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Lorlatinib is a potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ALK and ROS1 with preclinical activity against most known resistance mutations in ALK and ROS1. We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive non-small-cell lung cancer (NSCLC). In this open-label, single-arm, phase 1–2 trial, we enrolled patients (aged ≥18 years) with histologically or cytologically confirmed advanced ROS1-positive NSCLC, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 2 or less (≤1 for phase 1 only) from 28 hospitals in 12 countries worldwide. Lorlatinib 100 mg once daily (escalating doses of 10 mg once daily to 100 mg twice daily in phase 1 only) was given orally in continuous 21-day cycles until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was overall and intracranial tumour response, assessed by independent central review. Activity endpoints were assessed in patients who received at least one dose of lorlatinib. This study is ongoing and is registered with ClinicalTrials.gov, NCT01970865. Between Jan 22, 2014, and Oct 2, 2016, we assessed 364 patients, of whom 69 with ROS1-positive NSCLC were enrolled. 21 (30%) of 69 patients were TKI-naive, 40 (58%) had previously received crizotinib as their only TKI, and eight (12%) had previously received one non-crizotinib ROS1 TKI or two or more ROS1 TKIs. The estimated median duration of follow-up for response was 21·1 months (IQR 15·2–30·3). 13 (62%; 95% CI 38–82) of 21 TKI-naive patients and 14 (35%; 21–52) of 40 patients previously treated with crizotinib as their only TKI had an objective response. Intracranial responses were achieved in seven (64%; 95% CI 31–89) of 11 TKI-naive patients and 12 (50%; 29–71) of 24 previous crizotinib-only patients. The most common grade 3–4 treatment-related adverse events were hypertriglyceridaemia (13 [19%] of 69 patients) and hypercholesterolaemia (ten [14%]). Serious treatment-related adverse events occurred in five (7%) of 69 patients. No treatment-related deaths were reported. Lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC, including those with CNS metastases and those previously treated with crizotinib. Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent. Pfizer.

Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer. In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1–6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1–5 only), and safety data for all treated patients (EXP1–6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5–97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4–99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2–5), objective responses were achieved in 93 (47·0%; 39·9–54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5–73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1–80·8) of 59 patients who had only received previous crizotinib (EXP2–3A), nine (32·1%; 15·9–52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6–48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4–5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4–97·2) of 23 patients with measurable baseline CNS lesions in EXP2–3A, five (55·6%; 21·2–86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3–67·5) of 49 patients in EXP4–5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3–4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3–4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported. Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. Pfizer.

Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care.

The treatment landscape for patients with advanced non-small cell lung cancer has evolved greatly with the advent of immune checkpoint inhibitors. However, many patients do not derive benefit from checkpoint blockade, developing either primary or secondary resistance, highlighting a need for alternative approaches to modulate immune function. In this review, we highlight the absence of a common definition of primary and secondary resistance and summarize their frequency and clinical characteristics. Furthermore, we provide an overview of the biomarkers and mechanisms of resistance involving the tumor, the tumor microenvironment and the host, and suggest treatment strategies to overcome these mechanisms and improve clinical outcomes.

Presence and frequency of rare circulating tumor cells (CTCs) in bloodstreams of cancer patients are pivotal to early cancer detection and treatment monitoring. Here, we use a spiral microchannel with inherent centrifugal forces for continuous, size-based separation of CTCs from blood ( Dean Flow Fractionation (DFF)) which facilitates easy coupling with conventional downstream biological assays. Device performance was optimized using cancer cell lines (> 85% recovery), followed by clinical validation with positive CTCs enumeration in all samples from patients with metastatic lung cancer (n = 20; 5–88 CTCs per mL). The presence of CD133 + cells, a phenotypic marker characteristic of stem-like behavior in lung cancer cells was also identified in the isolated subpopulation of CTCs. The spiral biochip identifies and addresses key challenges of the next generation CTCs isolation assay including antibody independent isolation, high sensitivity and throughput (3 mL/hr); and single-step retrieval of viable CTCs.

Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using “PD-L1” as a search term for 01/01/2015 to 31/08/2018, with limitations “English” and “human”. 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.

