Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.

RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.

Brain metastasis screening in the molecular age.

The incidence of brain metastases (BM) amongst cancer patients has been increasing due to improvements in therapeutic options and an increase in overall survival. Molecular characterization of tumors has provided insights into the biology and oncogenic drivers of BM and molecular subtype-based screening. Though there are currently some screening and surveillance guidelines for BM, they remain limited. In this comprehensive review, we review and present epidemiological data on BM, their molecular characterization, and current screening guidelines. The molecular subtypes with the highest BM incidence are epithelial growth factor receptor-mutated non-small cell lung cancer (NSCLC), BRCA1, triple-negative (TN), and HER2+ breast cancers, and BRAF-mutated melanoma. Furthermore, BMs are more likely to present asymptomatically at diagnosis in oncogene-addicted NSCLC and BRAF-mutated melanoma. European screening standards recommend more frequent screening for oncogene-addicted NSCLC patients, and clinical trials are investigating screening for BM in hormone receptor+, HER2+, and TN breast cancers. However, more work is needed to determine optimal screening guidelines for other primary cancer molecular subtypes. With the advent of personalized medicine, molecular characterization of tumors has revolutionized the landscape of cancer treatment and prognostication. Incorporating molecular characterization into BM screening guidelines may allow physicians to better identify patients at high risk for BM development and improve patient outcomes.

Intraoperative awake language mapping correlates to preoperative connectomics imaging: An instructive case.

Connectomics enables the study of structural-functional relationships in the brain, and machine learning technologies have enabled connectome maps to be developed for individual brain tumor patients. We report our experience using connectomics to plan and guide an awake craniotomy for a tumor impinging on the language area. Preoperative connectomics imaging demonstrated proximity of the tumor to parcellations of the language area. Intraoperative awake language mapping was performed, revealing speech arrest and paraphasic errors at areas of the tumor boundary correlating to functional regions that explained these findings. This instructive case highlights the potential benefits of implementing connectomics into neurosurgical planning.

The abscopal effect: inducing immunogenicity in the treatment of brain metastases secondary to lung cancer and melanoma.

PURPOSE: The phenomenon of radiation therapy (RT) causing regression of targeted lesions as well as lesions outside of the radiation field is known as the abscopal effect and is thought to be mediated by immunologic causes. This phenomena has been described following whole brain radiation (WBRT) and stereotactic radiosurgery (SRS) of brain metastasis (BM) in advanced melanoma and non-small-cell lung cancer (NSCLC). We systematically reviewed the available literature to identify which radiation modality and immunotherapy (IT) combination may elicit the abscopal effect, the optimal timing of RT and IT, and potential adverse effects inherent to the combination of RT and IT. METHODS: Using PRISMA guidelines, a search of PubMed, Medline, and Web of Science was conducted to identify studies demonstrating the abscopal effect during treatment of NSCLC or melanoma with BM. RESULTS: 598 cases of irradiated BM of melanoma or NSCLC in 18 studies met inclusion criteria. The most commonly administered ITs included PD-1 or CTLA-4 immune checkpoint inhibitors (ICI), with RT most commonly administered within 3 months of ICI. Synergy between ICI and RT was described in 16 studies including evidence of higher tumor response within and outside of the irradiated field. In the 12 papers (n = 232 patients) that reported objective response rate (ORR) in patients with BM treated with RT and concurrent systemic IT, the non-weighted mean ORR was 49.4%; in the 5 papers (n = 110 patients) that reported ORR for treatment with RT or IT alone, the non-weighted mean ORR was 27.8%. No studies found evidence of significantly increased toxicity in patients receiving RT and ICI. CONCLUSION: The combination of RT and ICIs may enhance ICI efficacy and induce more durable responses via the abscopal effect in patients with brain metastases of melanoma or NSCLC.

Mature Type T-Lymphoblastic Leukemia/Lymphoma Presenting With Isolated Central Nervous System Symptomatology in a Patient With Giant Cell Arteritis on Long-Term Steroid Treatment.

T-lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) is a malignancy comprised of T-lymphoblasts that can present as one of four clinical subtypes (pro-T, pre-T, cortical T, and mature T). Clinical presentation is typically characterized by leukocytosis with diffuse lymphadenopathy and/or hepatosplenomegaly. Beyond clinical presentation, specific immunophenotypic and cytogenetic classifications are utilized to diagnose mature T-ALL. In later disease stages it can spread to the central nervous system (CNS); however, presentation of mature T-ALL by way of CNS pathology and clinical symptomatology alone is rare. Even more rare is the presence of poor prognostic factors without correlating significant clinical presentation. We present a case of mature T-ALL in an elderly female with isolated CNS symptoms in combination with poor prognostic factors including terminal deoxynucleotidyl transferase (TdT) negativity and a complex karyotype. Our patient lacked the classical symptomatology and laboratory findings of mature T-ALL but deteriorated quickly upon diagnosis due to the aggressive genetic profile of her cancer.

