FDA regulatory considerations for the review of drugs intended to treat pediatric cancers and rare tumors.

PURPOSE OF REVIEW: We describe select recent FDA approvals in pediatric cancers and rare tumors, and the unique regulatory considerations raised by each application. RECENT FINDINGS: The approvals of naxitamab, selumetinib, selpercatinib, and crizotinib for pediatric and adolescent patients between April 2020 and January 2021 all represented first FDA approvals in their respective pediatric or adolescent populations. In addition, all represent approvals of targeted therapies administered in select patient populations, and were based on overall response rate (ORR) and duration of response (DOR) data in single-arm trials. SUMMARY: Recent approvals for the pediatric oncology indications have often, but not always, relied in part upon investigator-sponsored clinical trials. Early engagement with regulatory agencies to discuss drug development in rare populations is critical to obtain early agreement on trial design and streamline development. Although reliance on ORR and DOR data may be feasible to support an approval, the ability to rely on response rate depends on many factors, including the disease context, reliability of radiographic assessment, and the results of the trial. In some cases, a time-to-event endpoint may be most appropriate to assess clinical benefit; early consideration should be given to the feasibility of conducting of a randomized trial.

FDA Supplemental Approval Summary: Lenvatinib for the Treatment of Unresectable Hepatocellular Carcinoma.

On August 16, 2018, the U.S. Food and Drug Administration approved lenvatinib (Lenvima, Eisai Inc.) for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Approval was based on an international, multicenter, randomized, open-label, noninferiority trial (REFLECT; NCT01761266) conducted in 954 patients with previously untreated metastatic or unresectable HCC. Patients were randomized (1:1) to receive lenvatinib (12 mg orally once daily for patients with a baseline body weight ≥60 kg and 8 mg orally once daily for patients with a baseline body weight <60 kg) or sorafenib (400 mg orally twice daily) until radiological disease progression or unacceptable toxicity. REFLECT demonstrated that lenvatinib was noninferior but not statistically superior to sorafenib for overall survival (OS; hazard ratio, [HR] 0.92; 95% confidence intervals [CI], 0.79-1.06), with median OS of 13.6 and 12.3 months in the lenvatinib and sorafenib arms, respectively. REFLECT also demonstrated statistically significant improvements in investigator-assessed progression-free survival (PFS; HR, 0.66; 95% CI, 0.57-0.77]; p < 0.001), corresponding to median PFS of 7.4 and 3.7 months and overall response rate of 24.1% vs 9.2% per modified RECIST for HCC (mRECIST) in the lenvatinib and sorafenib arms, respectively. Consistent results were observed by an independent review facility per RECISTv1.1 and per mRECIST. The most common adverse reactions observed in the lenvatinib-treated patients (≥20%) in decreasing frequency were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. IMPLICATIONS FOR PRACTICE: This article describes the U.S. Food and Drug Administration's review of data from a single trial, REFLECT, that supported the approval of lenvatinib, as a single agent, for the first-line treatment of unresectable hepatocellular carcinoma (HCC). REFLECT was an open-label, noninferiority trial that randomized 954 patients with HCC who were ineligible for liver-directed therapy with no prior systemic therapy for HCC to lenvatinib or sorafenib. REFLECT demonstrated that lenvatinib-treated patients had similar survival, more responses, and longer time to progression than those receiving sorafenib. Serious side effects were more common among lenvatinib-treated patients. Lenvatinib is an effective treatment for patients with previously untreated HCC.

Benefit-Risk Summary of Nivolumab for the Treatment of Patients with Unresectable Advanced, Recurrent, or Metastatic Esophageal Squamous Cell Carcinoma After Prior Fluoropyrimidine- and Platinum-Based Chemotherapy.

