FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA-Mutated Metastatic Castrate-Resistant Prostate Cancer.

The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open-label single-arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%-57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty-six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly-(ADP-ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3-4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. IMPLICATIONS FOR PRACTICE: The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single-arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug.

Pediatric Cancer Drug Development: Leveraging Insights in Cancer Biology and the Evolving Regulatory Landscape to Address Challenges and Guide Further Progress.

The discovery and development of anticancer drugs for pediatric patients have historically languished when compared to both past and recent activity in drug development for adult patients, notably the dramatic spike of targeted and immune-oncology therapies. The reasons for this difference are multifactorial. Recent changes in the regulatory landscape surrounding pediatric cancer drug development and the understanding that some pediatric cancers are driven by genetic perturbations that also drive disparate adult cancers afford new opportunities. The unique cancer-initiating events and dependencies of many pediatric cancers, however, require additional pediatric-specific strategies. Research efforts to unravel the underlying biology of pediatric cancers, innovative clinical trial designs, model-informed drug development, extrapolation from adult data, addressing the unique considerations in pediatric patients, and use of pediatric appropriate formulations, should all be considered for efficient development and dosage optimization of anticancer drugs for pediatric patients.

FDA Approval Summary: Ivosidenib in Combination with Azacitidine for Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation.

On May 25, 2022, FDA approved a supplemental application for ivosidenib (Tibsovo; Servier) extending the indication in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML) in older adults or those with comorbidities to include the combination with azacitidine. The efficacy of ivosidenib in combination with azacitidine was evaluated in Study AG120-C-009, a phase 3, multicenter, double-blind, randomized (1:1), controlled study of ivosidenib or matched placebo in combination with azacitidine in adults with previously untreated AML with an IDH1 mutation who were 75 years or older or had comorbidities that precluded use of intensive induction chemotherapy. Efficacy was established on the basis of improved event-free survival and overall survival on the ivosidenib + azacitidine arm [HR, 0.35; 95% confidence interval (CI), 0.17-0.72; P = 0.0038, and HR, 0.44; 95% CI, 0.27-0.73; P = 0.0010], respectively. Furthermore, the rate and duration of complete remission (CR) were improved with ivosidenib versus placebo [CR 47% versus 15%, two-sided P < 0.0001; median duration of CR not estimable (NE; 95% CI, 13.0-NE) months versus 11.2 (95% CI, 3.2-NE) months. The safety profile of ivosidenib in combination with azacitidine was consistent with that of ivosidenib monotherapy, with important adverse reactions including differentiation syndrome (15%) and QT interval prolongation (20%).

FDA Approval Summary: Alpelisib for PIK3CA-Related Overgrowth Spectrum.

On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data (RWD) from EPIK-P1 (NCT04285723), a single-arm clinical study in patients 2 years of age and older with severe or life-threatening PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use. The primary endpoint was confirmed radiologic response rate at week 24 as determined by blinded independent central review (BICR), using volumetric-based criteria given the atypical growth pattern and irregular shape of PROS lesions. Radiologic response was defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to three lesions. Of the 37 patients in the efficacy population, 27% [95% confidence interval (CI), 14-44] had a radiologic response at week 24. Duration of response (DOR) was an additional efficacy outcome measure, and among responders, 60% had a response lasting ≥12 months. Furthermore, supportive clinical documentation suggested early signals of clinical benefit (i.e., improvement in PROS-related signs and symptoms). The most common (≥10%) adverse reactions were diarrhea, stomatitis, and hyperglycemia.

FDA Approval Summary: Capecitabine Labeling Update under Project Renewal.

On December 14, 2022, the U.S. Food and Drug Administration (FDA) approved revisions to the United States Prescribing Information (USPI) for capecitabine that revised existing indications and dosage regimens, added new indications and their recommended dosage regimens, revised safety information, updated the description of the risk of capecitabine in patients with dihydropyrimidine dehydrogenase (DPD) deficiency, and edited other sections of the USPI to conform with FDA's current labeling guidance. These supplements were reviewed and approved under Project Renewal, a public health initiative established by the FDA's Oncology Center of Excellence that aims to update the prescribing information of certain older oncology drugs to ensure information is clinically meaningful and scientifically up to date. This article summarizes the FDA approach that supported revisions to the capecitabine USPI within the context of Project Renewal.

