© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
The rapid advances in the understanding of oncogenic process and the maturation of affordable precision diagnostic tools have enabled the development of targeted therapeutic agents, such as those targeting BCR-ABL, epithelial growth factor receptor L858R, EML4-anaplastic lymphoma kinase, and BRAF V600E, to treat cancers that harbor specific molecular alterations. Traditionally, each targeted drug has been developed for a particular tumor type where such alteration is most frequently found. Recently, the widespread adoption of next generation sequencing has led to an increase in the identification of rare and ultra-rare alterations, and, in some cases, the same rare alterations are found across multiple tumor types. The rarity of these alterations makes clinical trials traditionally designed for specific tumor types infeasible. As a result, tissue-agnostic trials have been developed to study the efficacy of these treatments and increase patient access. This review summarizes current successful cases of tissue-agnostic development, such as drugs targeting tropomyosin receptor kinase fusions, and proposes the next wave of potential tissue-agnostic targets, including fusions of ROS1, anaplastic lymphoma kinase, fibroblast growth factor receptor, and rearranged during transfection. In addition, the advantages and the challenges of such approach are discussed in the context of clinical development and approval.
Tissue agnostic, basket trial, tropomyosin receptor kinase, anaplastic lymphoma kinase, ROS1, fibroblast growth factor receptor, rearranged during transfection
The past two decades have witnessed a significant paradigm shift in cancer treatment practices based on increased understanding of oncogenic process. Molecular alterations in specific targets, usually kinases, can result in constitutive activation of the targets and their downstream signaling activities, leading to unchecked cellular proliferation, resistance to cell death, promotion of angiogenesis, and evasion of immune surveillance, all of which are hallmarks of cancer. Matching a patient‘s cancer with a therapeutic agent designed to specifically address the underlying molecular alteration has become the cornerstone of precision oncology. Alongside the rapid advancement in cancer biology, the technical revolution of molecular diagnostic platforms, particularly high-throughput next generation sequencing (NGS), has made comprehensive profiling of tumor tissue and liquid biopsy samples feasible and affordable, not only for scientific interrogation of cancer genome, transcriptome, and epigenome for target discovery and mechanistic characterization, but also for patient selection and stratification in the clinical setting[3,4].
Several large-scale cancer sequencing efforts involving thousands of patient samples have not only confirmed relatively frequent molecular alterations such as mutations in Kirsten rat sarcoma gene (KRas), tumor protein p53 (TP53), and epithelial growth factor receptor (EGFR), but also revealed, in many cases for the first time, low- and ultra-low frequency mutations that otherwise had been difficult to detect without high-throughput deep sequencing in large number of samples. For instance, in a study by Armenia and colleagues, whole exome sequencing data from 1,013 cases of prostate cancer (680 primary and 333 metastatic tumors) and matched germline were assembled and uniformly analyzed. The study identified a total of 97 potential oncogenic genes, about 70 of which had not been previously implicated in the disease. The majority of these newly identified mutated genes were found in less than 5% of the 1,013 cases. In statistical terms, this is known as a “long-tail” distribution; in other words, some genes are mutated in comparatively many cases, but many genes with oncogenic mutations are only found in few cases. This “long tail” distribution also suggests that additional discovery of rarely mutated oncogenic drivers is likely to continue along with the dramatic increase in the number of tumors sequenced. A similar “long tail” distribution has also been observed in other tumor types, such as lung adenocarcinoma, head and neck, and breast. Arguably, this “long tail” phenomenon exists in most, if not all, tumors. Interestingly, some of the same “long tail” genes are found across many distinct tumor types, suggesting common underlying mechanism of tumorigenesis[9,10].
The United States Food and Drug Administration (FDA) and other regulatory agencies generally approve anti-cancer drugs on the basis of efficacy and safety data obtained from clinical trials with patients of a particular tumor type. An example of this “one target, one tumor type” is the FDA’s 2001 landmark approval of imatinib, a kinase inhibitor of Abelson tyrosine kinase (c-ABL), for the use in treating BCR-ABL positive, chronic myeloid leukemia (CML), which heralded a new era in approval of drugs for single indications with characteristic gene alterations. A decade later, crizotinib, a small molecule tyrosine kinase inhibitor (TKI) of mesenchymal-epithelial transition factor (c-MET), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and recepteur d’Origine Nantais (RON), received accelerated approval for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EML4-ALK fusion. The approval was based on two single-arm trials demonstrating objective response rates (ORRs) of 50% and 61% and median response durations of 42 and 48 weeks.
Even with the life-changing success of the “one target, one tumor type” approach, it is important to remember that cancer is a complex disease. On the one hand, tumors that originate from the same tissue or organ can be segmented into multiple subtypes, each of which can be defined by differentiating molecular, pathological, and etiological features[13-15]. On the other hand, some distinct and seemingly unrelated tumors of different histology can be traced back to a common dominant genetic defect that can be exploited for therapeutic intervention by the same targeted agent, regardless of the histological tumor type or anatomical site of origin. Recently, drugs that target these common features, for example microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) and tropomyosin receptor kinase (TRK) fusions, across multiple tumor types have been approved by the FDA as the first wave of tissue-agnostic therapies (one target, all/many tumor types).
This review summarizes the current status of the tissue-agnostic approach and proposes additional molecular alterations, with the emphasis on oncogenic fusions, that are potential targets for drug discovery and development.
The FDA and its international counterparts traditionally approve cancer drugs on the basis of clinical studies in patients of a particular tumor type. Even for biomarker-driven approvals such as erlotinib and crizotinib, these drugs have generally been approved for a specific tumor type that harbors the target of interest.
In 2017, however, a significant paradigm shift took place, when the FDA granted accelerated approval of pembrolizumab, an anti-programmed cell death protein 1 (PD-1) therapy, in adult and pediatric patients with locally advanced or metastatic solid tumors of any tumor type (hence, tissue agnostic) that are dMMR or MSI-H, who have progressed after prior treatment, and who have no satisfactory alternative treatment options. This approval was based on collective data from several clinical trials. In the Phase II study code-named KEYNOTE-016 in patients (n = 58) with progressive metastatic carcinoma, high somatic mutation burden was associated with significant prolonged progression-free survival (PFS). In addition, two separate studies (KEYNOTE-158, n = 19; KEYNOTE-164, n = 61) specifically enrolled solid tumor patients with MSI-H or dMMR. Additional data from KEYNOTE-12 (n =6) and KEYNOTE-28 (n = 5) were included in the dataset after retrospective analysis of MSI and MMR status. By tumor type, among 149 patients with MSI-H and/or dMMR cancers across the five trials, the majority (n = 90) had colorectal cancer (CRC), while 14 other distinct tumor types accounted for the remaining 59 patients. Collectively, the ORR was 39.6%, which included 11 complete responses (CR) and 48 partial responses (PR). The response rate for patients with colorectal cancer and those with other cancers were similar.