Intrathecal therapy for the management of leptomeningeal metastatic disease: a scoping review of the current literature and ongoing clinical trials.

PURPOSE: Leptomeningeal metastatic disease (LMD) from advanced malignancies has poor prognoses and limited treatments. Intrathecal therapy (ITT) protocols are available, showing variable outcomes. We reviewed the therapeutic and toxicity profiles of ITT in LMD. METHODS: PubMed, EMBASE, Web-of-Science, and Scopus were searched following the PRISMA-ScR guidelines to include studies reporting ITT for LMD. CLINICALTRIAL: gov and Cochrane were searched to identify ongoing clinical trials. RESULTS: We included 27 published studies encompassing 2161 patients and 4 ongoing trials. LMD originated from brain metastases (85.5%), lymphomas (5.4%), high-grade gliomas (4.6%), medulloblastomas (2.3%), and leukemias (2.1%). LMD was mostly diagnosed with the co-presence of neurological-related symptoms and positive imaging and/or cerebrospinal fluid cytology (60.8%). The most common ITT agents were methotrexate (35.9%), cytarabine (21.9%), and thiotepa (8.2%), standalone or combined. Patients received a median of 6.5 ITT cycles (range, 1.0-71.0) via intraventricular (58.8%) or lumbar intrathecal (41.2%) routes. The Ommaya reservoir was implanted in 38.5% cases. Concurrent systemic chemotherapy (45.2%) and/or radiotherapy (30.6%) were used. After 1-3 cycles, 44.7% patients had improved clinical status and 29.9% converted into negative cerebrospinal fluid cytology. The most common ITT-related severe adverse events were neutropenia (6.5%), meningitis (5.2%) and encephalopathy (4.5%). Median freedom from progression was 2.4 months (range, 0.1-59.5) and median overall survival 5.5 months (range, 0.1-148.0). CONCLUSION: Current ITT protocols are variable but effective and well-tolerated in LMD. Ongoing trials are investigating dose-limiting toxicity profiles and long-term overall survival. Future studies should analyze the therapeutic and safety profiles of ITT compared to newer systemic therapies.

A Rapidly Accumulating Effusion in an Immunocompetent Woman.

CASE PRESENTATION: An 87-year-old woman with a medical history of stroke, paroxysmal atrial fibrillation, type 2 diabetes mellitus, diastolic heart failure, and chronic bilateral lymphedema presents with 1 week of shortness of breath. The patient had a 20-pack-year smoking history and at baseline was able to ambulate freely without assistance. Her symptoms of dyspnea were mostly exertional and progressively worsening for 1 week before admission, despite compliance with her home furosemide. On admission, her temperature was 36.3 °C, BP was 101/59 mm Hg, heart rate was 82 beats/min, respirations were 18 breaths/min, and oxygen saturation was 91% on room air. On physical examination, the patient was tachypneic at rest, and auscultation of the lungs revealed minimal breath sounds on the left side. Admission laboratory test results were notable for leukocyte count of 11.67 × 109/L (82.2% neutrophils, 8.3% monocytes, 6.4% lymphocytes, and 2.1% eosinophils). Results of HIV screening tests were negative.

Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements.

NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity-enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion-positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion-positive metastatic cancer were treated with Zeno. Two patients with ATP1B1-NRG1-positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74-NRG1-positive non-small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion-positive cancers. SIGNIFICANCE: NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion-positive cancers and is thus an effective therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1171.

A 33-Year-Old Man With Chest Pain.

CASE PRESENTATION: A 33-year-old man was admitted with a 4-week history of intermittent, right-sided chest pain. Two weeks before the incident, he had completed a 10-day course of levofloxacin for a presumed right-sided pneumonia without much improvement. He denied any dyspnea, cough, sputum production, hemoptysis, night sweats, or weight loss. He was an active smoker with a 20-pack-year smoking history and 1-year history of vaping nicotine.

Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper.

The Anti-HER3 mAb Seribantumab Effectively Inhibits Growth of Patient-Derived and Isogenic Cell Line and Xenograft Models with Oncogenic NRG1 Fusions.

PURPOSE: Oncogenic fusions involving the neuregulin 1 (NRG1) gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion-driven cancers. EXPERIMENTAL DESIGN: We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks in vitro and in vivo. RESULTS: Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, DOC4-NRG1 fusion) and lung (LUAD-0061AS3, SLC3A2-NRG1 fusion) cancer cells harboring NRG1 fusions or NRG1 amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a CD74-NRG1 fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with CLU-NRG1 fusion) PDX tumors induced regression of tumors by 50%-100%. Afatinib was much less effective at blocking tumor growth. CONCLUSIONS: Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion-dependent tumorigenesis in vitro and in vivo in breast, lung, and ovarian patient-derived cancer models.

Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion-Positive Lung Cancer by Combining Selpercatinib with Crizotinib.