FDA Approval Summary: Asciminib for Ph+ CML in Chronic Phase Treated with Two or More Tyrosine Kinase Inhibitors and for the T315I Mutation.

On October 29, 2021, FDA granted accelerated approval to asciminib (SCEMBLIX; Novartis), a tyrosine kinase inhibitor (TKI), for the treatment of adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more TKIs, and granted traditional approval to asciminib for adult patients with Ph+ CML in CP with the T315I mutation. The first indication was approved based on major molecular response (MMR) at 24 weeks in the ASCEMBL study, a randomized trial comparing asciminib with bosutinib in patients who had failed two or more TKIs. This indication was ultimately granted traditional approval on October 12, 2022, based on safety data and MMR rate at 96 weeks of 38% [95% confidence interval (CI), 30-46] in the asciminib arm versus 16% (95% CI, 8-26) in the bosutinib arm (P value: 0.001). The second indication was approved based on MMR rate by 96 weeks of 49% (95% CI, 34-64) in the single-arm CABL001X2101 study. The most common (≥20%) adverse reactions included upper respiratory tract infections, musculoskeletal pain, headache, fatigue, nausea, rash, and diarrhea. The most common (≥20%) laboratory abnormalities were thrombocytopenia, neutropenia, anemia, lymphopenia, hypertriglyceridemia, hyperuricemia, and increases in creatine kinase, alanine aminotransferase, aspartate aminotransferase, lipase, and amylase. This manuscript describes the basis for approval of these indications.

FDA Approval Summary: Olutasidenib for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation.

On December 1st, 2022, the FDA approved the new molecular entity olutasidenib (Rezlidhia: Rigel Pharmaceuticals), a small-molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of olutasidenib was established based on complete remission (CR) + CR with partial hematological recovery (CRh) rate, duration of CR + CRh, and conversion of transfusion dependence (TD) to transfusion independence (TI) in Study 2102-HEM-101. In the pivotal trial, 147 adult patients treated with 150mg twice daily (BID) of olutasidenib were evaluable for efficacy. With a median follow-up of 10.2 months, the CR/CRh rate was 35% (95% CI: 27-43%), with a median duration of response of 25.9 months (95% CI: 13.5 months, not reached [NR]). Of the 86 patients that were TD at baseline, 29 became TI (34%). The most common (≥20%) adverse reactions were nausea, fatigue, arthralgia, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea, and transaminitis. An assessment of long-term safety of olutasidenib is a condition of this approval.

Methodology for Good Machine Learning with Multi-Omics Data.

In 2020, Novartis Pharmaceuticals Corporation and the U.S. Food and Drug Administration (FDA) started a 4-year scientific collaboration to approach complex new data modalities and advanced analytics. The scientific question was to find novel radio-genomics-based prognostic and predictive factors for HR+/HER- metastatic breast cancer under a Research Collaboration Agreement. This collaboration has been providing valuable insights to help successfully implement future scientific projects, particularly using artificial intelligence and machine learning. This tutorial aims to provide tangible guidelines for a multi-omics project that includes multidisciplinary expert teams, spanning across different institutions. We cover key ideas, such as "maintaining effective communication" and "following good data science practices," followed by the four steps of exploratory projects, namely (1) plan, (2) design, (3) develop, and (4) disseminate. We break each step into smaller concepts with strategies for implementation and provide illustrations from our collaboration to further give the readers actionable guidance.

The expanding universe of NUTM1 fusions in pediatric cancer.

NUT midline carcinoma family member 1 (NUTM1) fusions were originally identified in poorly differentiated and clinically aggressive carcinomas typically located in the midline structures of children and young adults, and collectively known as NUT (midline) carcinomas. Next-generation sequencing later uncovered NUTM1 fusions in a variety of other pediatric and adult cancers of diverse location and type, including hematologic malignancies, cutaneous adnexal tumors, and sarcomas. A vast array of NUTM1 fusions with bromodomain containing 4 (BRD4) or bromodomain containing 3 (BRD3), which are characteristic of NUT carcinoma, and with several other fusion partners have been identified and associated with variable prognosis. These non-kinase fusions are thought to cause epigenetic reprogramming, thereby promoting proliferation, and hindering the differentiation of cancer cells. Many questions about both the function of the naïve NUTM1 protein, which is mostly restricted to the germ cells of the testis and is related to spermatogenesis and the oncogenic mechanisms of the various NUTM1 fusions in both adult and pediatric cancer, are still unanswered. Moreover, whether there is a relationship defined by the presence of NUTM1 fusions between conventional NUT carcinoma and other NUTM1-rearranged neoplasms remains to be elucidated. This review will focus on recent discoveries of NUTM1 fusions found in pediatric cancers, their prognostic impact, and emergence as novel oncogenic drivers.