About a year later in November 2018, the second tissue-agnostic cancer therapy, larotrectinib, won accelerated approval by the FDA for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. It is the second tissue-agnostic FDA approval for the treatment of cancer, and the first small molecule TKI that gained the tissue-agnostic status. The approval was based on clinical outcome in 55 patients with unresectable or metastatic, NTRK-fusion-positive solid tumors from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). The identification of positive NTRK gene fusion status was prospectively determined in local laboratories using NGS or fluorescence in situ hybridization (FISH). The ORR was 75%, including 22% CR and 53% PR across 12 cancer types, with the most common being salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%), as well as lung, melanoma, gastrointestinal stromal tumor (GIST), and colon cancer.
Soon after, the TRK/ROS1 inhibitor, entrectinib, was also granted accelerated approval by the FDA for the treatment of adults and pediatric patients 12 years of age and older with solid tumors that have a 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 standard therapy. The approval was based on clinical outcome in 54 adult patients across three multicenter, single-arm, clinical trials: ALKA, STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267). The identification of positive NTRK gene fusion status was determined in local laboratories or a central laboratory using nucleic acid-based tests prior to enrollment. Among 54 adult patients, the ORR was 57%, with 7.4% of patients achieving CR. The most common cancers were sarcoma, NSCLC, mammary analog secretory carcinoma, breast, thyroid, and colorectal. Compared to larotrectinib, the patient populations of entrectinib leaned more heavily on adult patients with more prior lines of therapies. Importantly, entrectinib also showed meaningful responses in brain cancer patients and those whose tumors metastasized to the brain.
The approvals of these tissue-agnostic therapies represented a new paradigm in cancer treatment and validated the notion that, under certain circumstances, the biomarker in essence, rather than the tissue origin, would define the disease [Figure 1].
Figure 1. Tissue-agnostic approach offers biomarker-informed treatment strategy regardless of histological origin of the tumor
It is important to point out that the latest tissue-agnostic approvals are both small molecule receptor tyrosine kinase (RTK) inhibitors that treat oncogenic fusions in rare tumors. There are a number of novel compounds in development for other oncogenic fusion genes, and it is highly likely that next tissue-agnostic approval will be from one of these experimental agents.
In the past several decades, cancer epidemiological and molecular studies have identified a variety of genetic alterations including point mutations, chromosomal rearrangements and translocations, gene amplification, and overexpression that are believed to play a driver role in various cancer histologies. Many of these changes lead to constitutive activation of the oncoprotein and downstream signaling pathways, resulting in uncontrolled cell proliferation, survival, and migration, which are hallmarks of cancer.
Oncogenic gene fusions are somatic genetic alteration caused by interchromosomal translocation, intrachromosomal translocation, insertion, deletion, tandem duplication, inversion, chromothripsis, and read-through. The first identified cancer-causing fusion gene is BCR-ABL gene, product of a reciprocal interchromosomal translocation between the q arms of chromosomes 9 and 22 that occurs in more than 96% of patients with CML. The first fusion gene in epithelial solid tumors, rearranged during transfection (RET)-CCDC6, was found in papillary thyroid carcinoma more than 30 years ago. Since then, many gene fusions have been discovered, facilitated by large scale sequencing efforts such as those championed by The Cancer Genome Atlas (TCGA), International Collaboration for Clinical Genomics (ICCG), International Cancer Genome Consortium (ICGC), and numerous other institutional studies. With the technological advancement in detection methods, the identity of gene rearrangement partners, the spectrum of tumor histologies where the gene rearrangements have been found, and their overall prevalence have significantly expanded in the past few years.
For instance, a recent study by Gao et al. interrogated 9,624 samples belonging to 33 cancer types in the TCGA collection and identified 25,664 distinct fusion events. Importantly, among all fusions involving receptor and non-receptor kinases, 1,275 cases contain an intact kinase domain, many of which are believed to be the sole onco-driver in a particular tumor biopsy. Many of these fusion events lead to constitutive activation of the kinase activity and downstream signaling pathways including mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) cascades, which enables cells to hyper-proliferate and evade apoptosis[28-30][Figure 2]. The mechanisms of activation include overexpression of the kinase as a result of the activity of the promoter of the fusion partner, constitutive ligand-independent dimerization of the fusion kinase proteins, and release of kinase auto-inhibitory mechanism. Since kinases are generally druggable targets, studies such as this provided the rationale for developing small molecule targeted therapies to treat fusion-driven hematological and solid tumors[31-34].
Figure 2. Oncogenic fusions lead to ligand-independent, constitutive activation of kinases and their downstream signal pathways. A: Fusions with N-terminal partners, represented by tropomyosin receptor kinase (TRK) fusions; B: fusions with C-terminal partners, represented by fibroblast growth factor receptor fusions. AKT: protein kinase B
Although conceivably, specific drugs can be developed to address these distinct fusion proteins in each of the tumor types involved individually, in reality, with the exception of a few cases, such as ALK and ROS1 fusions in NSCLC and fibroblast growth factor receptor (FGFR) fusions in cholangiocarcinoma, the majority of the fusions occur at low frequencies. The low and ultra-low frequency alterations sometimes are called the “long tail”. As discussed above, the rarity of the fusions and the resulting small patient pool make the development of a particular targeted drug for a single tumor type impractical.
One potential solution to address this challenge lies in the observation that a number of recurring gene fusions, such as those formed by ALK, ROS1, FGFR, NTRK, and RET, have been identified in multiple cancer histologies. For example, ALK fusions are found in anaplastic large cell lymphoma, NSCLC, papillary thyroid cancer, colorectal cancer, renal cell cancer, and esophageal cancer, as well as in spitzoid tumors. Similar to ALK fusions, FGFR fusions have been reported in a wide range of tumors such as cholangiocarcinoma, breast cancer, prostate cancer, NSCLC, gastric adenocarcinoma, colorectal adenocarcinoma, and glioblastoma, with a large number of distinct fusion partners. The long-tail phenomena (rare and ultra-rare patient populations) and recurring fusions across multiple tumor types necessitate biomarker-driven cross-tumor type clinical trials, to enroll a sufficient number of patients for efficacy and safety assessment and to offer patients with a rare actionable mutation access to an experimental therapy.
The tyrosine kinase receptors TRKA, TRKB, and TRKC, are encoded by neurotrophic tropomyosin receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3, respectively. Their ligands are neurotrophins, a family of nerve growth factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins. Neurotrophin binding to TRK receptors results in receptor autophosphorylation and activation of downstream signaling cascades. Physiologically, the TRK family members play a key role in normal central and peripheral neuronal cell development and differentiation. NTRK gene mutations, overexpression, splice variants, and fusions/rearrangements have been found in a number of human cancer types.
The first NTRK gene fusion, TPM3-NTRK1, was identified in a colon carcinoma biopsy through a transformation assay. Subsequently, TPM3-NTRK1 has been identified in additional CRC tumors, sarcoma, lipofibromatosis-like neural tumors, spitzoid melanoma, invasive mucinous adenocarcinoma of the lung, and papillary thyroid carcinoma. With the use of advanced molecular diagnostic techniques, additional NTRK1 fusion partners have been identified in various tumor types, with 5’ fusion partners including LMNA, SQSTM1, BCAN, CD74, IRF2BP2, MDM4, MPRIP, and others.