PURPOSE: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. PATIENTS AND METHODS: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). RESULTS: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion-positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. CONCLUSIONS: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.

NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors.

Tyrosine kinase domains dynamically fluctuate between two main structural forms that are referred to as type I (DFG-in) or type II (DFG-out) conformations. Comprehensive data comparing type I and type II inhibitors are currently lacking for NTRK fusion-driven cancers. Here we used a type II NTRK inhibitor, altiratinib, as a model compound to investigate its inhibitory potential for larotrectinib (type I inhibitor)-resistant mutations in NTRK. Our study shows that a subset of larotrectinib-resistant NTRK1 mutations (V573M, F589L and G667C) retains sensitivity to altiratinib, while the NTRK1V573M and xDFG motif NTRK1G667C mutations are highly sensitive to type II inhibitors, including altiratinib, cabozantinib and foretinib. Moreover, molecular modeling suggests that the introduction of a sulfur moiety in the binding pocket, via methionine or cysteine substitutions, specifically renders the mutant kinase hypersensitive to type II inhibitors. Future precision treatment strategies may benefit from selective targeting of these kinase mutants based on our findings.

RET inhibition in novel patient-derived models of RET-fusion positive lung adenocarcinoma reveals a role for MYC upregulation.

Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET-fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5' fusion partners (CCDC6, KIF5B and TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and down-regulated by cabozantinib treatment, opening up potentially new therapeutic avenues for combinatorial targeting RET-fusion driven lung cancers. The novel RET fusion-dependent preclinical models described herein represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.

Acquired BRAF Rearrangements Induce Secondary Resistance to EGFR therapy in EGFR-Mutated Lung Cancers.

INTRODUCTION: Multiple genetic mechanisms have been identified in EGFR-mutant lung cancers as mediators of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs), but many cases still lack a known mechanism. METHODS: To identify novel mechanisms of AR, we performed targeted large panel sequencing of samples from 374 consecutive patients with metastatic EGFR-mutant lung cancer, including 174 post-TKI samples, of which 38 also had a matched pre-TKI sample. Alterations hypothesized to confer AR were introduced into drug-sensitive EGFR-mutant lung cancer cell lines (H1975, HCC827, and PC9) by using clustered regularly interspaced short palindromic repeats/Cas9 genome editing. MSK-LX138cl, a cell line with EGFR exon 19 deletion (ex19del) and praja ring finger ubiquitin ligase 2 gene (PJA2)/BRAF fusion, was generated from an EGFR TKI-resistant patient sample. RESULTS: We identified four patients (2.3%) with a BRAF fusion (three with acylglycerol kinase gene (AGK)/BRAF and one with PJA2/BRAF) in samples obtained at AR to EGFR TKI therapy (two posterlotinib samples and two posterlotinib and postosimertinib samples). Pre-TKI samples were available for two of four patients and both were negative for BRAF fusion. Induction of AGK/BRAF fusion in H1975 (L858R + T790M), PC9 (ex19del) and HCC827 (ex19del) cells increased phosphorylation of BRAF, MEK1/2, ERK1/2, and signal transducer and activator of transcription 3 and conferred resistance to growth inhibition by osimertinib. MEK inhibition with trametinib synergized with osimertinib to block growth. Alternately, a pan-RAF inhibitor as a single agent blocked growth of all cell lines with mutant EGFR and BRAF fusion. CONCLUSION: BRAF fusion is a mechanism of AR to EGFR TKI therapy in approximately 2% of patients. Combined inhibition of EGFR and MEK (with osimertinib and trametinib) or BRAF (with a pan-RAF inhibitor) are potential therapeutic strategies that should be explored.

Serendipitous Finding of Asymptomatic Babesiosis in a Patient With Symptomatic Thrombocytopenia.

We report a case of isolated immune thrombocytopenic purpura (ITP) as a result of babesiosis infection. The patient initially presented with a history, physical exam and laboratory findings consistent with idiopathic thrombocytopenic purpura. She was treated with standard of care therapy without clinical response. Daily evaluation of the peripheral smear ultimately revealed a red blood cell inclusion, identified and confirmed as a low-titer babesiosis infection indicative of past exposure. As described below, isolated thrombocytopenia related to babesiosis infection has not been reported prior to the patient's presentation. There are a few cases reported to show a relationship between babesiosis and autoimmune hemolytic anemia without an understood pathophysiologic mechanism. We review the literature, propose a possible pathophysiologic mechanism of disease and consider the implications of swift identification to prevent clinical deterioration.

Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14-mutant Non-small Cell Lung Cancer.

PURPOSE: MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear. EXPERIMENTAL DESIGN: We examined clinical and genomic data from 113 patients with lung cancer with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models. RESULTS: Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models. CONCLUSIONS: KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.

Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers.

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686-95. ©2018 AACR.See related commentary by Wilson and Politi, p. 676This article is highlighted in the In This Issue feature, p. 663.