Over the past month, the U.S. Food and Drug Administration (FDA) issued several regulatory decisions for novel treatments for patients with cancer.
Priority Review for Relatlimab and Nivolumab Fixed-Dose Combination in Unresectable or Metastatic Melanoma
The FDA accepted for Priority Review the biologics license application for the LAG-3–blocking antibody relatlimab and nivolumab fixed-dose combination, administered as a single infusion, for the treatment of adult and pediatric patients (12 years and older and weighing at least 40 kg) with unresectable or metastatic melanoma. The FDA assigned a Prescription Drug User Fee Act (PDUFA) goal date of March 19, 2022.
The biologics license application submission was based on the efficacy and safety results of the phase II/III RELATIVITY-047 trial, which demonstrated a statistically significant and clinically meaningful progression-free survival benefit of the combination therapy over standard of care anti–PD-1 monotherapy in metastatic melanoma. Relatlimab is the first LAG-3-blocking antibody to demonstrate a clinical benefit for patients with phase III data. Primary results from the RELATIVITY-047 trial were presented in an oral session during the ASCO Annual Meeting in June 2021 and were selected for the official ASCO press program.
Priority Review for Cemiplimab-rwlc in Advanced Cervical Cancer
The FDA accepted for Priority Review the supplemental biologics license application for the PD-1 inhibitor cemiplimab-rwlc to treat patients with recurrent or metastatic cervical cancer whose disease progressed on or after chemotherapy. The target action date for the FDA decision is January 30, 2022. The supplemental biologics license application is also being reviewed under the FDA's Project Orbis initiative, which will allow for concurrent review by participating health authorities in Australia, Brazil, Canada, and Switzerland.
The sBLA is supported by results from the phase III EMPOWER-Cervical 1 trial. The trial investigated cemiplimab-rwlc monotherapy vs investigator's choice of chemotherapy in patients with recurrent or metastatic cervical cancer who had progressed on platinum-based chemotherapy. Patients were enrolled regardless of tumor PD-L1 expression status or histology in 14 countries. Detailed results were first presented as part of a European Society for Medical Oncology (ESMO) Virtual Plenary in May 2021.
Priority Review for LuPSMA in Metastatic Castration-Resistant Prostate Cancer
The FDA accepted and granted Priority Review to a new drug application for lutetium-177–PSMA-617 (LuPSMA), an investigational targeted radioligand therapy, for the treatment of metastatic castration-resistant prostate cancer. The Prescription Drug User Fee Act date is anticipated in the first half of 2022.
Priority Review was based on positive data from the pivotal, phase III VISION study showing LuPSMA plus standard of care significantly improved overall survival and radiographic progression–free survival for men with progressive PSMA-positive metastatic castration-resistant prostate cancer compared to standard of care alone.
Data from the VISION study were published in The New England Journal of Medicine and presented at the 2021 ASCO Annual Meeting.
Two additional studies with LuPSMA in earlier lines of treatment for metastatic prostate cancer are ongoing, investigating clinical utility in the pre-taxane setting (PSMAfore) and in the metastatic hormone-sensitive setting (PSMAddition).
Fam-trastuzumab Deruxtecan-nxki Granted Breakthrough Therapy Designation for Pretreated HER2-Positive Metastatic Breast Cancer
The FDA granted fam-trastuzumab deruxtecan-nxki Breakthrough Therapy designation 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. Trastuzumab deruxtecan is a HER2-directed antibody drug conjugate.
The FDA granted Breakthrough Therapy designation based on data from the DESTINY-Breast03 phase III trial presented during the ESMO Congress 2021.
In DESTINY-Breast03, trastuzumab deruxtecan demonstrated a 72% reduction in the risk of disease progression or death compared to T-DM1 (hazard ratio = 0.28, 95% confidence interval = 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. Nearly all patients treated with trastuzumab deruxtecan were alive at 1 year (94.1%) compared to 85.9% of patients treated with T-DM1. Confirmed objective response rate more than doubled in the trastuzumab deruxtecan arm vs the T-DM1 arm (79.7% vs 34.2%). The safety profile of trastuzumab deruxtecan was consistent with previous clinical trials, with no new safety concerns identified and no grade 4 or 5 treatment-related interstitial lung disease events.
Breakthrough Therapy Designation for Repotrectinib in NTRK-Positive Pretreated Advanced Solid Tumors
The FDA granted Breakthrough Therapy designation to the tyrosine kinase inhibitor repotrectinib for the treatment of patients with advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with one or two prior TRK tyrosine kinase inhibitors, with or without prior chemotherapy, and have no satisfactory alternative treatments.