Similarly, oncogenic fusions have also been identified with NTRK2 and NTRK3 genes, as well as across a variety of cancer histologies. For example, NTRK2 forms fusions with partners such as AGBL4, NACC2, QKI, and VCL, which were identified in non-brainstem high-grade glioma, soft tissue liposarcoma, head and neck squamous cell carcinoma, pilocytic astrocytoma, ganglioglioma, and diffuse intrinsic pontine glioma. NTRK3 fusion partners include ETV6, BTBD1, and EML4, which were identified in diffuse intrinsic pontine glioma, congenital fibrosarcoma, papillary thyroid carcinoma, mammary analog secretory carcinoma (MASC) of the thyroid gland, secretory breast cancer, and inflammatory myofibroblastic tumor[48,57-60], as well as in hematological malignancies such as acute myeloid leukemia, Philadelphia-like acute lymphoblastic leukemia, and chronic eosinophilic leukemia[61-63].
NTRK gene fusions have also been reported in pediatric solid tumors. For instance, oncogenic gene fusions involving the NTRK3 kinase domain have been identified in congenital fibrosarcoma and pediatric mesoblastic nephroma and acute leukemias. A survey of 2 pediatric cancer databases, St. Jude pediatric cancer database (PeCan; total n = 1,604) and the University of Michigan database (Peds-MiOncoSeq; total n = 91) resulted in the identification of three gene rearranged-cancers, one each involving NTRK1, NTRK2, and NTRK3 in a sarcoma, a low-grade glioma, and a B-cell acute lymphoblastic leukemia, respectively. In addition, the following tumor types, which are largely confined to the pediatric patient population, are also known to harbor NTRK gene fusions: congenital or infantile fibrosarcoma, secretory (juvenile) breast cancer, mesoblastic nephroma, and intrinsic pontine gliomas.
Fusion of 3’ NTRK gene sequences encoding the tyrosine kinase domain to various 5’ partner sequences via intra- or inter-chromosomal rearrangement results in an oncogenic chimera protein that can ligand-independently homodimerize, autophosphorylate, and constitutively activate downstream signaling pathways, such as MAPK, PI3K/protein kinase B (AKT), and phospholipase C (PLC)-ɣ, which can result in hyperproliferation and cell survival in tumors expressing these proteins. The growth of cancer cells thus becomes dependent on or “addicted” to this abnormal kinase signaling.
Although oncogenic NTRK gene fusions are observed across a large number of adult and pediatric solid and hematological tumors, they are rare events in most common cancers (e.g., frequency of < 0.1% in NSCLC or CRC). Although much higher frequencies of NTRK fusions are present in certain tumor types such as MASC, these cancers are ultra-rare, collectively representing less than 1% of all malignancies. As a result, the overall population of NTRK-fusion-positive patients is very small.
The rarity of the molecularly defined patients and the vastly diverse histologies of the patients clearly called for an innovative, tissue-agnostic approach. Fortunately, data generated in preclinical studies provided rationale to perform tissue-agnostic clinical trials in multiple molecularly defined cancers: (1) regardless of the fusion partner or the tissue of origin, the NTRK gene fusions result in a constitutively active kinase and provide the driving force for transformation and tumor progression; and (2) regardless of the identity of the fusion partners, TRK inhibitors such as entrectinib exhibit similar anti-tumor potency in cell lines harboring NTRK1, NTRK2, or NTRK3 fusion genes (i.e., TPM3-NTRK1, LMNA-NTRK1, SQSTM1-NTRK1, BCAN-NTRK1, MPRIP-NTRK1, AFAP1-NTRK2, VCL-NTRK2, and ETV6-NTRK3), and in NTRK-fusion-positive xenograft models derived from various tumor types. For instance, tumor growth inhibition was observed in cancer cell line-derived xenograft models of CRC harboring TPM3-NTRK1 fusion, AML harboring ETV6-NTRK3 fusion, and NSCLC harboring MPRIP-NTRK1 fusion, as well as in patient-derived xenograft (PDX) models of metastatic CRC harboring LMNA-NTRK1 fusion, head and neck cancer harboring ETV6-NTRK3 fusion, and sarcoma harboring TPM3-NTRK1 fusion.
As discussed above, the preclinical observations have been clinically validated in several clinical trials that led to the regulatory approvals of larotrectinib and entrectinib as the first two small molecule anti-cancer drugs that carry a tissue-agnostic label.
ROS1 belongs to the insulin-receptor superfamily of receptor tyrosine kinases and plays a role in relaying growth signals from the environment outside the cell into the cell’s nucleus. It is an orphan receptor tyrosine kinase with no known binding ligand. Genetic changes in ROS1, such as gene rearrangements, mutations, or copy number increases, create oncogenes that can lead to cancer. ROS1 gene rearrangements create fusion proteins with constitutively active kinase domains that activate downstream signaling pathways leading to oncogenic properties in cells, including uncontrolled proliferation and resistance to cell death with prolonged tumor cell survival. These pathways include Ras-ERK for cellular proliferation and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and PI3K/AKT pathways, which regulate cell survival (anti-apoptosis) and proliferation. ROS1 fusion proteins may also activate the mammalian target of the rapamycin pathway, which is critical for the regulation of protein translation. Cancers that have these pathways activated tend to be more aggressive, with invasion and metastasis leading to poor patient survival.
In NSCLC patients, ROS1 fusion protein is found in approximately 1%-2.5% of patients[70,71]. ROS1 gene rearrangements have also been detected in a variety of other cancers, including glioblastoma multiforme[72,73]; biliary tract carcinoma (3.9%); ovarian cancer, gastric adenocarcinoma (0.61%); CRC (0.85%); inflammatory myofibroblastic tumor, angiosarcoma, and epithelioid hemangioendothelioma[69,70,75,77]; and Spitz nevus (benign) (25.3%), atypical Spitz tumors (6.2%), and spitzoid melanomas (9.1%).
Thus far, more than two dozen N-terminal fusion partners have been identified. All the fusion proteins retain the ROS1 kinase domain, but rarely its transmembrane domain. The most common ROS1 fusion partner is CD74. Other commonly observed ROS1 fusion partners include SDC4, SLC34A2, LRIG3, EZR, and TPM3[77,78]. A survey of cBioPortal for Cancer Genomics (https://www.cbioportal.org) and The Cancer Genome Atlas (TCGA) generated the following breakdown of ROS1 fusion partners: 38% CD74, 12% EZR, 12% SLC34A2, 9% SDC4, 6% CEP85L, 6% GOPC, and rare cases of CLTC, GOLGB1, SLC4A4, TFG, TMEM181, and TPM3. More than half of the partners have dimerization domains that are retained in the fusion, presumably leading to constitutive ROS1 tyrosine kinase activation. Additional mechanism of activation of the ROS1 fusion proteins may include removal of the auto-inhibitory domain from the full-length ROS1 as the result of the fusing event. Recent survey of responses to crizotinib in 106 NSCLC patients with ROS1 fusions of various fusion partners (49.1% CD74, 17% EZR, 14.2% SDC4 and 4.7% TPM3) showed no significant difference among patients with various types of ROS1 fusion partners in overall survival (OS) and progression-free survival (PFS).
