Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial.

BACKGROUND: Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma. METHODS: Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively). RESULTS: After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression-free survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%). CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.

Clinical Activity of Nivolumab for Human Papilloma Virus-Related Juvenile-Onset Recurrent Respiratory Papillomatosis.

BACKGROUND: Juvenile-onset recurrent respiratory papillomatosis (JO-RRP) is a human papilloma virus-mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO-RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth. MATERIALS AND METHODS: We treated two patients with refractory JO-RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling. RESULTS: Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on-treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma. CONCLUSION: Nivolumab appears to have promising activity in JO-RRP, and further clinical investigation with more patients in clinical trials is warranted. IMPLICATIONS FOR PRACTICE: To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death-1 (PD-1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD-1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.

Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study.

BACKGROUND: Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma. METHODS: We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis. FINDINGS: 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14-26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8-38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity. INTERPRETATION: Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential. FUNDING: Merck & Co.

A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours.

BACKGROUND: Veliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours. METHODS: Patients received veliparib (10-270 mg BID, days 1-5, 15-19) and FOLFIRI (days 1-3, 15-17) in three regimens containing 5-fluorouracil 2,400 mg/m2: irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2, folinic acid 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (part 3). The RP2D was further evaluated in safety expansion cohorts. Preliminary antitumour activity was also assessed. RESULTS: Ninety-two patients received ≥1 veliparib dose. MTD was not reached; RP2D was set at 200 mg BID veliparib plus FOLFIRI (without 5-fluorouracil bolus). Most common treatment-emergent adverse events were neutropenia (66.3%), diarrhoea, and nausea (60.9% each). Dose-limiting toxicities (n = 4) were grade 3 gastritis and grade 4 neutropenia and febrile neutropenia. Veliparib exposure was dose-proportional, with no effects on the pharmacokinetics of FOLFIRI components. Fifteen patients had a partial response (objective response rate, 17.6%). CONCLUSIONS: The acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination.

Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors.

BACKGROUND: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors. METHODS: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures. RESULTS: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%). CONCLUSION: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes. TRIAL REGISTRATION NUMBER: NCT02335918.

A Phase I Trial of Dasatinib and Osimertinib in TKI Naïve Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer.

BACKGROUND: Osimertinib is an effective first-line therapy option for EGFR-mutant NSCLC, but virtually all patients develop resistance. CRIPTO, through Src activation, has been implicated in resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Dasatinib, a Src inhibitor, has shown preclinical synergy with EGFR-TKI therapy. METHOD: This is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced EGFR-mutant NSCLC (NCT02954523). A 3 + 3 design was used in the phase I to establish the recommended phase II dose (RP2D). Osimertinib 80 mg QD was combined with dasatinib 70 mg BID (DL2), 50 mg BID (DL1), 70 mg QD (DL-1), and 50 mg QD (DL-2). RESULTS: Ten patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches/body pain, neutropenia, rash, one each). Common treatment-related adverse events included pleural effusion (n=10), diarrhea (n=8), rash (n=7), transaminitis (n=7), thrombocytopenia (n=7), and neutropenia (n=7). While the MTD was not determined by protocol-defined DLT criteria, DL-2 was chosen as the RP2D, considering overall tolerability. Nine (90%) patients had a PR, including 1 unconfirmed PR. Median PFS was 19.4 months and median OS 36.1 months. The trial was closed to accrual prematurely due to slow accrual after the approval of osimertinib as first-line therapy. CONCLUSIONS: The combination of dasatinib and osimertinib demonstrated anticancer activity. The treatment was limited by chronic toxicities mainly attributed to dasatinib. To improve the safety and tolerability of Src and EGFR co-inhibition, Src inhibitors with a more favorable safety profile should be utilized in future studies. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02954523.

Real-world impact of brain metastases on healthcare utilization and costs in patients with non-small cell lung cancer treated with EGFR-TKIs in the US.

