FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations.

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.

FDA Approval Summary: Eflornithine for High-Risk Neuroblastoma Following Prior Multiagent, Multimodality Therapy.

On December 13, 2023, the U.S. Food and Drug Administration (FDA) approved eflornithine (IWILFIN, US WorldMeds) to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. The approval was based on an externally controlled trial (ECT) consisting of a single-arm trial, Study 3(b), compared to an external control derived from a National Cancer Institute (NCI)/Children's Oncology Group (COG)-sponsored clinical trial (Study ANBL0032) and supported by confirmatory evidence. In the protocol-specified primary analysis, the event-free survival (EFS) hazard ratio (HR) was 0.48 (95% confidence interval [CI]: 0.27, 0.85) and overall survival (OS) HR was 0.32 (95% CI: 0.15, 0.70). The most common adverse reactions (≥5%) were hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. Notably, this is the first oncology drug approval which relies on an ECT as the primary clinical data to support substantial evidence of effectiveness. This was made possible by a distinctly high-quality, comparable external control dataset with consistent treatment effect estimations demonstrated in multiple sensitivity and supportive analyses. Eflornithine's manageable safety profile and strong nonclinical and mechanistic data provided further support for the approval, and the evidentiary package was evaluated in the context of high unmet need in a rare, life-threatening cancer.

FDA Approval Summary: Repotrectinib for locally advanced or metastatic ROS1-positive non-small cell lung cancer.

On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro®, Bristol Myers Squibb Corporation), for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter "ROS1-positive") NSCLC, (NCT03093116), who were either treatment naïve or had received prior ROS1 TKI and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors (RECIST) version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI 68, 88); median duration of response was 34.1 months (95% CI 26, NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI 25, 52). The median duration of response was 14.8 months (95% CI 7.6, NE) BICR-assessed responses were observed in CNS metastases in patients in both cohorts, and in patients who developed resistance mutations following prior TKI therapy. The most common (> 20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.

FDA Approval Summary: Durvalumab and Pembrolizumab, Immune Checkpoint inhibitors for the Treatment of Biliary Tract Cancer.

On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials, which randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial the median OS of patients receiving durvalumab was 12.8 months (95% confidence interval [CI] 11.1, 14.0) and 11.5 months (95% CI 10.1, 12.5) in patients receiving placebo (HR 0.80 [95% CI 0.66, 0.97]). In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI 11.5, 13.6) and 10.9 months (95% CI 9.9, 11.6) in patients receiving placebo (HR 0.83 [95% CI 0.72, 0.95]). The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic option for these patients.

Reflections and Roadmaps: Career Development Beyond the FDA-AACR Oncology Educational Fellowship.

In 2020, the U.S. Food and Drug Administration's Oncology Center of Excellence, in collaboration with the American Association for Cancer Research, launched a novel educational partnership known as the FDA-AACR Oncology Educational Fellowship. This year-long program is aimed for hematology/oncology fellows, scientists, and early-career investigators, offering an in-depth exploration of the regulatory review process by blending didactic learning with practical cases discussing oncology drug approvals. The fellowship has been met with enthusiastic feedback, with participants lauding its role in demystifying the regulatory landscape and enhancing their professional careers. This paper reflects on the experiences of four alumni, showcasing the program's transformative impact across diverse oncology career paths in government, academia, and industry.

FDA Approval Summary: Fruquintinib for the Treatment of Refractory Metastatic Colorectal Cancer.

On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy, an anti­VEGF therapy, and, if RAS wild­type and medically appropriate, an anti EGFR therapy. Approval was based on Study FRESCO-2, a globally-conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival (PFS). A total of 691 patients were randomized (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 (95% CI: 0.55, 0.80; p<0.001). The median OS was 7.4 months (95% CI: 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI: 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with inhibition of the VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI: 0.51, 0.83; p<0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild­type and medically appropriate, an anti-EGFR therapy.

Remote Monitoring and Data Collection for Decentralized Clinical Trials.