Clinically, multiple ROS1 inhibitors have been approved for ROS1-fusion-positive NSCLC. Although the clinical efficacy of ROS1 inhibitors has not been systemically established, several preclinical studies have shown support of potential broad efficacy across tumor types that are driven by ROS fusion. For instance, Davare et al. showed that CEP85L-ROS1 and GOPC-ROS1 are transforming oncogenes in cells of astrocytic lineage, and they are sensitive to pharmacologic inhibition with several ROS1 inhibitors in vitro. Furthermore, systemic therapy with a BBB-penetrant ROS1 inhibitor, lorlatinib, significantly prolonged survival in an intracranially xenografted, ROS1-fusion-positive glioblastoma tumor model. In a separate study, ROS1 inhibitors were able to inhibit FIG-ROS-driven cholangiocarcinoma in vitro and in vivo. These data provide the rational support to a potential tissue-agnostic approach for treating ROS1-fusion-positive cancers.
ALK belongs to the insulin-receptor superfamily and aberrant ALK fusion proteins lead to self-activation and constitutive activity within cancer cells via activation of signal transduction pathways and intracellular kinases that drive uncontrolled tumor cell growth, metabolism, and survival. In addition to anaplastic lymphomas (ALCL), ALK oncogenes are found in a number of cancers such as NSCLC, diffuse large B-cell lymphoma, neuroblastomas, colorectal cancer, inflammatory myofibroblastic tumors (IMT), esophageal/gastric cancers, and renal cell cancers[35,83]. The currently available ALK inhibitor drugs, crizotinib, ceritinib, alectinib, and brigatinib, have demonstrated clinical benefit in NSCLC. In a recent report based on the CREATE Study in eight European countries, Schoffski et al. showed that, in ALK-fusion-positive IMT, crizotinib treatment resulted in 50% ORR (6 responders out of 12 patients) with nine-month median duration of response and 73% one-year PFS. On the contrary, the ORR was 14% (one out of seven) in ALK-negative IMT. In addition to the CREATE study, similar or higher ORRs were observed in ALK-fusion-positive patients enrolled in studies COG and PROFILE 1013. These two studies also demonstrated ORRs of 53%-88% in ALCL.
The FGFR protein family consists of four highly conserved transmembrane receptor tyrosine kinases (FGFR1-4). Receptor activation by the fibroblast growth factor (FGF) ligands or oncogenic alterations leads to intracellular signaling to promote cell proliferation, differentiation, morphogenesis and patterning, angiogenesis, and survival. The FGFR signaling pathway is aberrantly activated in multiple types of human cancers through various molecular alterations including point mutations, gene amplification and overexpression, and chromosomal rearrangements/translocations. Many of these changes lead to constitutive receptor activation and upregulation of the downstream signaling pathways, leading to uncontrolled cell proliferation, survival, and migration, which are hallmarks of cancer. Both the overall frequency of FGFR alterations and the relative distribution of the types of alterations vary by cancer type[46,87,88].
FGFR fusions are the result of gene rearrangements and have been detected in different types of human cancers[46,89][Table 1]. Particularly, FGFR2 fusions with different partners, such as BICC1, TACC3, CCDC6, and AHCYL1, have been detected in approximately 10%-20% of intrahepatic cholangiocarcinomas[90-92]. Lower frequencies of FGFR1-3 fusions have also been detected in breast cancer, bladder cancer, glioblastoma, head and neck squamous cell carcinoma, low-grade glioma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, prostate adenocarcinoma, and thyroid carcinoma[46,87,88,93]. FGFR fusion partners generally contain dimerization or oligomerization domains that lead to ligand-independent constitute activation of the receptor and downstream RAS-MAPK and JAK-STAT signaling pathways, resulting in uncontrolled cell proliferation, survival, and migration, which are hallmarks of cancer. In solid tumors, these FGFR fusions are typically formed by fusing near full-length FGFR with intact kinase domain at the N-terminus and various fusion partners at the C-terminus (Type II fusions), suggesting that these may serve as potential therapeutic targets via kinase inhibition. However, it is also possible for the fusion to occur so that the FGFR gene remains intact on the 3’ end of the gene (Type I fusions) allowing the fusion partner to be present on the 5’ end[88,94]; these fusions are mostly found in hematological malignancies.
FGFR fusions and fusion partners in solid tumors
TACC3, TNIP2, JAKMIP1, BAIAP2L1
CCDC6, AFF3, CASP7, NCALD, WHSC1
|Cholangiocarcinoma||FGFR2||AFF4, AHCYL1, BICC1, CCDC6, VCL, CLIP1, POC1B, CELF2, CREB5, DNAJC12, HOOK1, KCTD1, KIAA1217, KIAA1598, MGEA5, NOL4, OPTN, PARK2, PCMI, PPHLN1, RASAL2, SLMAP2, SORBS1, STK26, STK3, TACC3, TBC1D1, TFEC, TRA2B, UBQLN1, WAC, ZMYM4|
|Colorectal cancer||FGFR2||NPM1, COL14A1|
|Gastric cancer||FGFR2||C100rf68, PDHX, TACC2|
|Head and neck squamous cell carcinoma||FGFR3||TACC3, TPRG1|
|Lung squamous cell carcinoma|| BAG4|
CCAR2, CIT, KIAA1967
|Prostate adenocarcinoma|| FGFR2|
|KLK2, PPAPDC1A, SLC45A3|
|Renal cell carcinoma||FGFR3||TACC3|
|Thyroid cancer|| FGFR2|
Given the significance of constitutive FGFR signaling in tumorigenesis and progression, small molecule inhibitors targeting this pathway have been developed and their anti-tumor activities are currently being evaluated in clinical trials[88,96,97]. For instance, recent results from several clinical trials in FGFR2-fusion-positive cholangiocarcinoma have demonstrated meaningful clinical efficacy, which supports potential approvals as second line therapy for the treatment of advanced cholangiocarcinoma with FGFR2 fusions. For example, in a Phase II study of infigratinib in 71 cholangiocarcinoma patients with FGFR2 fusions, ORR 31% and SD 58% were observed, with median PFS and OS of 6.8 and 12.5 months, respectively. Similar results were reported based on an interim update from the Phase II study of pemigatinib in FGFR2-fusion-positive cholangiocarcinoma patients. Erdatinib, recently approved for advanced or metastatic urothelial carcinoma with susceptible FGFR3 mutations, has demonstrated efficacy in therapeutic trials for cholangiocarcinoma patients with FGFR2 fusions, although these trials contained fewer patients. Additionally, a covalent pan-FGFR inhibitor, futibatinib, has shown limited efficacy in cholangiocarcinoma patients previously treated with a different FGFR inhibitor, suggesting a potential utility for later line therapy when drug sequencing is needed.
In addition to cholangiocarcinoma, there is evidence, albeit very limited, that FGFR inhibitors work in other solid tumors with FGFR1, -2, or -3 fusions[97,102-104]. Based on these data there is a rationale for performing tumor-agnostic clinical trials in molecularly defined cancers to maximally benefit patients with serious and life-threatening diseases.
RET encodes a single-pass transmembrane receptor tyrosine kinase important for normal cellular proliferation, development, and maintenance. It has four cadherin-like repeats at the N-terminal extracellular domain, a cysteine-rich region, a transmembrane domain, and C-terminal cytoplasmic tyrosine kinase domain. Under normal conditions, wild-type RET is activated through binding of glial cell line-derived neurotrophic factor (GDNF) family of ligands and a co-receptor, and it functions through the modulation of downstream signaling including RAS-MAPK, PI3K-AKT, and phospholipase Cγ (PLCγ) pathways[107,108]. During development, RET protein plays an important role in the development of the enteric nervous system and homeostasis of neural, neuroendocrine, hematopoietic, and male germ tissues[106,110].
