transferase Inhibitor

The FDA cleared the Investigational New Drug application for KO-2806, a next-generation farnesyl transferase inhibitor (FTI), for the treatment of advanced solid tumors. The research intends to evaluate the safety, tolerability, and preliminary antitumor activity of KO-2806 in a Phase I first-in-human study as a monotherapy and in combination with other targeted therapies.


The Phase I first-in-human study is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of KO-2806 when administered as a monotherapy and in combination therapy for adult patients with advanced solid tumors. Following completion of the dose-escalation as a monotherapy, researchers plan to evaluate KO-2806 in dose-escalation combination cohorts in advanced solid tumors. Researchers expect to initiate the Phase I study in the third quarter of 2023.


KO-2806 is a potent next-generation inhibitor of farnesyl transferase designed to improve upon the potency, pharmacokinetic, and physicochemical properties of earlier FTI drug candidates. Research has demonstrated encouraging clinical activity in HRAS-mutant head and neck squamous cell carcinoma (HNSCC) via farnesyl transferase inhibition with tipifarnib and is currently evaluating tipifarnib in combination with the PI3K[alpha] inhibitor alpelisib to address larger genetic subsets of HNSCC patients. In addition, preclinical data is supportive of FTIs in combination with other targeted therapies to potentially overcome or prevent the emergence of drug resistance to certain classes of drugs.


Fast Track Designation for Endometrial Carcinoma With HER2 Overexpression

The FDA has granted Fast Track designation to DB-1303 for the treatment of patients with advanced, recurrent, or metastatic endometrial carcinoma with HER2 overexpression who have progressed on or after standard systemic treatment. DB-1303 is a novel antibody-drug conjugate comprised of an anti-HER2 monoclonal antibody, enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor P1003. It is designed to have potent anti-tumor activity and bystander killing effect, high plasma stability, low free payload in circulation, and a wide therapeutic index.


Researchers are currently evaluating DB-1303 in an ongoing Phase I/IIa clinical trial for preliminary safety and efficacy in advanced/metastatic solid tumors with HER2 expression, including both HER2-positive and HER2-low patients.


DB-1303, a third-generation HER2 ADC molecule built from a proprietary DITAC platform, exhibited potent antitumor activity in both HER2-positive and HER2-low tumor models with superior efficacy, safety, and expanded therapeutic window. Both preclinical data and preliminary clinical data suggest the potential of DB-1303 to address unmet medical needs in various HER2-expressing cancers.