Importance: Less than 5% of patients with cancer enroll in a clinical trial, partly due to financial and logistic burdens, especially among underserved populations. The COVID-19 pandemic marked a substantial shift in the adoption of decentralized trial operations by pharmaceutical companies. Objective: To assess the current global state of adoption of decentralized trial technologies, understand factors that may be driving or preventing adoption, and highlight aspirations and direction for industry to enable more patient-centric trials. Design, Setting, and Participants: The Bloomberg New Economy International Cancer Coalition, composed of patient advocacy, industry, government regulator, and academic medical center representatives, developed a survey directed to global biopharmaceutical companies of the coalition from October 1 through December 31, 2022, with a focus on registrational clinical trials. The data for this survey study were analyzed between January 1 and 31, 2023. Exposure: Adoption of decentralized clinical trial technologies. Main Outcomes and Measures: The survey measured (1) outcomes of different remote monitoring and data collection technologies on patient centricity, (2) adoption of these technologies in oncology and all therapeutic areas, and (3) barriers and facilitators to adoption using descriptive statistics. Results: All 8 invited coalition companies completed the survey, representing 33% of the oncology market by revenues in 2021. Across nearly all technologies, adoption in oncology trials lags that of all trials. In the current state, electronic diaries and electronic clinical outcome assessments are the most used technology, with a mean (SD) of 56% (19%) and 51% (29%) adoption for all trials and oncology trials, respectively, whereas visits within local physician networks is the least adopted at a mean (SD) of 12% (18%) and 7% (9%), respectively. Looking forward, the difference between the current and aspired adoption rate in 5 years for oncology is large, with respondents expecting a 40% or greater absolute adoption increase in 8 of the 11 technologies surveyed. Furthermore, digitally enabled recruitment, local imaging capabilities, and local physician networks were identified as technologies that could be most effective for improving patient centricity in the long term. Conclusions and Relevance: These findings may help to galvanize momentum toward greater adoption of enabling technologies to support a new paradigm of trials that are more accessible, less burdensome, and more inclusive.

Cytoreductive nephrectomy in the era of immune checkpoint inhibitors: a US Food and Drug Administration pooled analysis.

BACKGROUND: This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma with or without cytoreductive nephrectomy before a combination of immune checkpoint inhibitor and antiangiogenic therapy. METHODS: Data from 5 trials of immune checkpoint inhibitors plus antiangiogenic therapy were pooled. Only patients with stage 4 disease at initial diagnosis were included to ensure that nephrectomy was performed for cytoreductive purposes and not to previously treat an earlier stage of disease. The effect of cytoreductive nephrectomy before immune checkpoint inhibitor therapy on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and the presence of sarcomatoid differentiation. RESULTS: A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively; the adjusted hazard ratio was 0.71 (95% confidence interval = 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively; the adjusted hazard ratio was 0.63 (95% confidence interval = 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without cytoreductive nephrectomy. CONCLUSIONS: Patients with metastatic renal cell carcinoma who undergo cytoreductive nephrectomy before immune checkpoint inhibitor plus antiangiogenic therapy had improved outcomes compared with patients without cytoreductive nephrectomy. Selection factors for cytoreductive nephrectomy may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior cytoreductive nephrectomy may be considered when designing clinical trials to assess the impact of this factor on prognosis.

Correlations of response rate and progression-free survival with overall survival in immunotherapy trials for metastatic non-small-cell lung cancer: an FDA pooled analysis.