In certain cancers, aberrant, ligand-independent RET activation is associated with gain of function RET mutations or gene rearrangements (fusions). The first known RET fusion was an in-frame fusion of CCDC6-RET identified in a patient with papillary thyroid carcinoma. Subsequently, RET fusions were reported in 13%-43% of papillary thyroid carcinomas, and multiple fusion partners have been reported. RET fusions mostly occur in irradiation-induced papillary thyroid carcinoma.
The first group of RET fusions in lung cancer, KIF5B-RET, was reported in 2012 with estimated incidence rates between 1.3% and 6% of lung adenocarcinomas tested. The KIF5B-RET fusion contains RET kinase domain fused with a coiled-coil domain from KIF5B, which mediates homodimerization and ligand-independently activates the oncogenic pathways by autophosphorylation. It is also believed that the fusion event eliminates the auto-inhibitory domain of RET[107,108]. Later studies with much larger samples put the fusion rate at 1%-2%[114,115]. Interestingly, a review of 936 patients with surgically resected NSCLC suggested that RET-fusion-positive patients tended to be associated with younger age, never-smoker status, early lymph node metastases, poor differentiation, and a solid-predominant subtype. Not surprisingly, and similar to other oncogenic drivers, RET fusions are largely mutually exclusive from other known oncogenic alterations.
Besides coiled-coil domain-containing protein 6 (CCDC6) and KIF5B, other partners of RET include nuclear receptor coactivator 4 (NCOA4), the tripartite motif-containing 33 (TRIM33), myosin VC gene (MYO5C), EPH receptor A5 gene (EPHA5), CAP-Gly domain containing linker protein family member one gene (CLIP1), ELKS/RAB6-interacting/CAST family member one gene (ERC1), phosphatidylinositol binding clathrin assembly protein gene (PICALM), FERM domain containing 4A gene (FRMD4A) RUN, RYVE domain containing two gene (RUFY2), tripartite motif containing 24 gene (TRIM24), tripartite motif containing 27, and many others. All of these fusion counterparts have a dimerization domain that induces ligand-independent activation of the RET kinase[118-120].
In addition to papillary thyroid cancer and lung adenocarcinoma, RET fusions have been identified in other solid tumors, including colorectal cancer (CRC)[121,122], breast cancer, and Spitz tumor[45,123][Table 2].
RET fusions and fusion partners in solid tumors other than lung cancer
|Tumor histology||RET fusion detection rate (%)||Fusion partners|
|PTC||6% (Kondo et al. 2006, Stransky et al. 2014)||AKAP13, FKBP15, HOOK3, PCM1, PRKAR1A, SPECC1L, TBL1XR1, TRIM24, TRIM27, CCDC6, ERC1, KIF5B, NCOA4, GOLGA5, KTN1, RFG9|
|CRC||0.2%-0.4% (Stransky et al. 2014, Le Rolle et al. 2015)||CCDC6, NCOA4|
|BC||0.1% (Stransky et al. 2014)||ERC1|
|Spitz tumors||3% (Wiesner et al. 2014)||GOLGA5, KIF5B|
Given the importance of RET fusions in cancer biology and preclinical support of targeting RET as a potential intervention agent for cancer[124,125], multiple selective small molecule kinase inhibitors, such as RXDX-105, BLU-667, and LOXO-292, have entered clinical development. In the most recent update, LOXO-292 demonstrated a 68% ORR in RET-fusion-positive NSCLC patients who had previously received chemotherapy. Additionally, BLU-667 achieved 60% response in second line RET-fusion-positive NSCLC and 63% response in RET-altered medullary thyroid cancer (MTC) who had previously been treated with Caprelsa or Cabometyx.
Six years ago, Lacombe et al. in their opinion article “The dream and reality of histology agnostic cancer clinical trials”, while appreciating the need and advantages of tissue-agnostic trials, expressed great uncertainty whether a true tissue-agnostic approach was feasible and approvable. Six years later, however, with three tissue-agnostic cancer drugs approved and more than a dozen in various stages of development, the tissue-agnostic approach is becoming a viable route for demonstrating efficacy of a targeted agent in multitude of tumor types with shared molecular aberration or target as the common denominator. This approach is especially attractive for those cancers with rare or ultra-rare patient populations. At the same time, it is important to acknowledge that there are still many challenges and limitations in this emerging area of research and development.
The first challenge is to determine, at the target and biology levels, whether same aberrations in different histologies have similar biological, functional, and pathological significance. The preclinical data and clinical experience in targeting NTRK fusions clearly confirmed that NTRK fusions are the single dominant oncogenic driver in fusion positive cancers, independent of tissue origin of the cancer. Therefore, NTRK fusions represent an ideal tissue-agnostic target. On the other hand, one of the prominent failures during early days of tissue-agnostic exploration involved BRAF targeting in different tumors including melanoma, thyroid carcinoma, and colorectal cancer. Whereas vemurafenib was efficacious in BRAF V600E melanoma and thyroid carcinomas, it failed to halt colorectal cancer with the same BRAF mutation, partly due to a tissue-specific feedback activation of EGFR pathway in CRC patients. This exemplifies the role of histological context plays in certain cancers that influence the drug-target response. It is unclear what level of influence the tissue context has on the oncogenic fusions. Will the oncogenic fusions of ALK, ROS1, FGFR, and RET behave similarly to NTRK fusions upon treatment? For example, it has been shown that different ROS1 fusions exhibited different subcellular localizations, which could lead to varied levels of activation and pathway involvement. Whether differential subcellular localization is a more general feature regulating oncogenesis across different oncoprotein fusions remains unclear. Therefore, extensive translational research efforts need to be an integral part of these trials to guide patient selection strategy.
The clinical development path for tissue-agnostic indication can be challenging. For instance, how is the sample size determined for each of the tumor types? What are the common endpoints, considering each tumor type is likely to have distinct natural history, standard of care option(s) and treatment algorithm (line of therapy), reference response rates and duration of response, and survival end points? Particularly, response assessment criteria would require cross-tumor harmonization, since these can differ depending on tumor type. There is no standard design of basket trials, especially for the very rare and ultra-rare patient populations. For instance, larotrectinib was conditionally approved based on a 55-patient trial that spanned 12 distinct tumor types, some of which were represented by just one patient. Will this happen to a future trial and still get approved? It is obvious that in these trials the statistical analyses are different from well-established practices and innovative approach will be needed to support drug development decisions. Operationally, basket trials require well-coordinated effort from different specialists and their teams of the respective departments, which are typically organized by organ site. This holds particularly true for the collection and processing of the patients’ biological material for molecular diagnostics.