On June 10, 2020, the U.S. Food and Drug Administration (FDA) approved nivolumab (OPDIVO; Bristol Myers Squibb, New York, NY) for the treatment of patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. Approval was based on the results of a single, randomized, active-control study (ATTRACTION-3) that randomized patients to receive nivolumab or investigator's choice of taxane chemotherapy (docetaxel or paclitaxel). The study demonstrated a significant improvement in overall survival (OS; hazard ratio = 0.77; 95% confidence interval: 0.62-0.96; p = .0189) with an estimated median OS of 10.9 months in the nivolumab arm compared with 8.4 months in the chemotherapy arm. Overall, fewer patients in the nivolumab arm experienced treatment-emergent adverse events (TEAEs) of any grade, grade 3-4 TEAEs, and serious adverse events compared with the control arm. The safety profile of nivolumab in patients with ESCC was generally similar to the known safety profile of nivolumab in other cancer types with the following exception: esophageal fistula was identified as a new, clinically significant risk in patients with ESCC treated with nivolumab. Additionally, the incidence of pneumonitis was higher in the ESCC population than in patients with other cancer types who are treated with nivolumab. This article summarizes the FDA review of the data supporting the approval of nivolumab for the treatment of ESCC. IMPLICATIONS FOR PRACTICE: The approval of nivolumab for the treatment of adult patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy was based on an overall survival (OS) benefit from a randomized, open-label, active-controlled study called ATTRACTION-3. Prior to this study, no drug or combination regimen had demonstrated an OS benefit in a randomized study for patients with ESCC after prior fluoropyrimidine- and platinum-based chemotherapy.

FDA Approval Summary: Nivolumab Plus Ipilimumab for the Treatment of Patients with Hepatocellular Carcinoma Previously Treated with Sorafenib.

On March 10, 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval to nivolumab in combination with ipilimumab for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. The recommended approved dosage was nivolumab 1 mg/kg i.v. plus ipilimumab 3 mg/kg i.v. every 3 weeks for four cycles, followed by nivolumab 240 mg i.v. every 2 weeks. The approval was based on data from cohort 4 of CheckMate 040, which randomized patients with advanced unresectable or metastatic HCC previously treated with or who were intolerant to sorafenib to receive one of three different dosing regimens of nivolumab in combination with ipilimumab. Investigator-assessed overall response rate (ORR) was the primary endpoint, and ORR assessed by blinded independent central review (BICR) was an exploratory endpoint. BICR-assessed ORR and duration of response (DoR) form the primary basis of the FDA's regulatory decision, and BICR-assessed ORR was comparable in all three arms at 31%-32% with 95% confidence interval [CI] 18%-47%. The DoR ranged from 17.5 to 22.2 months across the three arms, with overlapping 95% CIs. Adverse events (AEs) were generally consistent with the known AE profiles of nivolumab and ipilimumab, and no new safety events were identified. This article summarizes the FDA review of the data supporting the approval of nivolumab and ipilimumab for the treatment of HCC. IMPLICATIONS FOR PRACTICE: Nivolumab and ipilimumab combination therapy is another option for patients with advanced hepatocellular carcinoma who experience radiographic progression during or after sorafenib or sorafenib intolerance. No new toxicities were identified, but, as expected, increased toxicity was observed with the addition of ipilimumab to nivolumab as compared with nivolumab alone, which is also approved for the same indication. Whether to administer nivolumab as a single agent or in combination with ipilimumab is expected to be a joint decision between the oncologist and patient, taking into consideration the potential for a higher likelihood of response and the potentially higher rate of toxicity with the combination.

FDA Approval Summary: Pembrolizumab for Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Expressing PD-L1.

On September 22, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab (Keytruda, Merck & Co., Inc., Whitehouse Station, NJ) for the treatment of patients with recurrent, locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after two or more systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test. Approval was based on demonstration of durable overall response rate (ORR) in a multicenter, open-label, multicohort trial (KEYNOTE-059/Cohort 1) that enrolled 259 patients with locally advanced or metastatic gastric or GEJ adenocarcinoma. Among the 55% (n = 143) of patients whose tumors expressed PD-L1 based on a combined positive score ≥1 and either were microsatellite stable or had undetermined microsatellite instability or mismatch repair status, the confirmed ORR as determined by blinded independent central review was 13.3% (95% CI, 8.2-20.0); 1.4% had complete responses. Response durations ranged from 2.8+ to 19.4+ months; 11 patients (58%) had response durations of 6 months or longer, and 5 patients (26%) had response durations of 12 months or longer. The most common (≥20%) adverse reactions of pembrolizumab observed in KEYNOTE-059/Cohort 1 were fatigue, decreased appetite, nausea, and constipation. The most frequent (≥2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Pembrolizumab was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx test (Dako, Agilent, Santa Clara, CA) for selection of patients with gastric cancer for treatment with pembrolizumab based on PD-L1 tumor expression. IMPLICATIONS FOR PRACTICE: This report presents key information on the basis for Food and Drug Administration approval of pembrolizumab for the treatment of patients with locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1. The report discusses the basis for limiting the indication to patients with PD-L1-expressing tumors and the basis for recommending that PD-L1 status be assessed using a fresh tumor specimen if PD-L1 expression is not detected in an archival gastric or GEJ cancer specimen.