BACKGROUND: Non-small cell lung cancer (NSCLC) with brain metastases (BM) is difficult to treat and associated with poor survival. This study assessed the impact of BM on healthcare-related utilization and costs (HRUC) among patients receiving epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Adults newly-diagnosed with metastatic NSCLC, initiating first-/second-generation EGFR-TKI treatment, with BM or no BM (NBM), were identified retrospectively from IBM MarketScan healthcare claims databases (2013-2017). HRUC were measured during the variable-length follow-up period. Generalized linear models assessed the impact of BM on total healthcare costs, standardized to 2017 US$. RESULTS: Overall, 222 BM and 280 NBM patients were included, with a mean duration of follow-up of 14 months. Adjusted NSCLC-related and all-cause costs over average follow-up were 1.2 times higher among BM patients (Δ$5,640 and Δ$6,366, respectively; p <0.05); differences were driven primarily by radiation treatment and radiology. More than two times more BM than NBM patients received NSCLC-related radiation treatment, in both inpatient (15.3% vs 6.8%; p <0.05) and outpatient settings (87.8% vs 37.5%; p <0.05). Per-patient per-month (PPPM) radiation costs were also higher among BM patients, both inpatient ($796 vs $464, p =0.172) and outpatient ($2,443 vs $747, p <0.05). All-cause PPPM radiology visits (2.0 vs 1.3) and associated costs ($3,824 vs $1,621) were higher among BM patients (both p <0.05). CONCLUSION: NSCLC-related HRUC, especially those attributable to radiation treatment, were higher among patients with BM. Future research should compare the potential for CNS-active EGFR-TKIs vs first-/second-generation EGFR-TKIs combined with radiotherapy to reduce HRUC.

Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells.

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1- T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells. SIGNIFICANCE: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy.See related commentary by Burton and Tawbi, p. 1008.This article is highlighted in the In This Issue feature, p. 995.

Phase I study of the 177Lu-DOTA0-Tyr3-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung.

BACKGROUND: Lutathera is a 177Lutetium-labeled somatostatin analog approved for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Somatostatin receptors are expressed in small cell lung cancer (SCLC). Nivolumab, an anti-PD-1 antibody, may act synergistically with lutathera to generate antitumor immunity. We conducted a phase I study of lutathera plus nivolumab in patients with advanced NETs of the lung. METHODS: Patients with relapsed/refractory extensive-stage SCLC (ES-SCLC), non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed a standard 3+3 design, assessing two dose levels (dose level 1: lutathera 3.7 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks; dose level 2: lutathera 7.4 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks). RESULTS: Nine patients were enrolled (six ES-SCLC, two pulmonary atypical carcinoid, one high-grade pulmonary neuroendocrine carcinoma). No dose-limiting toxicities (DLTs) were observed at dose level 1. At dose level 2, one patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related adverse events (TRAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). The most common grade 3 TRAE was lymphopenia (n=4). Among the seven patients with measurable disease, one patient with ES-SCLC had a partial response. Two patients with pulmonary atypical carcinoid had stable disease lasting 6 months. The RP2D was dose level 2. CONCLUSIONS: Lutathera plus nivolumab was well tolerated and showed signs of antitumor activity. This combination warrants further exploration. TRIAL REGISTRATION NUMBER: NCT03325816.

Molecular diagnostics and targeted therapies in non-small cell lung cancer (NSCLC): an update.

The understanding of genetic alterations that drive non-small cell lung cancer (NSCLC) is evolving. As many of these molecularly-defined subtypes are potentially actionable, new strategies in molecular diagnostics and targeted therapies in NSCLC to detect and treat them are being explored. At the International Association for Study of Lung Cancer 19th World Conference, several abstracts and oral presentations related to this topic. In this report, we discuss some of these updates.

A phase I study of HER1, HER2 dual kinase inhibitor lapatinib plus the proteasome inhibitor bortezomib in patients with advanced malignancies.

PURPOSE: This phase I trial evaluated the maximum tolerated dose, safety and preliminary efficacy of lapatinib, a HER1, HER2 dual kinase inhibitor plus bortezomib, a proteasome inhibitor, in adult patients with advanced malignancies. METHODS: Patients were enrolled in a standard 3 + 3 design with lapatinib (L) 750, 1000, 1250 or 1500 mg daily, and bortezomib (B) 0.7, 1.0, 1.3 or 1.6 mg/m2 for 3 weeks with 1 week off. Dose-limiting toxicities (DLT) were assessed during the first 28 days RESULTS: Fifteen patients received the combination of lapatinib and bortezomib in three different cohorts and ten were evaluable for DLT. There were no DLTs. Anorexia was the most common adverse event. Biomarker analysis showed upregulation of p27 expression with lapatinib and the combination. No tumor response was observed and thus the study was closed early. CONCLUSION: The combination of lapatinib and bortezomib was well tolerated but no complete or partial tumor responses were observed at the dose levels tested. CLINICALTRIALS. GOV IDENTIFIER: NCT01497626.