The challenges in the regulatory processes should not be ignored either. Regulatory agencies in different countries and geographic regions, such as US/North America, European Union, Japan, and other Asia-Pacific countries, may have different degrees of acceptance of the tissue-agnostic approach. It is encouraging that recently the regulatory authorities in the US (larotrectinib and entrectinib), EU (larotrectinib), and Japan (entrectinib) all gave the green light to tissue-agnostic indication for NTRK fusions. However, the comfort level of these agencies may be different if the next agent does not have the splendid response rates larotrectinib and entrectinib exhibited, and the future approvals are likely to be reviewed on case-by-case basis and no established playbook exists.
With the rapid advances in cancer genomics, drug design and precision diagnostics, the field of oncology drug development has entered an era when both traditional tissue-restricted and innovative tissue-agnostic approaches provide precedented approval paths. Despite the challenges, we anticipate that tissue-agnostic approvals will continue to grow and expand the therapeutic options for cancer patients in need.
Researched and gathered the material and data: Li IW
Reviewed the manuscript: Li IW, Wei G, Li G
Drafted the manuscript: Krishnamurthy N, Wei G, Li G
Proposed the concept: Li GAvailability of data and materials
Not applicable.Financial support and sponsorship
Li IW and Krishnamurthy N were supported by the Emperor Science Awards, an initiative of Stand Up To Cancer (SU2C), made possible by support from Genentech, Bristol-Myers Squibb Company, and Novartis.Conflicts of interest
Wei G and Li G are employees of QED Therapeutics and equity owners.Ethical approval and consent to participate
Not applicable.Consent for publication
© The Author(s) 2020.
1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74.DOIPubMed
2. Garraway LA, Lander ES. Lessons from the cancer genome. Cell 2013;153:17-37.DOIPubMed
3. Bennett CW, Berchem G, Kim YJ, El-Khoury V. Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer. Oncotarget 2016;7:71013-35.DOIPubMedPMC
4. Luthra R, Chen H, Roy-Chowdhuri S, Singh RR. Next-generation sequencing in clinical molecular diagnostics of cancer: advantages and challenges. Cancers (Basel) 2015;7:2023-36.DOIPubMedPMC
5. Armenia J, Wankowicz SAM, Liu D, Gao J, Kundra R, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet 2018;50:645-51.DOIPubMedPMC
6. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008;455:1069-75.DOIPubMedPMC
7. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011;333:1157-60.DOIPubMedPMC
8. Santarpia L, Bottai G, Kelly CM, Gyorffy B, Szekely B, et al. Deciphering and targeting oncogenic mutations and pathways in breast cancer. Oncologist 2016;21:1063-78.DOIPubMedPMC
9. Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 2014;158:929-44.DOIPubMedPMC
10. Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, et al. Comprehensive characterization of cancer driver genes and mutations. Cell 2018;174:1034-5.DOIPubMed
11. Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 2002;8:935-42.PubMed
12. Kazandjian D, Blumenthal GM, Chen HY, He K, Patel M, et al. FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist 2014;19:e5-11.DOIPubMedPMC
13. Rodriguez-Canales J, Parra-Cuentas E, Wistuba II. Diagnosis and molecular classification of lung cancer. Cancer Treat Res 2016;170:25-46.DOIPubMed
14. Vuong D, Simpson PT, Green B, Cummings MC, Lakhani SR. Molecular classification of breast cancer. Virchows Arch 2014;465:1-14.DOIPubMed
15. Heestand GM, Kurzrock R. Molecular landscape of pancreatic cancer: implications for current clinical trials. Oncotarget 2015;6:4553-61.DOIPubMedPMC
16. Offin M, Liu D, Drilon A. Tumor-agnostic drug development. Am Soc Clin Oncol Educ Book 2018;38:184-7.DOIPubMed
17. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res 2019;25:3753-8.DOIPubMed
18. Kummar S, Lassen UN. TRK Inhibition: a new tumor-agnostic treatment strategy. Target Oncol 2018;13:545-56.DOIPubMed
19. Scott LJ. Larotrectinib: first global approval. Drugs 2019;79:201-6.DOIPubMed
20. Al-Salama ZT, Keam SJ. Entrectinib: first global approval. Drugs 2019;79:1477-83.DOIPubMed
21. Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271-82.DOIPubMed
22. Schram AM, Chang MT, Jonsson P, Drilon A. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat Rev Clin Oncol 2017;14:735-48.DOIPubMed
23. Tuna M, Amos CI, Mills GB. Molecular mechanisms and pathobiology of oncogenic fusion transcripts in epithelial tumors. Oncotarget 2019;10:2095-111.DOIPubMedPMC
24. Nakanishi Y, Akiyama N, Tsukaguchi T, Fujii T, Satoh Y, et al. Mechanism of oncogenic signal activation by the novel fusion kinase FGFR3-BAIAP2L1. Mol Cancer Ther 2015;14:704-12.DOIPubMed
25. Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 1960;25:85-109.PubMed
26. Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, et al. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 1987;328:170-2.DOIPubMed
27. Gao Q, Liang WW, Foltz SM, Mutharasu G, Jayasinghe RG, et al. Driver fusions and their implications in the development and treatment of human cancers. Cell Rep 2018;23:227-38.e3.DOIPubMedPMC
28. Cilloni D, Saglio G. Molecular pathways: BCR-ABL. Clin Cancer Res 2012;18:930-7.DOIPubMed
29. Davare MA, Tognon CE. Detecting and targetting oncogenic fusion proteins in the genomic era. Biol Cell 2015;107:111-29.DOIPubMedPMC
30. Farago AF, Azzoli CG. Beyond ALK and ROS1: RET, NTRK, EGFR and BRAF gene rearrangements in non-small cell lung cancer. Transl Lung Cancer Res 2017;6:550-9.DOIPubMedPMC
31. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703.DOIPubMedPMC
32. Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol 2013;14:590-8.DOIPubMed
33. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:1189-97.DOIPubMedPMC
34. Ou SH, Weitz M, Jalas JR, Kelly DF, Wong V, et al. Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation. Lung Cancer 2016;96:15-8.DOIPubMed
35. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012;18:378-81.DOIPubMed
36. Lamarca A, Barriuso J, McNamara MG, Valle JW. Molecular targeted therapies: ready for “prime time” in biliary tract cancer. J Hepatol 2020; doi: 10.1016/j.jhep.2020.03.007.DOIPubMed
37. Yu YP, Liu P, Nelson J, Hamilton RL, Bhargava R, et al. Identification of recurrent fusion genes across multiple cancer types. Sci Rep 2019;9:1074.DOIPubMedPMC
38. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31:1023-31.DOIPubMedPMC
39. Morris SW, Kirstein MN, Valentine MB, Dittmer K, Shapiro DN, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1995;267:316-7.DOIPubMed
40. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6.DOIPubMed