Orphan Drug Designation for Gavocabtagene Autoleucel in Cholangiocarcinoma
The FDA granted Orphan Drug designation to gavocabtagene autoleucel (gavo-cel) for the treatment of cholangiocarcinoma. New clinical data from the dose-escalation portion of a phase I/II clinical trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors was presented at the ESMO Congress 2021 (Abstract 959O), and included data for gavo-cel in malignant mesothelioma, ovarian cancer, and cholangiocarcinoma.
Acceptance of Biologics License Application for Tislelizumab in Esophageal Squamous Cell Carcinoma
The FDA accepted for review a biologics license application for the anti–PD-1 antibody tislelizumab for patients with unresectable, recurrent, locally advanced or metastatic esophageal squamous cell carcinoma after prior systemic therapy. The Prescription Drug User Fee Act target action date is July 12, 2022.
The biologics license application submission is based on results from RATIONALE 302, a randomized, open-label, multicenter global phase III trial designed to evaluate the efficacy and safety of tislelizumab when compared to investigator’s choice of chemotherapy as a second-line treatment for patients with advanced or metastatic esophageal squamous cell carcinoma. Results of this trial were presented at the 2021 ASCO Annual Meeting (Abstract 4012). The submission also included safety data on 1,972 patients who received tislelizumab as a monotherapy from seven clinical trials.
FDA Accepts Applications for Nivolumab/Ipilimumab and Nivolumab/Chemotherapy for Unresectable, Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma
The FDA accepted the supplemental biologics license applications for both nivolumab in combination with ipilimumab and nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatments for adult patients with unresectable, advanced, recurrent or metastatic esophageal squamous cell carcinoma, based on results from the CheckMate 648 trial. The FDA assigned a Prescription Drug User Fee Act goal date of May 28, 2022.
In CheckMate 648, both nivolumab-based treatment combinations demonstrated a statistically significant and clinically meaningful overall survival benefit compared to chemotherapy in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma with tumor cell PD-L1 expression ≥ 1%, as well as in the all-randomized population. Nivolumab plus ipilimumab is the first dual immunotherapy combination to demonstrate a superior survival benefit vs chemotherapy in this setting. The safety profiles of nivolumab/ipilimumab and nivolumab/chemotherapy were consistent with the known safety profiles of the individual components.
Results from CheckMate 648 were presented during the 2021 ASCO Annual Meeting and were selected for the official ASCO press program.
FDA Authorizes Software to Help Pathologists Identify Prostate Cancer
The FDA has authorized marketing of software to assist pathologists in the detection of areas that are suspicious for cancer as an adjunct to the review of digitally scanned slide images from prostate biopsies. The software, called Paige Prostate, is the first artificial intelligence (AI)-based software designed to identify an area of interest on the prostate biopsy image with the highest likelihood of harboring cancer so it can be reviewed further by the pathologist if the area of concern has not been identified on initial review.
Paige Prostate is compatible for use with slide images that have been digitized using a scanner. The digitized slide image can then be visualized using a slide image viewer.
The FDA evaluated data from a clinical study where 16 pathologists examined 527 slide images of prostate biopsies (171 cancerous and 356 benign) that were digitized using a scanner. For each slide image, each pathologist completed two assessments: one without Paige Prostate’s assistance (unassisted read) and one with Paige Prostate’s assistance (assisted read). While the clinical study did not evaluate the impact on final patient diagnosis, which is typically based on multiple biopsies, the study found that Paige Prostate improved detection of cancer on individual-slide images by 7.3% on average when compared to pathologists’ unassisted reads for whole-slide images of individual biopsies, with no impact on the read of benign slide images.
Potential risks include false-negative and false-positive results, which are mitigated by the device’s use as an adjunct and by the professional evaluation by a qualified pathologist who takes into account patient history among other relevant clinical information, and who may perform additional laboratory studies on the samples prior to rendering a final diagnosis.
The FDA reviewed the device through the De Novo premarket review pathway, a regulatory pathway for low- to moderate-risk devices of a new type. Along with this authorization, the FDA is establishing special controls for devices of this type, including requirements related to labeling and performance testing. When met, the special controls, along with general controls, provide reasonable assurance of safety and effectiveness for devices of this type. This action creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through FDA’s 510(k) premarket process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a predicate device.
The FDA granted marketing authorization of the Paige Prostate software to Paige.AI.