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation.

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.

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.

Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma Clinical Trials: An FDA Educational Symposium.

In October 2022, the FDA Oncology Center of Excellence hosted an educational symposium entitled, "Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma (pLGG) Clinical Trials." The symposium brought together patient advocates, regulators from the FDA and the European Medicines Agency (EMA), and an international group of academic thought leaders in the field of pediatric neuro-oncology to discuss the potential role of functional outcomes, including visual acuity, motor function, and neurocognitive performance, as endpoints in clinical trials enrolling patients with pLGG. The panel discussed challenges and opportunities regarding the selection, implementation, and evaluation of clinical outcome assessments in these functional domains and outlined key considerations for their inclusion in future clinical trial design and role in new drug development.

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: 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: 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.

Paediatric strategy forum for medicinal product development of PI3-K, mTOR, AKT and GSK3ß inhibitors in children and adolescents with cancer.

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.

Transcriptomic analysis of pancreatic adenocarcinoma specimens obtained from Black and White patients.

In pancreatic cancer clinical trials, Black patients are under-represented while having higher morbidity and mortality rates as compared to other racial groups. Multiple factors, including socioeconomic and lifestyle factors may contribute to this disparity, but genomic contributions remain unclear. In an exploratory project to identify genes that may contribute to differences in survival between Black (n = 8) and White (n = 20) patients with pancreatic cancer, transcriptomic sequencing of over 24,900 genes was performed in human pancreatic tumor and non-tumor tissue obtained from Black and White patients. Over 4,400 genes were differentially expressed in tumor and non-tumor tissue, irrespective of race. To validate these results, the expression of four genes (AGR2, POSTN, TFF1, and CP) reported to be up-regulated in pancreatic tumor tissue as compared to non-tumor tissue were confirmed using quantitative PCR. Transcriptomic analysis that compared pancreatic tumor tissue from Black and White patients revealed differential expression in 1,200 genes, while a comparison of the non-tumor and tumor gene expression differences within each race revealed over 1,500 tumor-specific differentially expressed genes in pancreatic tumor and non-tumor tissue from Black patients. We identified TSPAN8 as a potential tumor-specific gene significantly overexpressed in pancreatic tumor tissue in Black patients as compared to White patients. Using Ingenuity Pathway Analysis software to compare the race-associated gene expression profiles, over 40 canonical pathways were identified to be potentially impacted by the gene expression differences between the races. Heightened expression of TSPAN8 was associated with poor overall survival, suggesting TSPAN8 as one potential genetic factor contributing to the differential outcomes in Black patients with pancreatic cancer, supporting the potential utility of larger genomic studies to further explore the role of TSPAN8 in pancreatic cancer.

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: Mobocertinib for Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

On September 15, 2021, the FDA granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals USA, Inc.) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The approval was based on data from Study AP32788-15-101 (NCT02716116), an international, non-randomized, multi-cohort clinical trial that included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The overall response rate in 114 patients whose disease had progressed on or after platinum-based chemotherapy was 28% [95% confidence interval (CI), 20%-37%] with a median duration of response of 17.5 months (95% CI, 7.4-20.3). The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a Boxed Warning for QTc prolongation and torsades de pointes. This is the first approval of an oral targeted therapy for patients with advanced EGFR exon 20 insertion mutation-positive NSCLC.