41. Hillier K, Hughes A, Shamberger RC, Shusterman S, Perez-Atayde AR, et al. A novel ALK fusion in pediatric medullary thyroid carcinoma. Thyroid 2019;29:1704-7.DOIPubMed
42. Lipson D, Capelletti M, Yelensky R, Otto G, Parker A, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 2012;18:382-4.DOIPubMedPMC
43. Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, et al. Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum. Mod Pathol 2011;24:430-42.DOIPubMed
44. Du XL, Hu H, Lin DC, Xia SH, Shen XM, et al. Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma. J Mol Med (Berl) 2007;85:863-75.DOIPubMed
45. Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun 2014;5:3116.DOIPubMedPMC
46. Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 2013;3:636-47.DOIPubMedPMC
47. Lamballe F, Klein R, Barbacid M. The trk family of oncogenes and neurotrophin receptors. Princess Takamatsu Symp 1991;22:153-70.PubMed
48. Light JE, Koyama H, Minturn JE, Ho R, Simpson AM, et al. Clinical significance of NTRK family gene expression in neuroblastomas. Pediatr Blood Cancer 2012;59:226-32.DOIPubMedPMC
49. Pulciani S, Santos E, Lauver AV, Long LK, Aaronson SA, et al. Oncogenes in solid human tumours. Nature 1982;300:539-42.DOIPubMed
50. Lee SJ, Li GG, Kim ST, Hong ME, Jang J, et al. NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target using patient-derived tumor cell line. Oncotarget 2015;6:39028-35.DOIPubMedPMC
51. Haller F, Knopf J, Ackermann A, Bieg M, Kleinheinz K, et al. Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern. J Pathol 2016;238:700-10.DOIPubMed
52. Agaram NP, Zhang L, Sung YS, Chen CL, Chung CT, et al. Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosis-like neural tumors. Am J Surg Pathol 2016;40:1407-16.DOIPubMedPMC
53. Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 2014;46:444-50.DOIPubMedPMC
54. Shim HS, Kenudson M, Zheng Z, Liebers M, Cha YJ, et al. Unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung. J Thorac Oncol 2015;10:1156-62.DOIPubMed
55. Sozzi G, Bongarzone I, Miozzo M, Cariani CT, Mondellini P, et al. Cytogenetic and molecular genetic characterization of papillary thyroid carcinomas. Genes Chromosomes Cancer 1992;5:212-8.DOIPubMed
56. Wei G, Patel R, Walsh C, Barrera M, Fagan P, et al. Entrectinib, a highly potent pan-Trk, ROS1, and ALK inhibitor, has broad-spectrum, histology-agnostic anti-tumor activity in molecularly defined cancers. Eur J Cancer 2016;69:S33.DOI
57. Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 2001;169:107-14.DOIPubMed
58. Thiele CJ, Li Z, McKee AE. On Trk--the TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin Cancer Res 2009;15:5962-7.DOIPubMedPMC
59. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015;5:25-34.DOIPubMedPMC
60. Jones DT, Hutter B, Jager N, Korshunov A, Kool M, et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 2013;45:927-32.DOIPubMedPMC
61. Eguchi M, Eguchi-Ishimae M, Tojo A, Morishita K, Suzuki K, et al. Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25). Blood 1999;93:1355-63.PubMed
62. Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 2014;371:1005-15.DOIPubMedPMC
63. Forghieri F, Morselli M, Potenza L, Maccaferri M, Pedrazzi L, et al. Chronic eosinophilic leukaemia with ETV6-NTRK3 fusion transcript in an elderly patient affected with pancreatic carcinoma. Eur J Haematol 2011;86:352-5.DOIPubMed
64. Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, et al. Analysis of NTRK Alterations in Pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol 2018; doi: 10.1200/PO.18.00183.DOIPubMedPMC
65. Weinstein IB, Joe A. Oncogene addiction. Cancer Res 2008;68:3077-80. discussion 80PubMed
66. Solomon JP, Benayed R, Hechtman JF, Ladanyi M. Identifying patients with NTRK fusion cancer. Ann Oncol 2019;30:viii16-22.DOIPubMed
67. Li G, Kim ST, Kim KM, Lee J, Russo M, et al. Abstract A173: potent anti-tumor activity of entrectinib in patient-derived models harboring oncogenic gene rearrangements of NTRKs. Mol Cancer Ther 2015;14:A173.DOI
68. Stumpfova M, Janne PA. Zeroing in on ROS1 rearrangements in non-small cell lung cancer. Clin Cancer Res 2012;18:4222-4.DOIPubMed
69. Davies KD, Doebele RC. Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer Res 2013;19:4040-5.DOIPubMedPMC
70. Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70.DOIPubMedPMC
71. Pan Y, Zhang Y, Li Y, Hu H, Wang L, et al. ALK, ROS1 and RET fusions in 1139 lung adenocarcinomas: a comprehensive study of common and fusion pattern-specific clinicopathologic, histologic and cytologic features. Lung Cancer 2014;84:121-6.DOIPubMed
72. Birchmeier C, Sharma S, Wigler M. Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc Natl Acad Sci U S A 1987;84:9270-4.DOIPubMedPMC
73. Davare MA, Henderson JJ, Agarwal A, Wagner JP, Iyer SR, et al. Rare but recurrent ROS1 fusions resulting from chromosome 6q22 microdeletions are targetable oncogenes in glioma. Clin Cancer Res 2018;24:6471-82.DOIPubMedPMC
74. Peraldo Neia C, Cavalloni G, Balsamo A, Venesio T, Napoli F, et al. Screening for the FIG-ROS1 fusion in biliary tract carcinomas by nested PCR. Genes Chromosomes Cancer 2014;53:1033-40.DOIPubMed
75. Lee J, Lee SE, Kang SY, Do IG, Lee S, et al. Identification of ROS1 rearrangement in gastric adenocarcinoma. Cancer 2013;119:1627-35.DOIPubMed
76. Aisner DL, Nguyen TT, Paskulin DD, Le AT, Haney J, et al. ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers. Mol Cancer Res 2014;12:111-8.DOIPubMedPMC
77. Shaw AT, Hsu PP, Awad MM, Engelman JA. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer 2013;13:772-87.DOIPubMedPMC
78. Uguen A, De Braekeleer M. ROS1 fusions in cancer: a review. Future Oncol 2016;12:1911-28.DOIPubMed
79. Neel DS, Allegakoen DV, Olivas V, Mayekar MK, Hemmati G, et al. Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. Cancer Res 2019;79:546-56.DOIPubMedPMC
80. Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 2007;7:233-45.DOIPubMed
81. He Y, Sheng W, Hu W, Lin J, Liu J, et al. Different types of ROS1 fusion partners yield comparable efficacy to Crizotinib. Oncol Res 2019;27:901-10.DOIPubMed
82. Davare MA, Saborowski A, Eide CA, Tognon C, Smith RL, et al. Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc Natl Acad Sci U S A 2013;110:19519-24.DOIPubMedPMC
83. Hallberg B, Palmer RH. The role of the ALK receptor in cancer biology. Ann Oncol 2016;27 Suppl 3:iii4-15.DOIPubMed
84. Li G, Dai WR, Shao FC. Effect of ALK-inhibitors in the treatment of non-small cell lung cancer: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci 2017;21:3496-503.PubMed
85. Schoffski P, Sufliarsky J, Gelderblom H, Blay JY, Strauss SJ, et al. Abstract CT045: Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 “CREATE”. Cancer Res 2018;78:CT045.
