Estimation of Percentage of Patients With Fibroblast Growth Factor Receptor Alterations Eligible for Off-label Use of Erdafitinib

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Question  What is the potential upper bound of off-label use of erdafitinib in cancers with fibroblast growth factor receptor (FGFR) alterations?

Findings  In this cross-sectional study, an estimated 76.1% of patients with advanced cancer expressing FGFR2 or FGFR3 alterations could be eligible for off-label treatment with erdafitinib. A total of 29 completed studies evaluating FGFR-targeting drugs in 11 cancer types and 10 ongoing studies on erdafitinib for different oncological indications were identified.

Meaning  This study indicates that the potential for off-label use of FGFR inhibitors, such as erdafitinib, spans a number of cancer types and a large patient population.

Importance  When a novel drug is granted accelerated approval, both its on-label and off-label uses must be taken into account.

Objectives  To estimate the potential upper bound of off-label use of erdafitinib to treat advanced cancer with fibroblast growth factor receptor gene (FGFR) alterations, compare it to the upper bound of on-label use in urothelial cancer, and to review studies that may support off-label use.

Design, Setting, and Participants  This cross-sectional study used frequency data on FGFR alterations by cancer type and the estimated number of deaths from all cancers for 2019 in the United States. Mortality statistics were used as surrogates for patients with advanced cancer. Analysis was conducted in May 2019.

Exposure  Percentage of patients with an FGFR2 or FGFR3 alteration.

Main Outcomes and Measures  Estimated number of patients with advanced cancer expressing an FGFR2 or FGFR3 alteration eligible for off-label use of erdafitinib by cancer type; number of studies investigating FGFR-targeting drugs for patients with cancer; and number of ongoing clinical trials on erdafitinib by cancer type.

Results  A total of 15 cancer types had reported FGFR alterations. Of 455 440 estimated patients who died of cancer in 2019, 17 019 (3.7%) were estimated to have FGFR2 or FGFR3 alterations. Of these patients, 12 955 (76.1%) could be eligible for off-label treatment with erdafitinib. A total of 29 completed studies evaluated FGFR-targeting drugs in 11 cancer types, and 10 ongoing studies are studying erdafitinib for different oncological indications.

Conclusions and Relevance  This study indicates that the potential for off-label use of FGFR inhibitors such as erdafitinib spans a number of cancer types and a large patient population. Systematic trials exploring off-label uses may be desirable for drugs that target clear, identifiable molecular alterations because this may be more efficient than off-label use in identifying clinical scenarios where the agent has activity.

Erdafitinib was recently granted accelerated approval by the US Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic urothelial cancer with fibroblast growth factor receptor 2 (FGFR2) or FGFR3 gene mutations or fusions.¹ Erdafitinib targets FGFR2 and FGFR3, receptors commonly expressed in metastatic urothelial cancer, and belongs to the more general class of tyrosine kinase inhibitors.² It was the first FGFR-targeting drug approved by the FDA. The approval of erdafitinib was based on overall response rate (ORR) in 87 patients with FGFR2 and FGFR3 alterations from a single-group, phase 2, multicenter study.^2,3 Among responders, median (interquartile range) duration of response was found to be 5.4 (4.2-6.9) months. The response rate varied considerably by alteration, with an ORR of 40.6% (26 of 64) for FGFR3 point mutations, 11.1% (2 of 18) for FGFR3 fusions, and 0% (0 of 6) for FGFR2 fusions.³

Urothelial cancer is not the only cancer type that harbors FGFR alterations, which may be found in breast cancer, non–small cell lung cancer, colorectal cancer, and endometrial cancer, among others.⁴ The availability of a drug targeting FGFR2 and FGFR3 alterations for 1 tumor type (ie, urothelial cancer) may encourage the off-label use in other types of cancers with these alterations. Patients with tumor types other than urothelial cancer already have access to erdafitinib through the expanded access program,⁵ and enthusiasm for precision therapies is high. Other studies have reported broad-based sequencing and off-label use of tyrosine kinase inhibitor paid for by insurers.⁶ Finally, empirical analyses show that molecularly targeted drugs are often recommended by expert panels for tumor types different from those that received approval.⁷

This study aimed to estimate the potential upper bound of off-label use of erdafitinib to treat other types of advanced cancer with FGFR alterations, determine an estimated ratio of off-label use to on-label use, and review studies that may support the benefit of off-label use.

