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FDA Pipeline: Priority Reviews in EGFR-Mutant Lung Cancer, Advanced Renal Cell Carcinoma; Fast Track Designations in CLL and Solid Tumors


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Recently, the U.S. Food and Drug Administration (FDA) granted Priority Review to treatments for EGFR-mutant lung cancer and advanced renal cell carcinoma; granted Fast Track designation to agents in chronic lymphocytic leukemia (CLL) and locally advanced or metastatic solid tumors; and more.

Priority Review for Osimertinib in Early-Stage EGFR-Mutant Lung Cancer

The FDA accepted a supplemental new drug application and granted Priority Review to osimertinib for the adjuvant treatment of patients with early-stage (IB, II, and IIIA) EGFR-mutated non–small cell lung cancer (NSCLC) after complete tumor resection with curative intent.

The Prescription Drug User Fee Act date, the FDA target for its regulatory decision, is during the first quarter of 2021. Osimertinib is a third-generation, irreversible EGFR tyrosine kinase inhibitor with clinical activity against central nervous system metastases. 

The supplemental new drug application was based on results from the phase III ADAURA trial, which showed osimertinib demonstrated a statistically significant and clinically meaningful improvement in disease-free survival in the primary analysis population of patients with stage II and IIIA EGFR-mutant NSCLC, and also in the overall trial population of patients with stage IB to IIIA disease, a key secondary endpoint.

In April 2020, an independent data monitoring committee recommended for the ADAURA trial to be unblinded 2 years early, based on its determination of efficacy. Investigators and patients continue to participate in the trial and remain blinded to treatment. The results from the ADAURA trial were presented during the plenary session of the ASCO20 Virtual Scientific Program and were recently published in The New England Journal of Medicine.

Osimertinib received Breakthrough Therapy designation in this setting in July 2020. The agent is approved for both the first-line treatment of patients with locally advanced or metastatic EGFR-mutant NSCLC and for the treatment of locally advanced or metastatic EGFR T790M–mutation positive NSCLC in the United States, Japan, China, the European Union, and many other countries around the world.

Priority Review for Nivolumab in Combination With Cabozantinib for Advanced Renal Cell Carcinoma

The FDA accepted a supplemental biologics license application and supplemental new drug application, respectively, for nivolumab in combination with cabozantinib for patients with advanced renal cell carcinoma. The FDA granted Priority Review to both applications and assigned a Prescription Drug User Fee Act goal date of February 20, 2021.

These filings were based on results from the phase III CheckMate 9ER trial, which evaluated nivolumab/cabozantinib vs sunitinib in patients with previously untreated advanced renal cell carcinoma. In CheckMate 9ER, nivolumab/cabozantinib demonstrated significant improvements across all efficacy endpoints, including overall survival, progression-free survival, and objective response rate vs the comparator, sunitinib.

The combination of nivolumab/cabozantinib was well tolerated, with a low rate of treatment-related discontinuations, and reflected the known safety profiles of the immunotherapy and tyrosine kinase inhibitor components in patients with previously untreated advanced renal cell carcinoma. In addition, patient-reported outcomes data from CheckMate 9ER showed that the combination was associated with statistically significant improvements in health-related quality of life at most time points vs sunitinib. In September 2020, results from the trial were presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Fast Track Designation for Ublituximab in Combination With Umbralisib for the Treatment of Adult Patients With CLL

The FDA granted Fast Track designation to the combination of ublituximab—an investigational glycoengineered anti-CD20 monoclonal antibody—and umbralisib, a once-daily, oral, dual inhibitor of PI3K-delta and CK1-epsilon, for the treatment of adult patients with chronic lymphocytic leukemia (CLL).

The application was based on data from UNITY-CLL, a phase III, global, randomized, controlled clinical trial comparing the combination of ublituximab plus umbralisib, or U2, to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment-naive and relapsed or refractory CLL. The trial randomly assigned patients into four treatment arms:

  • Single-agent ublituximab
  • Single-agent umbralisib
  • Ublituximab plus umbralisib (U2)
  • An active control arm of obinutuzumab plus chlorambucil. 