BACKGROUND: Radiographic changes might not fully capture the treatment effects of immune checkpoint inhibitors (ICIs). We aimed to assess correlations of overall response rate and progression-free survival with overall survival in trials of ICIs for metastatic non-small-cell lung cancer (NSCLC). METHODS: To assess trial-level and patient-level correlations of overall response rate and progression-free survival with overall survival, we conducted a pooled analysis of first-line randomised trials (including patients aged ≥18 years with metastatic squamous and non-squamous NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1) submitted to the US Food and Drug Administration from June 24, 2016, to March 16, 2021. Eligible trials evaluated at least one ICI in the experimental group versus chemotherapy in the control group. At the trial level, we used weighted linear regression to derive coefficients of determination (R2). At the patient level, we used Cox proportional hazards models to compare overall survival between responders versus non-responders per Response Evaluation Criteria in Solid Tumours (version 1.1). FINDINGS: A total of 13 trials including 9285 patients evaluated ICIs alone or in combination with chemotherapy versus chemotherapy alone. At the trial level, the R2 was 0·61 (95% CI 0·32-0·84) for correlation of overall response rate with overall survival and 0·70 (0·40-0·89) for correlation of progression-free survival with overall survival. Correlations ranged from weak to moderate when evaluating subgroups by PD-L1 expression and were consistent across trials evaluating ICIs alone or in combination with chemotherapy. At the patient level, responders had longer overall survival than non-responders (hazard ratio [HR] 0·28 [95% CI 0·26-0·30]). Among responders, overall survival was longer in patients enrolled in experimental groups than in control groups (HR 0·54 [95% CI 0·48-0·61]). INTERPRETATION: Correlations of overall response rate and progression-free survival with overall survival were generally moderate in this pooled analysis. The findings support routine analysis of mature overall survival data, where feasible, in first-line randomised trials of ICIs for metastatic NSCLC. FUNDING: US Food and Drug Administration.

FDA Approval Summary: Enfortumab Vedotin plus Pembrolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma.

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multicohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% confidence interval, 59-76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA.

US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The approval was based on the HRR gene-mutated (HRRm) population of TALAPRO-2, a randomized, double-blind trial that randomly assigned 1,035 patients with mCRPC to receive enzalutamide with either talazoparib or placebo. Two cohorts enrolled sequentially: an all-comer population (Cohort 1), followed by an HRRm-only population (Cohort 2). The independent primary end points were radiographic progression-free survival (rPFS) per blinded independent central review (BICR) in Cohort 1 (all-comers) and in the combined HRRm population (all HRRm patients from Cohorts 1 and 2). Overall survival (OS) was a key secondary end point. RESULTS: A statistically significant improvement in rPFS by BICR was demonstrated in both the all-comers cohort and the combined HRRm population, with hazard ratio (HR) of 0.63 (95% CI, 0.51 to 0.78; P < .0001) and 0.45 (95% CI, 0.33 to 0.61; P < .0001), respectively. In an exploratory analysis of the 155 patients with BRCA-mutated (BRCAm) mCRPC, rPFS HR was 0.20 (95% CI, 0.11 to 0.36). In the non-HRRm/unknown stratum of Cohort 1 (n = 636), the rPFS HR was 0.70 (95% CI, 0.54 to 0.89). OS was immature. CONCLUSION: Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.

Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer: A US Food and Drug Administration Pooled Analysis.

PURPOSE: We performed a pooled analysis of multiple trials of poly(ADP-ribose) polymerase inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) to investigate the efficacy of PARPi in each individual homologous recombination repair (HRR) mutated (m) gene. PATIENTS AND METHODS: We pooled patient-level data from trials of PARPi in mCRPC that reported mutation status in individual HRR genes. Any HRR gene with available data across all the randomized trials of PARPi in first-line mCRPC was selected. The hazard ratios (HRs; 95% CI) for radiographic progression-free survival (rPFS; by blinded independent review) and overall survival (OS) of a PARPi plus an androgen receptor pathway inhibitor (ARPI) relative to placebo plus an ARPI in the pool of three randomized trials in first-line mCRPC were calculated using Kaplan-Meier estimates and a Cox proportional hazards model. RESULTS: In ATMm (N = 268), rPFS HR was 1.05 (0.74 to 1.49) and OS HR was 1.18 (0.82 to 1.71). In BRCA1m (N = 64), rPFS HR was 0.51 (0.23 to 1.1) and OS HR was 0.74 (0.34 to 1.61). In BRCA2m (N = 422), rPFS HR was 0.31 (0.23 to 0.42) and OS HR was 0.66 (0.49 to 0.89). In CDK12m (N = 164), rPFS HR was 0.50 (0.32 to 0.80) and OS HR was 0.63 (0.39 to 0.99). In CHEK2m (N = 172), rPFS HR was 1.06 (0.67 to 1.66) and OS HR was 1.53 (0.95 to 2.46). In PALB2m (N = 41) rPFS HR was 0.52 (0.23 to 1.17) and OS HR was 0.78 (0.34 to 1.8). CONCLUSION: In this pooled analysis, benefit from PARPi appeared greatest for patients with BRCA1m, BRCA2m, CDK12m, and PALB2m. Given limitations of this exploratory analysis, the apparent lack of benefit from PARPi in patients with CHEK2m or ATMm should be further explored in future clinical trials.