In this cross-sectional study, we sought to estimate what percentage of FGFR2 and FGFR3 mutations and fusions were in approved vs unapproved tumor types for the drug erdafitinib. We also sought to document available, corroborative, or circumstantial evidence supporting the benefit of using erdafitinib to treat off-label tumor types.

Per Oregon Health and Science University human research protection program policy,⁸ this study did not require institutional review board approval as it did not involve personally identifiable data and all data are publicly available. This report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

We extracted cancer-specific FGFR aberration frequency data by histology from Helsten et al.⁴ We obtained the estimated number of deaths from all cancers from the American Cancer Society: Cancer Facts and Figures 2019.⁹ Cancer types were included in the analysis if found in data sets from Helsten et al⁴ and Cancer Facts and Figures 2019.⁹ We used mortality statistics as a surrogate for incident presentation of advanced or metastatic cancer. To determine the upper-bound number of patients eligible for off-label use of erdafitinib by cancer type, the number of cancer deaths was multiplied by the percentage of patients who had an FGFR2 or FGFR3 mutation or fusion for each cancer type. This process was replicated for patients with any FGFR alteration. By determining the number of cancer patients in each cancer type with any FGFR alteration, we sought to offer a second, broader estimation of potential eligibility for off-label treatment with erdafitinib.

Off-label use was defined as any use of erdafitinib for cancer types other than urothelial cancer. We determined off-label eligibility specifically for FGFR2 and FGFR3 alterations because erdafitinib was approved for these alterations in urothelial cancer. Our methods were similar to prior analyses of the estimated, upper-bound effect of genome-guided therapies¹⁰ and immunotherapy checkpoint inhibitors¹¹ in cancer medicine.

To review studies that may be used to support off-label use of erdafitinib, we searched PubMed for studies investigating therapies targeting FGFR alterations in cancer types other than urothelial cancer. To search PubMed, we used the article type filters of case reports, clinical study, and clinical trial and searched the phrase FGFR with 1 of the following cancer types: carcinoma of unknown primary site, non–small cell lung cancer, pancreatic exocrine cancer, breast cancer, endometrial cancer, colorectal cancer, glioma, head and neck squamous cell cancer, gastric or gastroesophageal junction cancer, ovarian cancer, renal cell cancer, cholangiocarcinoma, all sarcomas, and melanoma. All studies investigating the use of an FGFR-targeting drug to treat cancer patients were included. Articles investigating mouse models or in vivo studies were excluded as well as articles assessing FGFR alterations in patients without investigating a FGFR-targeting treatment. Data collected included the title of study, study type (case report, case series, or phase 1, 2, or 3 trial), randomization, primary outcome, and number of participants.

For ongoing trials of erdafitinib, a search was made on ClinicalTrials.gov using the term erdafitinib. Results were filtered by excluding trials that were suspended, terminated, completed, or withdrawn. We also excluded studies in healthy patients and registered studies that did not have an intervention (eg, estimating eligibility). Searches of PubMed and ClinicalTrials.gov were made on June 6, 2019.

We generated an estimate of the percentage of patients in the United States with cancer and FGFR alterations eligible for on-label and off-label treatment with erdafitinib by cancer type. All statistical analyses were conducted in Excel 2016 (Microsoft). The reviews of studies on targeting FGFR alterations and ongoing studies of erdafitinib were purely descriptive. Because all statistics are descriptive, no prespecified level of statistical significance was set. The study was conducted in May 2019.