Understanding molecular diagnostic technology in oncology through the lens of lung cancer.

Historically, advanced lung cancer conferred a poor prognosis, and chemotherapy only improved outcomes in patients with good performance status. The identification of certain molecular subtypes of non-small cell lung cancer changed the treatment paradigm by incorporating tumor genomic information into clinical decision-making. To meet the demands of this emerging approach, genomic technology rapidly expanded in an effort to detect specific driver mutations. While polymerase-chain reaction testing, immunohistochemistry, and fluorescent-in-situ hybridization have been standard-of-care, next-generation sequencing is increasingly replacing older technologies. Plasma-based testing is also gaining use given its convenience. Advances in molecular technology in this new era of precision medicine have led to the parallel development of companion diagnostics and novel tyrosine kinase inhibitors.

Management of Brain Metastases in Epidermal Growth Factor Receptor Mutant Non-Small-Cell Lung Cancer.

Lung cancer remains a leading cause of mortality with 1.69 million deaths worldwide. Activating mutations in epidermal growth factor receptor (EGFR), predominantly exon 19 deletions and exon 21 L858R mutations, are known oncogenic drivers identified in 20-40% of non-small-cell lung cancers (NSCLC). 70% of EGFR-mutant NSCLC patients develop brain metastases (BM), compared to 38% in EGFR wild-type patients. First-generation tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib have proven to be superior to chemotherapy in the front-line treatment of EGFR-mutant NSCLC, as has afatinib, a second-generation TKI. The most common acquired resistance mechanism is the development of a gatekeeper mutation in exon 20 T790M. Osimertinib has emerged as a third-generation EGFR TKI with proven activity in the front-line setting as well as in patients with a T790M acquired resistance mutation with remarkable CNS activity. As long-term survival outcomes in EGFR-mutant NSCLC continue to improve, the burden of BM becomes a greater challenge. Here, we review the literature related to the management of BM in EGFR-mutant NSCLC including the role of the three generations of EGFR TKIs, immunotherapy, and brain radiation.

A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer.

INTRODUCTION: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin. METHODS: Patients eligible for the phase Ib portion had advanced tumors that would be appropriate for doxorubicin therapy and those in the phase II portion had relapsed or refractory SCLC. All patients had an ECOG performance status, 0-1 and adequate organ function, including a cardiac ejection fraction ≥50%. Patients who received a lifetime cumulative doxorubicin dose of >150 mg/m2 or who had symptomatic brain metastases were excluded. Patients received ganetespib on Days 1 and 8 and doxorubicin 50 mg/m2 on day 1 in 21-day cycles. RESULTS: Eleven patients were enrolled including nine in the phase Ib dose escalation and two in the phase II expansion. The study was terminated by the sponsor. The dose recommended for future study is ganetespib 150 mg/m2 in combination with doxorubicin at a dose of 50 mg/m2. The most common adverse events of the combination were grade 1/2 diarrhea, nausea, fatigue, and transaminitis. No dose limiting toxicities were observed. Response rate was 25% and median duration of response was 137 days. CONCLUSION: Ganetespib plus doxorubicin was a well-tolerated combination and there remains potential for the clinical development of Hsp90 inhibitors in SCLC. CLINICAL TRIAL REGISTRATION: https://ClinicalTrials.gov/ct2/show/NCT02261805, identifier NCT02261805.

Long-Term Outcomes Following Conventionally Fractionated Stereotactic Boost for High-Grade Gliomas in Close Proximity to Critical Organs at Risk.