A Pooled Analysis of Treatment-Free Survival in Advanced Renal Cell Carcinoma.

PURPOSE: A clinically meaningful attribute of some immune-oncology (IO) regimens is potential durable clinical benefit during a treatment-free interval. We characterize treatment-free survival (TFS) with and without ongoing toxicity in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in patients with advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: Individual patient data were pooled by treatment arm from randomized trials submitted to the FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months of median follow-up. OS, TFS, TFS with and without toxicity, and time to all protocol therapy cessation were assessed. TFS was estimated by 30-month restricted mean times defined as area between Kaplan-Meier curves for two time-to-event endpoints originating at randomization: time to all protocol therapy cessation and time to subsequent systemic therapy initiation or death. RESULTS: Three trials met criteria for analysis; 1183 pts received IO-TKI versus 1184 on control arms received TKI alone (sunitinib [SUN]). IO-TKI and SUN groups spent 9% (2.7 months [95% confidence interval (CI): 1.8, 3.5]) and 10% (2.9 months [95% CI: 2.1, 3.8]) of the 30-mo period alive and treatment-free, respectively. Mean TFS without grade ≥3 toxicity was 1.7 and 2.3 months in IO-TKI and SUN groups, respectively. CONCLUSIONS AND RELEVANCE: In this post hoc partitioned survival analysis, TFS and TFS without toxicity appeared similar in the IO-TKI group compared to the SUN group. These findings may reflect continuation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in 2 trials.

US Food and Drug Administration Approval Summary: Elacestrant for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, ESR1-Mutated Advanced or Metastatic Breast Cancer.

PURPOSE: The US Food and Drug Administration (FDA) approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy (ET). PATIENTS AND METHODS: Approval was based on EMERALD (Study RAD1901-308), a randomized, open-label, active-controlled, multicenter trial in 478 patients with ER+, HER2- advanced or metastatic breast cancer, including 228 patients with ESR1 mutations. Patients were randomly assigned (1:1) to receive either elacestrant 345 mg orally once daily (n = 239) or investigator's choice of ET (n = 239). RESULTS: In the ESR1-mut subgroup, EMERALD demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review assessment (n = 228; hazard ratio [HR], 0.55 [95% CI, 0.39 to 0.77]; P value = .0005). Although the overall survival (OS) end point was not met, there was no trend toward a potential OS detriment (HR, 0.90 [95% CI, 0.63 to 1.30]) in the ESR1-mut subgroup. PFS also reached statistical significance in the intention-to-treat population (ITT, N = 478; HR, 0.70 [95% CI, 0.55 to 0.88]; P value = .0018). However, improvement in PFS in the ITT population was primarily attributed to results from patients in the ESR1-mut subgroup. More patients who received elacestrant experienced nausea, vomiting, and dyslipidemia. CONCLUSION: The approval of elacestrant in ER+, HER2- advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.

Review of Racial and Ethnic Representation of Participants Enrolled in Pediatric Clinical Trials of Oncology Drugs Conducted Through FDA Written Requests.