The clinical activity of fibroblast growth factor receptor (FGFR) inhibitors seems restricted to cancers harbouring rare FGFR genetic aberrations. In preclinical studies, high tumour FGFR mRNA expression predicted response to rogaratinib, an oral pan-FGFR inhibitor. We aimed to assess the safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, and preliminary clinical activity of rogaratinib. We did a phase 1 dose-escalation and dose-expansion study of rogaratinib in adults with advanced cancers at 22 sites in Germany, Switzerland, South Korea, Singapore, Spain, and France. Eligible patients were aged 18 years or older, and were ineligible for standard therapy, with an Eastern Cooperative Oncology Group performance status of 0–2, a life expectancy of at least 3 months, and at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. During dose escalation, rogaratinib was administered orally twice daily at 50–800 mg in continuous 21-day cycles using a model-based dose-response analysis (continuous reassessment method). In the dose-expansion phase, all patients provided an archival formalin-fixed paraffin-embedded (FFPE) tumour biopsy or consented to a new biopsy at screening for the analysis of FGFR1–3 mRNA expression. In the dose-expansion phase, rogaratinib was given at the recommended dose for expansion to patients in four cohorts: urothelial carcinoma, head and neck squamous-cell cancer (HNSCC), non-small-cell lung cancer (NSCLC), and other solid tumour types. Primary endpoints were safety and tolerability, determination of maximum tolerated dose including dose-limiting toxicities and determination of recommended phase 2 dose, and pharmacokinetics of rogaratinib. Safety analyses were reported in all patients who received at least one dose of rogaratinib. Patients who completed cycle 1 or discontinued during cycle 1 due to an adverse event or dose-limiting toxicity were included in the evaluation of recommended phase 2 dose. Efficacy analyses were reported for all patients who received at least one dose of study drug and who had available post-baseline efficacy data. This ongoing study is registered with ClinicalTrials.gov, number NCT01976741, and is fully recruited. Between Dec 30, 2013, and July 5, 2017, 866 patients were screened for FGFR mRNA expression, of whom 126 patients were treated (23 FGFR mRNA-unselected patients in the dose-escalation phase and 103 patients with FGFR mRNA-overexpressing tumours [52 patients with urothelial carcinoma, eight patients with HNSCC, 20 patients with NSCLC, and 23 patients with other tumour types] in the dose-expansion phase). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached; 800 mg twice daily was established as the recommended phase 2 dose and was selected for the dose-expansion phase. The most common adverse events of any grade were hyperphosphataemia (in 77 [61%] of 126 patients), diarrhoea (in 65 [52%]), and decreased appetite (in 48 [38%]); and the most common grade 3–4 adverse events were fatigue (in 11 [9%] of 126 patients) and asymptomatic increased lipase (in 10 [8%]). Serious treatment-related adverse events were reported in five patients (decreased appetite and diarrhoea in one patient with urothelial carcinoma, and acute kidney injury [NSCLC], hypoglycaemia [other solid tumours], retinopathy [urothelial carcinoma], and vomiting [urothelial carcinoma] in one patient each); no treatment-related deaths occurred. Median follow-up after cessation of treatment was 32 days (IQR 25–36 days). In the expansion cohorts, 15 (15%; 95% CI 8·6–23·5) out of 100 evaluable patients achieved an objective response, with responses recorded in all four expansion cohorts (12 in the urothelial carcinoma cohort and one in each of the other three cohorts), and in ten (67%) of 15 FGFR mRNA-overexpressing tumours without apparent FGFR genetic aberration. Rogaratinib was well tolerated and clinically active against several types of cancer. Selection by FGFR mRNA expression could be a useful additional biomarker to identify a broader patient population who could be eligible for FGFR inhibitor treatment. Bayer AG.

Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non‐small cell lung cancer (NSCLC) with acquired tyrosine kinase inhibitor (TKI) resistance. Mutated EGFR mediates TKI resistance through regulation of the fatty acid synthase (FASN), which produces 16‐C saturated fatty acid palmitate. Our work shows that the persistent signaling by mutated EGFR in TKI‐resistant tumor cells relies on EGFR palmitoylation and can be targeted by Orlistat, an FDA‐approved anti‐obesity drug. Inhibition of FASN with Orlistat induces EGFR ubiquitination and abrogates EGFR mutant signaling, and reduces tumor growths both in culture systems and in vivo . Together, our data provide compelling evidence on the functional interrelationship between mutated EGFR and FASN and that the fatty acid metabolism pathway is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC patients. Synopsis In EGFR mutated Non‐Small Cell Lung Carcinoma with acquired Tyrosine Kinase Inhibitors resistance, FASN mediates EGFR palmitoylation and supports tumor growth. With limited effective therapeutics, these data show that FASN is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC. Identification of a positive feedback loop involving mutated EGFR and FASN in EGFR mutated NSCLC with acquired TKI resistance. FASN‐mediated EGFR palmitoylaton is crucial for survival of NSCLC cells, and influences its translocation to the nucleus. FASN inhibition suppresses tumor growth in both cell culture systems and in vivo models, highlighting its potential as a target for therapeutic intervention. Graphical Abstract In EGFR mutated Non‐Small Cell Lung Carcinoma with acquired Tyrosine Kinase Inhibitors resistance, FASN mediates EGFR palmitoylation and supports tumor growth. With limited effective therapeutics, these data show that FASN is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC.

Circulating tumor cells (CTCs) are cancer cells that can be isolated via liquid biopsy from blood and can be phenotypically and genetically characterized to provide critical information for guiding cancer treatment. Current analysis of CTCs is hindered by the throughput, selectivity and specificity of devices or assays used in CTC detection and isolation. Here, we enriched and characterized putative CTCs from blood samples of patients with both advanced stage metastatic breast and lung cancers using a novel multiplexed spiral microfluidic chip. This system detected putative CTCs under high sensitivity (100%, n = 56) (Breast cancer samples: 12-1275 CTCs/ml; Lung cancer samples: 10-1535 CTCs/ml) rapidly from clinically relevant blood volumes (7.5 ml under 5 min). Blood samples were completely separated into plasma, CTCs and PBMCs components and each fraction were characterized with immunophenotyping (Pan-cytokeratin/CD45, CD44/CD24, EpCAM), fluorescence in-situ hybridization (FISH) (EML4-ALK) or targeted somatic mutation analysis. We used an ultra-sensitive mass spectrometry based system to highlight the presence of an EGFR-activating mutation in both isolated CTCs and plasma cell-free DNA (cf-DNA), and demonstrate concordance with the original tumor-biopsy samples. We have clinically validated our multiplexed microfluidic chip for the ultra high-throughput, low-cost and label-free enrichment of CTCs. Retrieved cells were unlabeled and viable, enabling potential propagation and real-time downstream analysis using next generation sequencing (NGS) or proteomic analysis.

New insight on the interaction between the immune system and tumor has identified the programmed death-1/programmed death-1 ligand pathway to be a key player in evading host immune response. The immune checkpoint modulator, nivolumab (BMS-936558/ONO-4538), is the first PD-1 inhibitor to gain regulatory approval, for the treatment of patients with unresectable melanoma. This review will discuss results from early phase studies of nivolumab in solid tumors including non-small cell lung cancer (NSCLC) as well as studies of nivolumab in combination with chemotherapy, other immune modulators and molecular targeted therapy in patients with NSCLC.