An estimated 455 440 individuals with cancer died in 2019. Of those, 17 019 (3.7%) were estimated to have either an FGFR2 or an FGFR3 alteration. A total of 15 cancer types, including urothelial cancer, had reported FGFR alterations (Table 1). Among the cancer types, urothelial cancer, carcinoma of unknown primary, non–small cell lung cancer, pancreatic exocrine cancer, and breast cancer had the highest number of patients with FGFR2 or FGFR3 alterations (urothelial cancer, 4064 of 17 670 patients [23.0%]; carcinoma of unknown primary sites, 2708 of 45 140 [6.0%]; non–small cell lung cancer 2140 of 142 670 [1.9%]; pancreatic exocrine cancer, 1601 of 45 750 [3.5%]; breast cancer, 1310 of 42 260 [3.1%]). We estimated that, of 17 019 patients with advanced cancer expressing FGFR2 or FGFR3 alterations, 12 955 (76.1%) could be eligible for off-label treatment with erdafitinib (Figure).

We also estimated the percentage of patients eligible for treatment with erdafitinib among a pool of patients with any FGFR alteration (ie, not necessarily FGFR2 or FGFR3) (eFigure in the Supplement). Among 455 440 estimated patients, 35 536 (7.8%) had any FGFR alteration, and of these patients, 5601 (15.8%) had urothelial cancer. Therefore, if treatment were targeted at any FGFR alteration, an estimated 84.2% of the potential use of FGFR inhibitors, such as erdafitinib, would be off-label.

We found 29 completed studies evaluating FGFR-targeting drugs in 11 of 14 cancer types analyzed in the off-label estimations (Table 2).^12-38 There were 8 (27.6%) case reports, 1 (3.4%) case series, 9 (31.0%) phase 1 studies, 2 (6.9%) phase 1/2 studies, and 9 (31.0%) phase 2 studies. While 2 phase 2 trials (22.2%) were randomized, the rest were noncomparator trials. All phase 1 studies had primary outcomes of either safety or dosage. Phase 2 trials evaluated ORR (5 studies [55.5%]), progression-free survival (4 studies [44.4%]), or event-free survival (1 study [11.1%]) as their primary outcome.

There were 10 ongoing studies of erdafitinib being used for oncological indications registered on ClinicalTrials.gov, 2 (20.0%) of which included patients with urothelial cancer (eTable in the Supplement). There were 2 (20.0%) phase 1 studies, 2 (20.0%) phase 1/2 studies, 5 (50.0%) phase 2 studies, and 1 (10.0%) phase 3 study. One study (10.0%) was evaluating overall survival as its primary outcome; the rest were evaluating ORR (7 studies [70.0%]) or safety (3 studies [30.0%]). Two of the 10 trials (20.0%) were randomized.

From our estimates, the number of patients with tumors exhibiting FGFR2 or FGFR3 alterations who may be potentially eligible for off-label treatment with an FGFR inhibitor is 3 times that of those eligible for on-label treatment. If interpretation of off-label use is understood more broadly to cover patients with any FGFR alteration, potential eligibility for off-label use would grow to be 5 times greater than on-label use. Alterations in FGFR are being studied in a number of cancers where these alterations are prevalent, and ORRs similar to that of erdafitinib in urothelial cancer may further encourage off-label treatments in other cancer types. Off-label use of targeted therapies is widely practiced in oncology.^7,39 Erdafitinib was provisionally approved based on a surrogate outcome in a nonrandomized trial, and proof of clinical benefit will only be known after a confirmatory randomized trial investigating overall survival is conducted. The trial which led to the approval of erdafitinib found that adverse reactions of grade 3 or higher were reported by 67% of participants, and 46% were considered by investigators to be related to treatment.² The FDA determined that the interim surrogate outcomes and toxic effects of erdafitinib were appropriate for patients with advanced urothelial cancer who had an FGFR2 or FGFR3 mutation or fusion. However, by approving this drug for this indication, the FDA has inevitably permitted off-label use of erdafitinib in many cancer types and among a considerably larger patient population.

