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Enobosarm for the Treatment of AR+ ER+ HER2- Metastatic Breast Cancer

The FDA has granted Fast Track Designation to a Phase III registration program for the investigation of enobosarm, a selective androgen receptor targeting agonist, for the treatment of androgen receptor positive, estrogen receptor positive, human epidermal growth factor receptor 2 negative (AR+ER+HER2-) metastatic breast cancer patients who have shown previous disease progression on a nonsteroidal AI, fulvestrant, and CDK 4/6 inhibitor therapy, and who have AR percent nuclei staining >=40 percent in breast cancer tissue (third-line metastatic setting).

FDA, oncology drug a... - Click to enlarge in new windowFDA, oncology drug approvals. FDA, oncology drug approvals

Enobosarm is an oral, first-in-class, new chemical entity, selective androgen receptor agonist that targets the androgen receptor in AR+ ER+HER2- metastatic breast cancer without unwanted masculinizing side effects. The Phase III ARTEST clinical study is evaluating enobosarm for the treatment of third-line metastatic AR+ER+HER2- breast cancer patients whose disease has progressed after treatment with a nonsteroidal aromatase inhibitor, fulvestrant, and a CDK4/6 inhibitor with an androgen.


BDTX-1535 for Treatment of Gliobastoma & Non-Small Cell Lung Cancer

The FDA has cleared an Investigational New Drug (IND) application for its MasterKey inhibitor BDTX-1535, an irreversible, mutant selective, brain-penetrant inhibitor of oncogenic mutations of epidermal growth factor receptor (EGFR) expressed in glioblastoma multiforme (GBM) and intrinsic and acquired resistance EGFR mutations in non-small cell lung cancer (NSCLC). Researchers expect to initiate the Phase I study of BDTX-1535 in the first quarter of 2022 and provide a clinical update in the second half of 2023.


In pre-clinical studies, researchers demonstrated that oncogenic alterations of EGFR, particularly those associated with GBM, result in distinct conformations which impart unique pharmacology and drug resistance. In cell-based assays, BDTX-1535 achieved potent and selective inhibition of a range of EGFR mutations expressed in GBM and NSCLC, including canonical, non-canonical, and drug-resistance mutations, such as EGFR-C797S that can arise following treatment with third-generation EGFR inhibitor. BDTX-1535 demonstrated a favorable brain-penetrant pharmacokinetic profile in animal models. In a range of tumor models, including intracranial GBM models and lung cancer drug resistance models expressing the targeted EGFR mutations, BDTX-1535 showed dose-dependent tumor growth inhibition and achieved complete regression without impact on body weight.


BDTX-1535 is designed as an irreversible, mutant-selective, brain-penetrant MasterKey inhibitor of oncogenic mutations of EGFR expressed in GBM and intrinsic and acquired resistance EGFR mutations in NSCLC. In pre-clinical studies, researchers have demonstrated that oncogenic alterations of EGFR, particularly those associated with GBM, result in distinct conformations which impart unique pharmacology and drug resistance. It is estimated that approximately 50 percent of GBM patients harbor an oncogenic EGFR alteration that has the potential to be addressed by BDTX-1535, representing a potential patient population of greater than 60,000 patients annually across the US, EU, Japan, and China.


NK Cell Therapy CYNK-101 for Gastric & Gastroesophageal Junction Cancers

The FDA has granted Fast Track Designation for a genetically modified cryopreserved human placental hematopoietic stem cell-derived natural killer (NK) cell therapy, CYNK-101, which is being developed in combination with standard chemotherapy, trastuzumab, and pembrolizumab in patients in first-line locally advanced unresectable or metastatic HER2/neu positive gastric or gastroesophageal junction adenocarcinoma. CYNK-101 is an investigational, genetically modified, NK cell therapy designed to synergize with approved antibody therapeutics through enhanced antibody-dependent cellular cytotoxicity.


Fam-Trastuzumab Deruxtecan-Nxki for HER2-Positive Metastatic Breast Cancer

The FDA accepted the supplemental Biologics License Application (sBLA) of fam-trastuzumab deruxtecan-nxki for the treatment of adult patients in the U.S. with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen. The application has also been granted Priority Review.


Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody drug conjugate. The sBLA is being reviewed under the Real-Time Oncology Review (RTOR) program and Project Orbis, two initiatives of the FDA which are designed to bring effective cancer treatments to patients as early as possible. RTOR allows the FDA to review components of an application before submission of the complete application. Project Orbis provides a framework for concurrent submission and review of oncology medicines among participating international partners.