A prespecified analysis was conducted to assess the contribution of ublituximab and umbralisib in the U2 combination arm and allowed for the termination of the single-agent arms. Accordingly, UNITY-CLL continued enrollment in a 1:1 ratio into the two combination arms: the investigational arm of U2 and the control arm of obinutuzumab plus chlorambucil. 

Full enrollment into UNITY-CLL was completed in October of 2017, with approximately 420 patients enrolled to the two combinations arms. The primary endpoint for this study was superior progression-free survival for the U2 combination compared to the control arm. Positive preliminary results from this trial were announced in May 2020.

UNITY-CLL is being conducted under a Special Protocol Assessment agreement with the FDA.

Fast Track Designation for Patients With p53 Y220C–Mutated Locally Advanced or Metastatic Solid Tumors

The FDA granted Fast Track designation to PC14586 for the treatment of patients with locally advanced or metastatic solid tumors that have a p53 Y220C protein mutation.

The p53 protein, encoded by the TP53 gene, plays a pivotal role in cellular function by preserving the integrity of DNA and preventing abnormal cells from entering or progressing through the cell cycle. Mutant TP53 takes on oncogenic properties that endow cancer cells with a growth advantage and resistance to anticancer therapy. Mutant p53 proteins are very common and are found in approximately half of all human cancers. The TP53 Y220C mutation is associated with many cancers, including but not limited to breast, non–small cell lung, colorectal, pancreatic, and ovarian cancers.

PC14586 is a first-in-class, orally available structural corrector of the p53 Y220C–mutant protein, designed to selectively bind to the crevice created by the p53 Y220C mutation, hence, restoring the wild-type p53 protein structure and tumor-suppressing function. PC14586 is being developed for the treatment of patients with locally advanced or metastatic solid tumors that have a p53 Y220C mutation.

A phase I/II open-label, multicenter study is being planned to assess the safety, tolerability, pharmacokinetics, and antitumor activity of PC14586 in adult patients with a p53 Y220C mutation in locally advanced or metastatic solid tumors. Phase I is a first-in-human, open-label, dose-escalation study designed for up to 30 patients with solid tumors that have a p53 Y220C mutation as determine by next-generation sequencing. Phase II is an open-label study designed to assess antitumor efficacy and safety in patients with solid tumors that have a p53 Y220C mutation; phase II is expected to enroll up to 100 patients.

APX005M Granted Orphan Drug Designations for the Treatment of Esophageal/Gastroesophageal Junction Cancers, Pancreatic Cancer

The FDA granted orphan drug designation status to APX005M for the treatment of esophageal and gastroesophageal junction cancers, and for the treatment of pancreatic cancer. APX005M is a novel, humanized monoclonal antibody that stimulates the antitumor immune response.

APX005M targets CD40, a co-stimulatory receptor that is essential for activating both innate and adaptive immune systems. Binding of APX005M to CD40 on antigen-presenting cells (ie, dendritic cells, monocytes, and B-cells) initiates a multifaceted immune response, bringing multiple components of the immune system (eg, T cells, macrophages) to work in concert against cancer.

APX005M is currently in phase II clinical development for the treatment of cancers such as pancreatic cancer, esophageal and gastroesophageal junction cancers, melanoma, non–small cell lung cancer, rectal cancer, and sarcoma in various combinations with immunotherapy, chemotherapy, radiation therapy, or a cancer vaccine.

Breakthrough Device Designation for Prostate Cancer Liquid Biopsy Test

The FDA granted breakthrough device designation for the miR Sentinel PCC4 Assay (miR Sentinel Prostate Test). The miR Sentinel Prostate Test is a new method to analyze small noncoding RNAs (sncRNA) derived from a simple, noninvasive urine specimen from age-eligible men.

Using only the expression level of these sncRNAs, a proprietary statistical classification algorithm derives scores that classify patients according to the likelihood of being in the following four possible groups: no molecular evidence of prostate cancer; low-risk; intermediate-risk; or high-risk prostate cancer.

Initial validation data for the miR Sentinel Prostate Test was published by Wang et al in The Journal of Urology. In comparison to currently available technologies alone, the specificity, sensitivity, and empirical negative predictive value and positive predictive value of the miR Sentinel Prostate Test may significantly reduce mortality and decrease the number of hospitalizations and physician visits, as well as reduce recovery time.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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