Purpose/Objective: High-grade glioma is the most common primary malignant tumor of the CNS, with death often resulting from uncontrollable intracranial disease. Radiation dose may be limited by the tolerance of critical structures, such as the brainstem and optic apparatus. In this report, long-term outcomes in patients treated with conventionally fractionated stereotactic boost for tumors in close proximity to critical structures are presented. Materials/Methods: Patients eligible for inclusion in this single institution retrospective review had a pathologically confirmed high-grade glioma status post-surgical resection. Inclusion criteria required tumor location within one centimeter of a critical structure, including the optic chiasm, optic nerve, and brainstem. Radiation therapy consisted of external beam radiation followed by a conventionally fractionated stereotactic boost. Oncologic outcomes and toxicity were assessed. Results: Thirty patients eligible for study inclusion underwent resection of a high-grade glioma. The median initial adjuvant EBRT dose was 50 Gy with a median conventionally fractionated stereotactic boost of 10 Gy. All stereotactic treatments were given in 2 Gy daily fractions. Median follow-up time for the entire cohort was 38 months with a median overall survival of 45 months and 5-year overall survival of 32.5%. The median freedom from local progression was 45 months, and the 5-year freedom from local progression was 29.7%. Two cases of radiation retinopathy were identified following treatment. No patient experienced toxicity attributable to the optic chiasm, optic nerve, or brainstem and no grade 3+ radionecrosis was observed. Conclusions: Oncologic and toxicity outcomes in high-grade glioma patients with tumors in unfavorable locations treated with conventionally fractionated stereotactic boost are comparable to those reported in the literature. This treatment strategy is appropriate for those patients with resected high-grade glioma in close proximity to critical structures.

Targetable Gene Fusions Associate With the IDH Wild-Type Astrocytic Lineage in Adult Gliomas.

Gene fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets. Using RNA-sequencing, we interrogated a large cohort of gliomas to assess for the incidence of targetable genetic fusions. Gliomas (n = 390) were profiled using the ArcherDx FusionPlex Assay. Fifty-two gene targets were analyzed and fusions with preserved kinase domains were investigated. Overall, 36 gliomas (9%) harbored a total of 37 potentially targetable fusions, the majority of which were found in astrocytomas (n = 34). Within this lineage 11% (25/235) of glioblastomas, 12% (5/42) of anaplastic astrocytomas, 8% (2/25) of grade II astrocytomas, and 33% (2/6) of pilocytic astrocytoma harbored targetable fusions. Fusions were significantly more frequent in IDH wild-type tumors (12%, n = 31/261) relative to IDH mutants (4%; n = 4/109) (p = 0.011). No fusions were seen in oligodendrogliomas. The most frequently observed therapeutically targetable fusions were in FGFR (n = 12), MET (n = 11), and NTRK (n = 8). Several additional novel fusions that have not been previously described in gliomas were identified including EGFR:VWC2 and FGFR3:NBR1. In summary, targetable gene fusions are enriched in IDH wild-type high-grade astrocytic tumors, which will influence enrollment in and interpretation of clinical trials of glioma patients.

Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer.

BACKGROUND: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. RESULTS: Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. CONCLUSION: In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.

Ganetespib for small cell lung cancer.

INTRODUCTION: Heat shock proteins (Hsps) are part of a complex network of chaperone proteins that are critically involved in the conformational maturation of intracellular proteins and regulate their degradation via the proteasome system Hsps (especially Hsp70 and Hsp90) are upregulated in many cancers and are potentially attractive therapeutic targets. Ganetespib is a potent non-geldanamycin analogue, and avoids the toxicities associated with older analogues due to its small molecular weight, lipophilicity and the absence of the benzoquinone moiety; strong pre-clinical data support its evaluation in lung cancer, especially small cell lung cancer (SCLC). Areas covered: The chemical structure of ganetespib, the biology of Hsp90 in cancer and the pharmacokinetic and pharmacodynamic data related to ganetespib are summarized; data from preclinical studies and multiple Phase I-III clinical trials, with a focus on its evaluation in SCLC are reviewed. Expert opinion: Recent progress made in the treatment of refractory SCLC with immune checkpoint inhibitors and DLL3-directed antibody-drug conjugate have made the development of ganetespib particularly challenging in SCLC. Hsp90 remains a critical therapeutic target. Hsp90 inhibitors with a wider therapeutic index and combinations with drugs targeting iHsp90 co-chaperones such as Cdc37 or Protein Kinase 2 may need to be explored in the future.

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.

PURPOSE: Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib. METHODS: This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR). RESULTS: Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa. CONCLUSIONS: Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.