The sBLA is based on data from the pivotal DESTINY-Breast03 Phase III trial that were presented at the 2021 ESMO Congress. In the trial, trastuzumab deruxtecan demonstrated a 72 percent reduction in the risk of disease progression or death compared to T-DM1 (HR=0.28; 95% CI: 0.22-0.37; p=7.8x10-22) in patients with HER2-positive, unresectable, and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The median progression-free survival (PFS) for patients treated with fam-trastuzumab deruxtecan-nxki was not reached (95% CI: 18.5-NE) compared to 6.8 months for T-DM1 (95% CI: 5.6-8.2) as assessed by blinded independent central review.


In the secondary endpoint analysis of PFS assessed by investigators, patients treated with trastuzumab deruxtecan experienced an improvement in PFS of 25.1 months (95% CI: 22.1-NE) compared to 7.2 months (95% CI: 6.8-8.3) for T-DM1 (HR=0.26; 95% CI: 0.20-0.35). There was a strong trend towards improved overall survival with fam-trastuzumab deruxtecan-nxki (HR=0.56; 95% CI: 0.36-0.86; p=0.007172). However, this analysis is not yet mature and is not statistically significant. Nearly all patients treated with fam-trastuzumab deruxtecan-nxki during the trial were alive at 1 year (94.1%; 95% CI: 90.3-96.4) compared to 85.9 percent of patients treated with T-DM1 (95% CI: 80.9-89.7). Confirmed objective response rate was more than doubled in the fam-trastuzumab deruxtecan-nxki arm versus the T-DM1 arm (79.7%; n=208; 95% CI: 74.3-84.4 versus 34.2%; n=90; 95% CI: 28.5-40.3; p<0.0001).


The safety profile of the most common adverse events with fam-trastuzumab deruxtecan-nxki in DESTINY-Breast03 was consistent with previous clinical trials with no new safety concerns identified. The most common Grade 3 or higher drug-related treatment emergent adverse events in the fam-trastuzumab deruxtecan-nxki arm were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), vomiting (1.6%), increase in ALT (1.6%), decreased appetite (1.2%), increase in AST (0.8%), diarrhea (0.4%), and alopecia (0.4%). Overall, 10.5 percent of patients had interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (9.7%) were low-grade (Grade 1; 2.7% or Grade 2; 7.0%) with two Grade 3 (0.8%) events reported. No Grade 4 or Grade 5 ILD or pneumonitis events occurred.


In September 2021, fam-trastuzumab deruxtecan-nxki received its fourth Breakthrough Therapy Designation in the U.S. for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens.


KIN-3248 Planned Initiation of Phase I Clinical Trial for KIN-3248 in 1H2022

The FDA has cleared an Investigational New Drug (IND) application for KIN-3248, a next-generation pan-FGFR inhibitor being developed for intrahepatic cholangiocarcinoma (ICC) and urothelial carcinoma (UC).


KIN-3248 is an irreversible, small molecule pan-FGFR inhibitor that has been developed to address both primary FGFR2 and FGFR3 oncogenic alterations and those predicted to drive acquired resistance to current FGFR-targeted therapies, including gatekeeper, molecular brake, and activation loop mutations observed in cancers such as ICC and other gastrointestinal cancers. In preclinical studies, KIN-3248 demonstrated inhibitory activity across a wide range of clinically relevant mutations that drive primary disease and acquired resistance.


The Phase I trial is expected to initiate in the first half of 2022 and will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-cancer activity of KIN-3248 in FGFR inhibitor naive and pretreated cancer patients with FGFR2 and/or FGFR3 gene alterations. The dose-escalation portion (Part A) of the trial will determine the recommended dose and schedule of KIN-3248 for further evaluation in patients with FGFR2 and/or FGFR3 gene alterations. The dose-expansion phase (Part B) of the trial will assess the safety and efficacy of KIN-3248 at the recommended dose and schedule in FGFR inhibitor-naive and pretreated patients with cancers driven by FGFR2 and/or FGFR3 gene alterations, including ICC, UC, and other selected adult solid tumors.


Oncogenic FGFR (FGFR1, FGFR2, FGFR3, and FGFR4) gene alterations are observed in approximately 7 percent of all human cancers. FGFR2 gene fusions and FGFR3 activating alterations are predicted oncogenic drivers in approximately 10-20 percent of cholangiocarcinoma and 20-35 percent of urothelial cancers, respectively. While currently approved FGFR inhibitors and those in development provide clinical benefit in these cancer indications, disease progression typically occurs within 6-12 months of starting treatment and is often associated with the emergence of on-target resistance mutations within the FGFR kinase domain.