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Abstract: On March 30, 2017, the U.S. Food and Drug Administration (FDA) approved osimertinib for the treatment of patients with metastatic, epidermal growth factor receptor (EGFR) T790M mutation‐positive, non‐small cell lung cancer (NSCLC), as detected by an FDA‐approved test, whose disease has progressed following EGFR tyrosine kinase inhibitor (TKI) therapy. Approval was based on demonstration of a statistically significant difference in the primary endpoint of progression‐free survival (PFS) when comparing osimertinib with chemotherapy in an international, multicenter, open‐label, randomized trial (AURA3). In this confirmatory trial, which enrolled 419 patients, the PFS hazard ratio for osimertinib compared with chemotherapy per investigator assessment was 0.30 (95% confidence interval 0.23–0.41), p < .001, with median PFS of 10.1 months in the osimertinib arm and 4.4 months in the chemotherapy arm. Supportive efficacy data included PFS per blinded independent review committee demonstrating similar PFS results and an improved confirmed objective response rate per investigator assessment of 65% and 29%, with estimated median durations of response of 11.0 months and 4.2 months, in the osimertinib and chemotherapy arms, respectively. Patients received osimertinib 80 mg once daily and had a median duration of exposure of 8 months. The toxicity profile of osimertinib compared favorably with the profile of other approved EGFR TKIs and chemotherapy. The most common adverse drug reactions (>20%) in patients treated with osimertinib were diarrhea, rash, dry skin, nail toxicity, and fatigue. Herein, we review the benefit‐risk assessment of osimertinib that led to regular approval, for patients with metastatic NSCLC harboring EGFR TKI whose disease has progressed on or after EGFR TKI therapy. Implications for Practice: Osimertinib administered to metastatic non‐small cell lung cancer (NSCLC) patients harboring an EGFR T790M mutation, who have progressed on or following EGFR TKI therapy, demonstrated a substantial improvement over platinum‐based doublet chemotherapy as well as durable intracranial responses. The ability to test for the T790M mutation in plasma using the FDA‐approved cobas EGFR Mutation Test v2 (Roche, Basel, Switzerland) identifies patients with NSCLC tumors not amenable to biopsy. Since a 40% false‐negative rate has been observed with the circulating tumor DNA test, re‐evaluation of the feasibility of tissue biopsy is recommended to identify patients with a false‐negative plasma test result who may benefit from osimertinib. [ABSTRACT FROM AUTHOR]

On December 14, 2023, the U.S. FDA approved belzutifan (Welireg, Merck & Co., Inc.) for patients with advanced renal cell carcinoma (RCC) following treatment with a PD-1/PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. The FDA granted traditional approval based on LITESPARK-005 (NCT04195750), an open-label, randomized, head-to-head trial of 746 patients with advanced RCC that progressed following treatment with both a PD-1/PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. Patients were randomized (1:1) to receive belzutifan or everolimus. The primary endpoints were progression-free survival (PFS) assessed by blinded independent central review and overall survival. A statistically significant improvement in PFS was demonstrated for belzutifan compared with everolimus [HR = 0.75; 95% confidence interval (CI), 0.63-0.90; one-sided P value = 0.0008]. Kaplan-Meier curves reflected nonproportional hazards with similar median PFS estimates of 5.6 months (95% CI, 3.9-7.0) in the belzutifan arm and 5.6 months (95% CI, 4.8-5.8) in the everolimus arm. Although not reaching full maturity, the overall survival results seemed to show a favorable trend in the belzutifan arm compared with the everolimus arm (HR, 0.88; 95% CI, 0.73-1.07). The confirmed objective response rate by blinded independent central review was 22% and 3.6% in the belzutifan and everolimus arms, respectively. Observed toxicities differed between treatment arms, but drug discontinuations and interruptions due to treatment-emergent adverse events were lower in the belzutifan arm compared with the everolimus arm, and a descriptive analysis of patient-reported symptom and functional outcomes was suggestive of favorable tolerability for belzutifan compared with everolimus., (©2024 American Association for Cancer Research.)