86. Porta R, Borea R, Coelho A, Khan S, Araujo A, et al. FGFR a promising druggable target in cancer: Molecular biology and new drugs. Crit Rev Oncol Hematol 2017;113:256-67.DOIPubMed
87. Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res 2016;22:259-67.DOIPubMed
88. Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer 2017;17:318-32.DOIPubMed
89. Borad MJ, Gores GJ, Roberts LR. Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma. Curr Opin Gastroenterol 2015;31:264-8.DOIPubMedPMC
90. Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 2014;59:1427-34.DOIPubMed
91. Jain A, Kwong LN, Javle M. Genomic profiling of biliary tract cancers and implications for clinical practice. Curr Treat Options Oncol 2016;17:58.DOIPubMed
92. Sia D, Losic B, Moeini A, Cabellos L, Hao K, et al. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat Commun 2015;6:6087.DOIPubMed
93. Parker BC, Engels M, Annala M, Zhang W. Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours. J Pathol 2014;232:4-15.DOIPubMed
94. Goyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov 2017;7:252-63.DOIPubMedPMC
95. Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol 2019;16:105-22.DOIPubMed
96. Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol 2018;36:276-82.DOIPubMedPMC
97. Pal SK, Rosenberg JE, Hoffman-Censits JH, Berger R, Quinn DI, et al. Efficacy of BGJ398, a fibroblast growth factor receptor 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. Cancer Discov 2018;8:812-21.DOIPubMedPMC
98. Javle M, Kelley R, Roychowdhury S, Weiss K, Abou-Alfa G, et al. LBA28Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions. Ann Oncol 2018;29.DOI
99. Hollebecque A, Borad M, Sahai V, Catenacci DVT, Murphy A, et al. Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations. Ann Oncol 2018;29:viii258.DOI
100. Park JO, Feng YH, Chen YY, Su WC, Oh DY, et al. Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations. J Clin Oncol 2019;37:4117.DOI
101. Meric-Bernstam F, Arkenau H, Tran B, Bahleda R, Kelley R, et al. Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors. Ann Oncol 2018;29:v100.DOI
102. Li G, Krook M, Roychowdhury S, Avogadri F, Ye Y, et al. Abstract 2206: anti-tumor activity of infigratinib, a potent and selective inhibitor of FGFR1, FGFR2 and FGFR3, in FGFR fusion-positive cholangiocarcinoma and other solid tumors. Cancer Res 2019;79:2206.DOI
103. Nauseef JT, Villamar DM, Lebenthal J, Vlachostergios PJ, Tagawa ST. An evaluation of the efficacy and safety of erdafitinib for the treatment of bladder cancer. Expert Opin Pharmacother 2020:1-8.DOIPubMed
104. Dizman N, Rosenberg JE, Hoffman-Censits JH, Quinn DI, Petrylak DP, et al. Infigratinib in upper tract urothelial carcinoma vs urothelial carcinoma of the bladder and association with comprehensive genomic profiling/cell-free DNA results. J Clin Oncol 2019;37:4510.DOI
105. Takahashi M, Cooper GM. Ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol Cell Biol 1987;7:1378-85.DOIPubMedPMC
106. Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002;3:383-94.DOIPubMed
107. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer 2014;14:173-86.DOIPubMed
108. Kohno T, Tsuta K, Tsuchihara K, Nakaoku T, Yoh K, et al. RET fusion gene: translation to personalized lung cancer therapy. Cancer Sci 2013;104:1396-400.DOIPubMedPMC
109. de Graaff E, Srinivas S, Kilkenny C, D’Agati V, Mankoo BS, et al. Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. Genes Dev 2001;15:2433-44.DOIPubMedPMC
110. Chi X, Michos O, Shakya R, Riccio P, Enomoto H, et al. Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell 2009;17:199-209.DOIPubMedPMC
111. Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990;60:557-63.DOIPubMed
112. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 2006;6:292-306.DOIPubMed
113. Ju YS, Lee WC, Shin JY, Lee S, Bleazard T, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res 2012;22:436-45.DOIPubMedPMC
114. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50.DOIPubMedPMC
115. Tsuta K, Kohno T, Yoshida A, Shimada Y, Asamura H, et al. RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer 2014;110:1571-8.DOIPubMedPMC
116. Wang R, Hu H, Pan Y, Li Y, Ye T, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol 2012;30:4352-9.DOIPubMed
117. Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, et al. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res 2017;23:1988-97.DOIPubMed
118. Chao BH, Briesewitz R, Villalona-Calero MA. RET fusion genes in non-small-cell lung cancer. J Clin Oncol 2012;30:4439-41.DOIPubMed
119. Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol 2018;13:27-45.DOIPubMed
120. Plenker D, Riedel M, Bragelmann J, Dammert MA, Chauhan R, et al. Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Sci Transl Med 2017;9.DOIPubMedPMC
121. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun 2014;5:4846.DOIPubMedPMC
122. Le Rolle AF, Klempner SJ, Garrett CR, Seery T, Sanford EM, et al. Identification and characterization of RET fusions in advanced colorectal cancer. Oncotarget 2015;6:28929-37.DOIPubMedPMC
123. Li AY, McCusker MG, Russo A, Scilla KA, Gittens A, et al. .
124. Li GG, Somwar R, Joseph J, Smith RS, Hayashi T, et al. Antitumor activity of RXDX-105 in multiple cancer types with RET rearrangements or mutations. Clin Cancer Res 2017;23:2981-90.DOIPubMedPMC
125. Matsubara D, Kanai Y, Ishikawa S, Ohara S, Yoshimoto T, et al. Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad. J Thorac Oncol 2012;7:1872-6.DOIPubMed
126. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, et al. .
127. Guo R, Schreyer M, Chang JC, Rothenberg SM, Henry D, et al. Response to selective RET inhibition with LOXO-292 in a patient with RET fusion-positive lung cancer with leptomeningeal metastases. JCO Precis Oncol 2019;3.DOIPubMedPMC
128. Drilon A, Oxnard G, Wirth L, Besse B, Gautschi O, et al. PL02.08 registrational results of LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. J Thorac Oncol 2019;14:S6-7.DOI
129. Gainor JF, Lee DH, Curigliano G, Doebele RC, Kim DW, et al. Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol 2019;37:9008.
130. Lacombe D, Burock S, Bogaerts J, Schoeffski P, Golfinopoulos V, et al. The dream and reality of histology agnostic cancer clinical trials. Mol Oncol 2014;8:1057-63.DOIPubMedPMC
131. Chu P, Batson S, Hodgson M, Mitchell CR, Steenrod A. Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy. Future Oncol 2020;16:61-74.DOIPubMed
132. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-54.DOIPubMed
133. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.DOIPubMedPMC
134. Kim YS, Kim JS, Bae JS, Park WC. Clinical implication of the BRAFV600E mutation in papillary thyroid carcinoma. World J Surg Oncol 2013;11:99.DOIPubMedPMC
135. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol 2015;33:4032-8.DOIPubMedPMC
136. Ducreux M, Chamseddine A, Laurent-Puig P, Smolenschi C, Hollebecque A, et al. Molecular targeted therapy of BRAF-mutant colorectal cancer. Ther Adv Med Oncol 2019;11:1758835919856494.DOIPubMedPMC
Li IW, Krishnamurthy N, Wei G, Li G. Opportunities and challenges in developing tissue-agnostic anti-cancer drugs. J Cancer Metastasis Treat 2020;6:14. http://dx.doi.org/10.20517/2394-4722.2020.27
Quantities of Full-Text Views Each Month
Quantities of PDF Downloads Each Month