Fine-Tuning the Relevance of Molecular Targets to Pediatric Cancer: Addressing Additional Layers of Complexity.

The Research to Accelerate Cures and Equity (RACE) for Children Act requires an assessment of molecular targets relevant to pediatric cancer. Due to the biological complexity, candidate molecular targets have been primarily evaluated based on single features such as the presence of mutations or deregulated expression. As the understanding of tumor biology evolves, the relevance of certain molecular targets may need to be assessed at isoform and/or mutation variant level to optimize tailored therapeutic interventions.

Assessing Information Gaps Associated with Initial Pediatric Study Plans for New Oncology Drug and Biological Products.

The Research Acceleration for Cure and Equity (RACE) for Children Act requires sponsors to submit a Pediatric Study Plan (PSP) with a proposed pediatric investigation of new molecularly targeted drugs and biologics that are intended for treatment of adult cancers, and whose target is relevant to pediatric cancer or provide a justification for a plan to request a deferral or waiver of the required investigation. A landscape analysis was performed to identify trends in information gaps associated with a sponsor's first initial PSP (iPSP) submission for oncologic new molecular entities received in 2021. Comments sent to sponsors by the US Food and Drug Administration (FDA) during the review process of each evaluated iPSP were categorized using nine flags relating to different portions of the PSP. For iPSPs that included a plan for a full waiver request, the most common information gap was inadequate justification based on molecular target relevance. All other sponsor proposed plans (deferral and/or partial waiver or investigation) were found to have information gaps related to clinical study features, clinical pharmacology, and/or missing clinical or nonclinical data. This landscape analysis of iPSPs shows the trends in comments that often occur during initial review and may help to provide sponsors with more direction for preparing an adequate iPSP to fulfill statutory requirements aimed at ensuring pediatric patients are considered in the development of new molecularly targeted drugs.

Effect of Obesity on the Pharmacokinetics and Pharmacodynamics of Anticancer Agents.

An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small-molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier-mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese.

FDA Approval Summary: Ripretinib for Advanced Gastrointestinal Stromal Tumor.

On May 15, 2020, the FDA approved ripretinib for adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with three or more kinase inhibitors, including imatinib. The approval was based on results from INVICTUS (NCT03353753), an international, multi-center, double-blind, placebo-controlled trial. Patients were randomly allocated (2:1) to receive either ripretinib 150 mg once daily (n = 85) or matching placebo (n = 44). The trial demonstrated a statistically significant improvement in progression-free survival (PFS) as assessed by modified RECIST v1.1 by blinded independent central review for patients randomized to ripretinib, with a median PFS of 6.3 months [95% confidence interval (CI): 4.6-6.9] compared with 1.0 month (95% CI: 0.9-1.7) for placebo [HR: 0.15 (95% CI: 0.09-0.25); P < 0.0001, stratified log-rank test]. There was no statistically significant difference in objective response rate in the ripretinib arm, 9% (95% CI: 4.2-18) compared with placebo 0% [(95% CI: 0-8); P = 0.0504, Fisher exact test]. The median overall survival (OS) in the ripretinib arm was 15.1 months (95% CI: 12.3-15.1) compared with 6.6 months (95% CI: 4.1-11.6) in the placebo arm. A formal statistical comparison of OS was not made due to the prespecified hierarchical analysis plan. The most common (≥20%) adverse events with ripretinib, in order of decreasing frequency, were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Other important risks of ripretinib include new primary cutaneous malignancies, hypertension, and cardiac dysfunction.