On December 15, 2023, the FDA granted traditional approval to enfortumab vedotin-ejfv plus pembrolizumab (EV + Pembro) for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Substantial evidence of effectiveness was obtained from EV-302/KEYNOTE-A39 (NCT04223856), an open-label, randomized trial evaluating EV + Pembro versus cisplatin or carboplatin plus gemcitabine (Plat + Gem) in patients with previously untreated la/mUC. A total of 886 patients were randomized (1:1) to receive EV 1.25 mg/kg intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity plus Pembro 200 mg intravenously on day 1 of each 21-day cycle for up to 35 cycles or Plat + Gem for up to 6 cycles. Dual primary endpoints were progression-free survival determined by blinded independent central review and overall survival. The median progression-free survival was 12.5 months [95% confidence interval (CI), 10.4-16.6] in the EV + Pembro arm and 6.3 months (95% CI, 6.2-6.5) in the Plat + Gem arm [HR, 0.450 (95% CI, 0.377-0.538); P value < 0.0001]. The median overall survival was 31.5 months (95% CI, 25.4-not estimable) in the EV + Pembro arm and 16.1 months (95% CI, 13.9-18.3) in the Plat + Gem arm [HR, 0.468 (95% CI, 0.376-0.582); P value < 0.0001]. The safety profile of EV + Pembro was similar to that observed in EV-103/KEYNOTE-869 in cisplatin-ineligible patients with la/mUC. This article summarizes the data and the FDA thought process supporting traditional approval of EV + Pembro, as well as additional exploratory analyses conducted by the FDA., (©2024 American Association for Cancer Research.)

On March 23, 2022, the FDA approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The recommended 177Lu-PSMA-617 dose is 7.4 gigabecquerels (GBq; 200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity. The FDA granted traditional approval based on VISION (NCT03511664), which was a randomized (2:1), multicenter, open-label trial that assessed the efficacy and safety of 177Lu-PSMA-617 plus best standard of care (BSoC; n = 551) or BSoC alone (n = 280) in men with progressive, PSMA-positive mCRPC. Patients were required to have received ≥1 androgen receptor pathway inhibitor, and one or two prior taxane-based chemotherapy regimens. There was a statistically significant and clinically meaningful improvement in overall survival (OS), with a median OS of 15.3 months in the 177Lu-PSMA-617 plus BSoC arm and 11.3 months in the BSoC arm, respectively (HR: 0.62; 95% confidence interval: 0.52-0.74; P < 0.001). The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving 177Lu-PSMA-617 were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. This article summarizes the FDA review of data supporting traditional approval of 177Lu-PSMA-617 for this indication., (©2022 American Association for Cancer Research.)