Importance: The Best Pharmaceuticals for Children Act states that in issuing a written request (WR), the US Food and Drug Administration (FDA) shall consider the adequate representation (eg, proportionate to the disease population) of children from racial and ethnic minority populations. If the terms of the WR are fulfilled, the FDA may grant an additional 6 months of exclusivity for any unexpired patents and exclusivities attached to approved indications. Objective: To report on the race and ethnicity of participants enrolled in pediatric studies conducted in response to WRs for which pediatric exclusivity was granted between 2001 and 2021. Design, Setting, and Participants: This retrospective review examines pediatric exclusivity request submissions for oncologic drugs that received pediatric exclusivity between December 2001 and January 2021 based on fulfillment of the requirements of a WR that were identified using the FDA's Document Archiving Reporting and Regulatory Tracking System. Demographic data were manually abstracted from supporting study reports, and data were pooled across submissions for the analysis. Data were analyzed throughout 2022 and 2023. Main Outcomes and Measures: Representation by race, sex, and ethnicity in pediatric studies conducted in response to WRs. Results: A total of 22 pediatric exclusivity requests were identified, comprising 40 studies and 2025 patients. Most trials (26 [65%]) in the analysis were cooperative group studies. Representation by race was as follows: American Indian/Alaska Native (13 [0.6%]), African American/Black (228 [11.3%]), Asian (92 [4.6%]), Native Hawaiian/other Pacific Islander (33 [1.6%]), White (1303 [64.3%]), other (194 [9.6%]), and unknown/not reported (162 [8.0%]). Representation by sex was female individuals (41.2%) and male individuals (58.8%). Ethnicity was as follows: Hispanic (226 [5.7%]), non-Hispanic (910 [22.5%]), unknown/not reported ethnicity (2800 [69.1%]), and other ethnicity (114 [2.8%]). Conclusions and Relevance: The study results suggest that overall, representation of participants of racial and ethnic minority groups in studies supporting pediatric exclusivity requests appear comparable with the racial distribution of childhood cancers in the US based on data from the National Childhood Cancer Registry Explorer. However, fewer Hispanic participants were enrolled in the trials we reviewed (8%) compared with the representation of Hispanic patients in the National Childhood Cancer Registry (28%). This discrepancy may be partially explained by the large proportion of participants with unknown information regarding ethnicity. Further research into the reasons for the large proportion of participants with missing ethnicity information is needed.

FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation-Positive Low-Grade Glioma.

On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35-59] in the D+T arm and 11% (95% CI, 3.0-25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5-NE) in the D+T arm and not estimable (95% CI, 6.6- NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6- 11.8) [HR, 0.31 (95% CI, 0.17-0.55); P < 0.001] in the D+T and C+V arms, respectively. The most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation.

FDA Approval Summary: Tremelimumab in Combination with Durvalumab for the Treatment of Patients with Unresectable Hepatocellular Carcinoma.

On October 21, 2022, the FDA approved tremelimumab (Imjudo) in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma. The approval was based on the results from the HIMALAYA study, in which patients with unresectable hepatocellular carcinoma who were naïve to previous systemic treatment were randomly assigned to receive one of three study arms: tremelimumab in combination with durvalumab (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The primary objective of improvement in overall survival (OS) for tremelimumab in combination with durvalumab compared with sorafenib met statistical significance with a stratified HR of 0.78 [95% confidence interval (CI), 0.66-0.92; P = 0.0035]. The median OS was 16.4 months (95% CI, 14.2-19.6) with tremelimumab in combination with durvalumab and 13.8 months (95% CI, 12.3-16.1) with sorafenib. Adverse reactions occurring in ≥20% of patients receiving tremelimumab in combination with durvalumab were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and abdominal pain. The recommended tremelimumab dose for patients weighing 30 kg or more is 300 mg, i.v., as a single dose in combination with durvalumab 1,500 mg at cycle 1/day 1, followed by durvalumab 1,500 mg, i.v., every 4 weeks. For those weighing less than 30 kg, the recommended tremelimumab dose is 4 mg/kg, i.v., as a single dose in combination with durvalumab 20 mg/kg, i.v., followed by durvalumab 20 mg/kg, i.v., every 4 weeks.

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%).