Over the past few weeks, the U.S. Food and Drug Administration (FDA) has issued designations and accepted applications for novel agents, as well as approved companion diagnostics. We summarize these regulatory movements below.
Breakthrough Therapy Designation for MK-6482 in von Hippel-Lindau Disease–Associated Renal Cell Carcinoma
The FDA granted Breakthrough Therapy designation to the hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor MK-6482 for the treatment of patients with von Hippel-Lindau disease–associated renal cell carcinoma (RCC) with nonmetastatic RCC tumors less than 3 cm in size, unless immediate surgery is required. The FDA also granted Orphan Drug designation to MK-6482 for von Hippel-Lindau disease.
These designations are based on data from a phase II trial evaluating MK-6482 in patients with von Hippel-Lindau disease–associated clear cell RCC, which was presented during the ASCO20 Virtual Scientific Program (Abstract 5003).
MK-6482 is an investigational, novel, potent, selective, oral HIF-2α inhibitor that is currently being evaluated in a phase III trial in advanced RCC, a phase II trial in von Hippel-Lindau disease–associated RCC, and a phase I/II dose-escalation and dose-expansion trial in advanced solid tumors, including advanced RCC. Proteins known as hypoxia-inducible factors, including HIF-2α, can accumulate in patients when VHL, a tumor-suppressor protein, is inactivated. The accumulation of HIF-2α can lead to the formation of both benign and malignant tumors. This inactivation of VHL has been observed in more than 90% of clear cell RCC tumors. Research into VHL biology that led to the discovery of HIF-2α was awarded the Nobel Prize in Physiology or Medicine in 2019.
Breakthrough Therapy Designation for Osimertinib for the Adjuvant Treatment of Patients With Stage IB-IIIA EGFR-Mutated NSCLC
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, has been granted Breakthrough Therapy designation by the FDA for the adjuvant treatment of patients with early-stage (IB, II, and IIIA) EGFR-mutated non–small cell lung cancer (NSCLC) after complete resection with curative intent.
The FDA granted the Breakthrough Therapy designation based on data from the phase III ADAURA trial, which was presented during the plenary session of the ASCO20 Virtual Scientific Program (Abstract LBA5). In the trial, treatment with osimertinib demonstrated a statistically significant and clinically meaningful improvement in disease-free survival, reducing the risk of disease recurrence or death by 79% (hazard ratio = 0.21, 95% confidence interval = 0.16–0.28, P < .0001) in a key secondary endpoint. In April 2020, an Independent Data Monitoring Committee recommended that the trial be unblinded 2 years early based on its determination of efficacy. ADAURA will continue to assess overall survival.
Breakthrough Therapy Designation for Pevonedistat in Higher-Risk Myelodysplastic Syndromes
The FDA has granted Breakthrough Therapy designation to pevonedistat for the treatment of patients with higher-risk myelodysplastic syndromes. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, could be the first novel treatment for patients with higher-risk myelodysplastic syndromes in more than a decade, expanding treatment options that have so far been limited to hypomethylating agent monotherapy alone.
The Breakthrough Therapy designation is based on the final analysis of the Pevonedistat-2001 phase II study, which evaluated pevonedistat plus azacitidine vs azacitidine alone in patients with rare leukemias, including higher-risk myelodysplastic syndromes. The FDA considered a number of endpoints, including overall survival, event-free survival, complete remission, and transfusion independence, as well as the adverse event profile.
Results of the Pevonedistat-2001 trial were presented during the ASCO20 Virtual Scientific Program (Abstract 7506) and the EHA25 Virtual 2020 Congress (Abstract S182).
Fast Track Designation for BDTX-189 in Adult Patients With a Solid Tumor Harboring an Allosteric HER2 Mutation or an EGFR or HER2 Exon 20 Insertion Mutation
The FDA granted Fast Track designation to BDTX-189 for the treatment of adult patients with solid tumors harboring an allosteric HER2 mutation or an EGFR or HER2 exon 20 insertion mutation who have progressed following prior treatment and who have no satisfactory treatment options. BDTX-189, an orally available, irreversible small-molecule inhibitor, is designed to selectively inhibit the activity of a broad range of previously unaddressed oncogenic driver mutations of the ErbB kinases in EGFR and HER2.
MasterKey-01 is a combined phase I/II open-label, two-part, multicenter study to assess the safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189 in adult patients with advanced solid tumors who have no standard therapy available or for whom standard therapy is considered unsuitable or intolerable.
Part A is a phase I, first-in-human, open-label dose escalation study comprised of initial single-patient, accelerated titration cohorts followed by multiple-patient cohorts utilizing a Bayesian design. Part A is designed to determine the recommended phase II dose and schedule in up to 88 patients with allosteric HER2 or HER3 mutations; EGFR or HER2 exon 20 insertion mutations; HER2-amplified or -overexpressing tumors; or an EGFR exon 19 deletion or L858R mutation. Part B is a phase II, open-label, multicenter basket study designed to determine antitumor activity and safety in adult patients with solid tumors that have an allosteric HER2 mutation or EGFR or HER2 exon 20 insertion mutations using next-generation sequencing. Part B will utilize a Simon 2-stage design and enroll up to 100 patients in four cohorts:
- NSCLC with EGFR or HER2 exon 20 insertion mutations
- Breast cancer with an allosteric ErbB mutation
- Solid tumors (except breast) with S310F/Y mutation
- Other tumors harboring allosteric ErbB mutations not included in the previous three cohorts.