There are strengths and limitations in our analysis. One strength is that we sought to capture the potential on-label and off-label use of a novel genome-targeted drug entering the US marketplace, and we estimated the ratio of potential on-label to off-label use. To our knowledge, this is the first article that seeks to do this at the time of product launch. Moreover, we compiled data that clinicians could use to justify off-label use (Table 2). We note that these studies are largely exploratory in nature and reliant on small uncontrolled studies, which are generally considered to be at the bottom of the hierarchy of medical evidence.⁴⁰

There are also limitations. We determined cancer-specific FGFR aberration frequencies through an analysis that looked at next-generation sequencing from 1 company,⁴ which may not be wholly representative of population-level frequencies. We used cancer deaths to estimate cases of metastatic disease in each cancer type, which is an imperfect surrogate. Cancer deaths are not all because of metastatic disease, and as patients with metastatic disease live longer, the incidence of metastatic cancer cases outpaces the incidence of cancer deaths. Unfortunately, to our knowledge, there are currently no data on metastatic disease in the United States, as staging data are only recorded at diagnosis. Nevertheless, we found that cancer death data were the best available option to explore our study objective. A study using the Cancer Registry of Norway⁴¹ found that the majority of cancer deaths were because of metastatic disease, and the recorded numbers are likely underestimated because of underreporting of metachronous metastases. If data on metastatic status are collected in the US population in the future, we encourage researchers exploring this topic to use incidence of metastatic cancer instead.

We have almost certainly overestimated the number of cases of metastatic disease and, within that number, the number of patients who would be treated with an off-label drug. This assessment was not conducted to accurately approximate the number of patients who will be treated with erdafitinib but instead to determine the proportion of patients eligible for off-label use and to highlight the fact that the consequences of this accelerated approval reach far beyond the patient population it was intended to treat. Off-label drug use is practiced across almost all cancer types, most likely prescribed to metastatic cancer patients in a later line because of unapproved indication for specific tumors.⁴² Completed and ongoing trials on erdafitinib and other FGFR-targeting drugs in various cancers exemplify the interest around this type of targeted therapy, and the fact that erdafitinib is the first FGFR-targeting drug to be approved by the FDA⁴³ makes it susceptible to off-label use for patients with FGFR alterations. Enthusiasm for precision oncology may fuel this extrapolation.^44-47

This study found that the potential for off-label use of FGFR inhibitors such as erdafitinib spans a number of cancer types and a large patient population. Off-label use may be 3-fold higher than on-label use, based on population cancer statistics and the frequency of molecular alterations. Clinicians interested in off-label use may easily find case reports or series that may provide exploratory or circumstantial support for those choices. Because it may be tempting and plausible to use FGFR inhibitors for nonapproved uses, our analysis suggests that the size of this market share may be several times larger than the approved indication. Systematic trials to explore off-label uses may be desirable for drugs that target clear, identifiable molecular alterations because this may be more efficient than off-label use in identifying clinical scenarios where this agent has activity.

Accepted for Publication: October 4, 2019.

Published: November 22, 2019. doi:10.1001/jamanetworkopen.2019.16091

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 de Almeida Carvalho LM et al. JAMA Network Open.

Corresponding Author: Vinay Prasad, MD, MPH, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, Oregon 97239 (prasad@ohsu.edu).

Author Contributions: Dr Prasad had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs de Almeida Carvalho and de Oliveira Sapori Avelar contributed equally as co–first authors.

Concept and design: Prasad.

Acquisition, analysis, or interpretation of data: de Almeida Carvalho, de Oliveira Sapori Avelar, Haslam, Gill.

Drafting of the manuscript: de Almeida Carvalho, de Oliveira Sapori Avelar, Gill.

Critical revision of the manuscript for important intellectual content: Haslam, Gill, Prasad.

Statistical analysis: Haslam.

Supervision: Prasad.

Conflict of Interest Disclosures: Dr Prasad reported receiving royalties from his book, Ending Medical Reversal; receiving funding from Arnold Ventures; receiving honoraria for grand rounds and lectures from several universities, medical centers, nonprofit groups, and professional societies; being a writer for Medscape; and hosting the Plenary Session podcast, which has Patreon support. No other disclosures were reported.