FDA Approval Summary: Amivantamab for the Treatment of Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

The FDA granted accelerated approval for amivantamab-vmjw (hereafter referred to as amivantamab), a bispecific antibody directed against EGFR and mesenchymal-epithelial transition receptor, on May 21, 2021, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Approval was based on results of an ongoing, multicenter, nonrandomized, open-label, multicohort clinical trial (CHRYSALIS, NCT02609776), demonstrating a substantial overall response rate (ORR) and durable responses, with an ORR of 40% [95% confidence interval (CI): 29-51] and a median response duration of 11.1 months (95% CI: 6.9-not evaluable). Guardant360 CDx was contemporaneously approved as a companion diagnostic for this indication to identify EGFR exon 20 insertion mutations in plasma specimens. The most notable safety finding was the high incidence (66%) of infusion-related reactions, which is addressed in both the Dosage and Administration and Warnings and Precautions sections of the product label. Other common adverse reactions (occurring in ≥20% of patients) were rash, paronychia, musculoskeletal pain, dyspnea, nausea and vomiting, fatigue, edema, stomatitis, cough, and constipation. The approval of amivantamab was the first approval of a targeted therapy for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations.

FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements.

On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120-101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%-52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement.

On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy. Safety was based on a total of 466 patients, 146 of whom had cholangiocarcinoma and received the recommended dose. Efficacy endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent review committee using RECIST 1.1. ORR was 36% (95% confidence interval: 27-45). Median DOR was 9.1 months. The most common adverse reactions were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib. The recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. FDA also approved the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.

FDA Approval Summary: Ivosidenib for the Treatment of Patients with Advanced Unresectable or Metastatic, Chemotherapy Refractory Cholangiocarcinoma with an IDH1 Mutation.

On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma (CCA) as detected by an FDA-approved test with disease progression after 1 to 2 prior lines of systemic therapy for advanced disease. The approval was based on data from Study AG120-C-005 (ClarIDHy), a double-blind placebo-controlled trial that randomly allocated (2:1) patients to receive either ivosidenib or placebo. Independently assessed progression-free survival (PFS) was the primary endpoint. With a median follow-up of 6.9 months, the HR for PFS was 0.37 [95% confidence interval (CI), 0.25-0.54; P < 0.0001). Overall survival (OS) was the key secondary endpoint. At the final analysis of OS, with 70.5% of patients in the placebo arm receiving ivosidenib post disease progression, a non-statistically significant improvement in the ivosidenib arm with an HR = 0.79 (95% CI, 0.56-1.12) and median OS of 10.3 months (95% CI, 7.8-12.4) and 7.5 months (95% CI, 4.8-11.1) in the ivosidenib and placebo arms, respectively, were reported. Adverse reactions occurring in >20% of patients receiving ivosidenib were fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, and decreased appetite. Adverse reactions occurring in >20% of patients receiving placebo were fatigue/asthenia, nausea, abdominal pain, and vomiting. This is the first approval for the subset of patients with CCA harboring an IDH1 mutation.

FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease-Associated Tumors.

On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease-associated RCC, ORR was 49% [95% confidence interval (CI), 36-62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41-81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52-98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication.

FDA Approval Summary: Margetuximab plus Chemotherapy for Advanced or Metastatic HER2-Positive Breast Cancer.

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.

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma.

On December 18, 2019, the FDA granted accelerated approval to enfortumab vedotin-ejfv (PADCEV; Astellas and Seattle Genetics) for treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 or programmed death ligand 1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Substantial evidence of effectiveness for this application is obtained from Cohort 1 of the single-arm, multicenter Study EV-201. Patients received enfortumab vedotin (EV) 1.25 mg/kg (up to a maximum dose of 125 mg) intravenously on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Confirmed objective response rate in the 125-patient efficacy population determined by blinded independent central review was 44% [95% confidence interval (CI), 35.1-53.2], with complete responses in 12%. Median response duration was 7.6 months (95% CI, 6.3-not estimable). Grade 3-4 adverse reactions occurred in 73% of patients. Hyperglycemia, peripheral neuropathy, ocular disorders, skin reactions, infusion site extravasations, and embryo-fetal toxicity are labeled as warnings and precautions for EV. The article summarizes the data and the FDA thought process supporting accelerated approval of EV. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).