Introduction: Accurate, patient-centered evaluation of physical function in patients with cancer can provide important information on the functional impacts experienced by patients both from the disease and its treatment. Increasingly, digital health technology is facilitating and providing new ways to measure symptoms and function. There is a need to characterize the longitudinal measurement characteristics of physical function assessments, including clinician-reported physical function (ClinRo), patient-reported physical function (PRO), performance outcome tests (PerfO) and wearable data, to inform regulatory and clinical decision-making in cancer clinical trials and oncology practice., Methods and Analysis: In this prospective study, we are enrolling 200 English- and/or Spanish-speaking patients with breast cancer or lymphoma seen at Mayo Clinic or Yale University who will receive standard of care intravenous cytotoxic chemotherapy. Physical function assessments will be obtained longitudinally using multiple assessment modalities. Participants will be followed for 9 months using a patient-centered health data aggregating platform that consolidates study questionnaires, electronic health record data, and activity and sleep data from a wearable sensor. Data analysis will focus on understanding variability, sensitivity, and meaningful changes across the included physical function assessments and evaluating their relationship to key clinical outcomes. Additionally, the feasibility of multi-modal physical function data collection in real-world patients with cancer will be assessed, as will patient impressions of the usability and acceptability of the wearable sensor, data aggregation platform, and PROs., Ethics and Dissemination: This study has received approval from IRBs at Mayo Clinic, Yale University, and the U.S. Food & Drug Administration. Results will be made available to participants, funders, the research community, and the public., Registration Details: The trial registration number for this study is NCT05214144., Strengths & Limitations: This study addresses an important unmet need by characterizing the performance characteristics of multiple patient-centered physical function measures in patients with cancerPhysical function is an important and undermeasured clinical outcome. Scientifically rigorous capture and measurement of physical function constitutes a key component of cancer treatment tolerability assessment both from a regulatory and clinical perspective.This study will include patients with lymphoma or breast cancer receiving a broad range of cytotoxic chemotherapy regimens. While recruitment will occur at two academic sites, patients who ultimately receive treatment at local community sites will be included.A patient-centered health data aggregating platform facilitates the delivery of patient-reported outcome measures and collection of wearable data to researchers, while reducing patient burden compared to traditional patient-generated data collection and aggregation methodsHeterogeneity in patient willingness or comfort engaging with mobile products including smartphones and wearables, enrollment primarily at large academic centers, and the modest sample size are potential limitations to the external validity of the study., Competing Interests: Dr. Thanarajasingam has received research funding from the from the Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938) that directly supports this work. She also receives grant funding from the National Cancer Institute (NCI) U01 Tolerability Consortium. Dr. Gross has received research funding from the NCCN Foundation (Astra-Zeneca) and Genentech, as well as funding from Johnson and Johnson to help devise and implement new approaches to sharing clinical trial data. Over the past three years, Dr. Jeffery reports grant funding from the US Food and Drug Administration, National Institutes on Drug Abuse, Centers for Disease Control and Prevention, Agency for Healthcare Research and Quality, American Cancer Society, and the National Center for Advancing Translational Sciences. Dr. Ross currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938), from the Medical Devices Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644), and from Arnold Ventures for the Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT); in addition, Dr. Ross is an expert witness at the request of Relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. Ms. Ritchie currently receives research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing and from the US Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938). Dr. Huntington has received consulting fees outside of this work from Janssen, Genentech, AbbVie, Flatiron Health, BeiGene, AstraZeneca, ADC Therapeutics, Epizyme, Merck, Seattle Genetics, TG Therapeutics, Tyme, Pharmacyclics, SeaGen, and Arvinas. Dr. Schellhorn has received consulting fees from Eisai, Celgene, SeaGen, and Cardinal Health. She has previously received research funding to her institution from Genentech and Pfizer.All other authors have no relevant conflicts of interest to disclose.

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication., (©2021 American Association for Cancer Research.)

On April 22, 2020, the FDA granted accelerated approval to sacituzumab govitecan-hziy (TRODELVY; Immunomedics, Inc.) for the treatment of patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease. Approval was based on data from the IMMU-132-01 trial, a single-arm, multicohort, multicenter, phase I/II trial of sacituzumab govitecan. The assessment of efficacy was based on 108 patients with mTNBC who had previously received at least two prior lines of therapy in the metastatic setting and who received sacituzumab govitecan 10 mg/kg i.v. The assessment of safety was based on 408 patients with advanced solid tumors who had received sacituzumab govitecan at doses up to 10 mg/kg i.v. The primary efficacy endpoint was investigator-assessed objective response rate (ORR) and duration of response (DoR) was a key secondary endpoint. The ORR was 33.3% [36/108; 95% confidence interval (CI), 24.6-43.1], and median DoR among responders was 7.7 months (95% CI, 4.9-10.8). The most common adverse reactions occurring in ≥25% of patients were nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain. This article summarizes the FDA review process and data supporting the approval of sacituzumab govitecan., (©2020 American Association for Cancer Research.)