Fast Track Designation for CMP-001 Combined With PD-1 Blockade in Some Patients With Metastatic or Unresectable Melanoma
The FDA granted Fast Track designation to CMP-001, a differentiated Toll-like receptor 9 (TLR9) agonist, in combination with a PD-1 blocking antibody (nivolumab or pembrolizumab) for two development programs, including:
- Initial treatment of patients with unresectable stage III or IV melanoma to prolong the time to disease progression
- Treatment of patients with unresectable or metastatic melanoma refractory to prior anti–PD-1 blockade to improve overall response rate.
The FDA previously granted Orphan Drug designation to CMP-001 for patients with stages IIB–IV melanoma.
CMP-001 comprises a virus-like particle utilizing a CpG-A oligonucleotide. It is designed to trigger the body’s innate immune system via TLR9 and infiltrate the tumor microenvironment by the subsequent induction of both innate and adaptive antitumor immune responses.
Orphan Drug Designation for Cobomarsen in T-cell Lymphoma
The FDA granted Orphan Drug designation to cobomarsen for the treatment of T-cell lymphoma. Cobomarsen is an inhibitor of miR-155 currently being developed to address different types of T-cell lymphoma, through a phase II trial in patients with cutaneous T-cell lymphoma and a phase I trial for adult patients with T-cell leukemia/lymphoma. Overexpression of microRNA-155 has been associated with poor prognosis in a variety of T-cell lymphomas and other blood cancers.
Orphan Drug Designation for Zenocutuzumab in Pancreatic Cancer
The FDA granted Orphan Drug designation to zenocutuzumab for the treatment of patients with pancreatic cancer.
Zenocutuzumab is a first-in-class bispecific antibody that potently binds to the HER2 and HER3 receptors to block the interaction of HER3 with its ligand, neuregulin 1 (NRG1). Zenocutuzumab has demonstrated early clinical responses in patients with previously treated pancreatic cancer harboring NRG1 gene fusions, as presented at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2019. The NRG1 gene fusion is a rare, powerful driver of cancer cell growth found in pancreatic, lung, and other types of solid cancers; NRG1 fusions are estimated to occur at a rate of approximately 0.5% to 1.5% in pancreatic ductal adenocarcinoma. Zenocutuzumab is now being evaluated in a global phase I/II study called the eNRGy trial.
Two sBLAs for Pembrolizumab in Triple-Negative Breast Cancer
The FDA accepted two new supplemental biologics license applications (sBLAs) for the anti–PD-1 therapy pembrolizumab.
The FDA has accepted and granted Priority Review for a new sBLA seeking accelerated approval for pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (combined positive score [CPS] ≥ 10), based on the phase III KEYNOTE-355 trial. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of November 28, 2020, for this sBLA.
In KEYNOTE-355, pembrolizumab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with chemotherapy alone in patients whose tumors expressed PD-L1 at CPS ≥ 10. Approximately 38% of patients enrolled in KEYNOTE-355 had tumors expressing PD-L1 at CPS ≥ 10. These data were presented during the ASCO20 Virtual Scientific Program (Abstract 1000). The trial will continue without changes to evaluate the other dual primary endpoint of overall survival.
The FDA also accepted for standard review a new sBLA for pembrolizumab for the treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, and then as a single agent as adjuvant treatment after surgery, based on the phase III KEYNOTE-522 trial. The PDUFA date for this sBLA is March 29, 2021.
In KEYNOTE-522—the first randomized trial of an anti–PD-1 therapy in the neoadjuvant/adjuvant setting for triple-negative breast cancer—neoadjuvant pembrolizumab plus chemotherapy resulted in a statistically significant increase in pathologic complete response in patients with early-stage triple-negative breast cancer, regardless of PD-L1 expression. The pembrolizumab regimen also demonstrated a favorable trend for the other dual primary endpoint of event-free survival. Data from the KEYNOTE-522 trial were presented at the European Society for Medical Oncology 2019 Congress (Abstract LBA8_PR) and the 2019 San Antonio Breast Cancer Symposium (Abstract GS3-03). Pembrolizumab plus chemotherapy was granted Breakthrough Therapy designation by the FDA for the neoadjuvant treatment of patients with high-risk early-stage triple-negative breast cancer.
FDA Approves New VENTANA HER2 Dual ISH test as Companion Diagnostic to Identify Patients Eligible for Targeted Breast Cancer Therapy
The FDA approved of the new VENTANA HER2 Dual ISH DNA Probe Cocktail assay for the detection of the HER2 biomarker in breast cancer and as a companion diagnostic for trastuzumab therapy. HER2 is an important biomarker sometimes found in breast cancers, and its detection and inhibition can help health-care professionals more effectively manage malignancies.
The VENTANA HER2 Dual ISH DNA Probe Cocktail assay is designed to be completed within the same day, enabling clinicians to get results back faster than with other common methods of confirmatory testing for HER2. Results can be read using light microscopy, eliminating the need for a specialized fluorescence microscope.