FDA Approval Summary: Nivolumab in Combination with Ipilimumab for the Treatment of Unresectable Malignant Pleural Mesothelioma.

On October 2, 2020, FDA approved nivolumab with ipilimumab as first-line treatment for adult patients with unresectable malignant pleural mesothelioma (MPM). The approval was based on results from Study CA209743 (CHECKMATE-743), an open-label trial of patients with MPM randomized to receive nivolumab and ipilimumab for up to 2 years (n = 303) or six cycles of chemotherapy with cisplatin or carboplatin plus pemetrexed (n = 302). Overall survival (OS) was improved for patients who received nivolumab and ipilimumab, with a median OS of 18.1 months [95% confidence interval (CI), 16.8-21.5] compared with 14.1 months (95% CI: 12.5-16.2; HR, 0.74; 95% CI, 0.61-0.89; P = 0.002), for patients who received chemotherapy. The magnitude of benefit was larger for patients with non-epithelioid versus epithelioid histology. Additional clinical pharmacology data support an alternative dosing regimen of nivolumab than evaluated in the trial, which will reduce the number of required treatment visits. This application was reviewed under FDA's Project Orbis, in collaboration with Australia's Therapeutic Goods Administration, Switzerland's Swissmedic, Health Canada, and Brazil's National Health Surveillance Agency or ANVISA (Agência Nacional de Vigilância Sanitária). Nivolumab and ipilimumab is the first drug regimen approved by FDA for MPM since 2004.

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: Pembrolizumab, Atezolizumab, and Cemiplimab-rwlc as Single Agents for First-Line Treatment of Advanced/Metastatic PD-L1-High NSCLC.

FDA's approval of cemiplimab-rwlc on February 22, 2021, follows prior approvals of pembrolizumab and atezolizumab for similar indications as first-line treatment for patients with programmed death ligand-1 (PD-L1)-high advanced non-small cell lung cancer (NSCLC). Approvals of these anti-PD-L1 agents were supported by statistically significant and clinically meaningful improvements in overall survival (OS) in international, multicenter, active-controlled randomized trials. In KEYNOTE-024, the OS HR was 0.60 [95% confidence interval (CI), 0.41-0.89; P = 0.005] favoring pembrolizumab over platinum-doublet chemotherapy. In IMpower110, the OS HR was 0.59 (95% CI, 0.40-0.89; P = 0.0106) favoring atezolizumab over platinum-doublet chemotherapy. In Study 1624, the OS HR was 0.68 (95% CI, 0.53-0.87; P = 0.0022) favoring cemiplimab-rwlc over platinum-doublet chemotherapy. The progression-free survival (PFS) effect sizes for these anti-PD-L1 antibodies were also comparable across their respective registrational trials, and their safety profiles were consistent with the anti-PD-L1 class adverse event profile. The consistent survival benefits and manageable toxicity profiles of these single-agent anti-PD-L1 antibodies have established them as important treatment options in the PD-L1-high NSCLC treatment landscape. FDA approvals of these anti-PD-L1 antibodies, based on their favorable benefit-risk profiles, present effective chemotherapy-free therapeutic options for patients with advanced PD-L1-high NSCLC in the United States.

Paediatric Strategy Forum for medicinal product development of multi-targeted kinase inhibitors in bone sarcomas: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities.

FDA Approval Summary: Entrectinib for the Treatment of NTRK gene Fusion Solid Tumors.

The FDA-approved entrectinib on August 15, 2019, for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy. Approval was based on demonstration of a durable overall response rate of 57% (95% confidence interval: 43-71), including a complete response rate of 7%, among 54 entrectinib-treated patients with 10 different tumor types harboring an NTRK fusion enrolled in one of three single-arm clinical trials. The durations of response ranged from 2.8 months to 26.0+ months; 68% of responses lasted ≥ 6 months. The most serious toxicities of entrectinib are congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation, and vision disorders. Adverse reactions were manageable through dose interruptions (46%), dose reductions (29%), or discontinuation of entrectinib (9%). This is the third approval of a cancer drug for treatment of a tissue agnostic, biomarker-defined cancer.