Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 133
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cancer Treat Rev ; 84: 101974, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32014824

RESUMO

Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are among the most common aberrations in cancer, including non-small cell lung cancer (NSCLC). The lack of an ideal small molecule binding pocket in the KRAS protein and its high affinity towards the abundance of cellular guanosine triphosphate (GTP) renders the design of specific small molecule drugs challenging. Despite efforts, KRAS remains a challenging therapeutic target. Among the different known mutations; the KRASG12C (glycine 12 to cysteine) mutation has been considered potentially druggable. Several novel covalent direct inhibitors targeting KRASG12C with similar covalent binding mechanisms are now in clinical trials. Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRASG12C at the cysteine at residue 12, keeping KRASG12C in its inactive GDP-bound state and inhibiting KRAS-dependent signaling. Both inhibitors are being studied as a single agent or as combination with other targets. In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019. Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps.

2.
Nat Med ; 26(1): 47-51, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31932802

RESUMO

MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)1. These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition2. Crizotinib is a multikinase inhibitor with potent activity against MET3. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.

3.
Cancer Discov ; 10(1): 54-71, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31658955

RESUMO

Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line- and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. SIGNIFICANCE: The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.See related commentary by Klempner and Hata, p. 20.This article is highlighted in the In This Issue feature, p. 1.

4.
Lung Cancer ; 139: 22-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31706099

RESUMO

OBJECTIVES: A pooled analysis of two open-label phase II studies of alectinib (NP28673 [NCT01801111] and NP28761 [NCT01871805]) demonstrated clinical activity in patients with advanced, anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) previously treated with crizotinib. Longer-term and final pooled analyses of overall survival (OS) and safety data from the two studies are presented here. PATIENTS AND METHODS: The pooled population totaled 225 patients (NP28673: n = 138, NP28761: n = 87) who received 600 mg oral alectinib twice daily until disease progression, death, or withdrawal. OS was defined as the time from date of first treatment to date of death, regardless of cause. OS was estimated using Kaplan-Meier methodology, with 95% confidence intervals (CIs) determined using the Brookmeyer-Crowley method. Safety was assessed through adverse event (AE) reporting. RESULTS: Baseline characteristics were generally comparable between the studies. At final data cutoff (October 27, 2017 [NP28673], October 12, 2017 [NP28761]; median pooled follow-up time, ∼21 months), 53.3% of patients had died, 39.1% were alive and in follow-up, and 7.6% had withdrawn consent or were lost to follow-up. Alectinib demonstrated a median OS of 29.1 months (95% CI 21.3-39.0). No new or unexpected safety findings were observed. The most common all-grade AEs included constipation (39.1%), fatigue (35.1%), peripheral edema (28.4%), myalgia (26.2%), and nausea (24.0%). CONCLUSION: Updated results from this pooled analysis further demonstrate that alectinib has robust clinical activity and a manageable safety profile in patients with advanced, ALK+ NSCLC pretreated with crizotinib.

5.
Oncologist ; 25(1): e39-e47, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31604903

RESUMO

PURPOSE: Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon. EXPERIMENTAL DESIGN: Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases. RESULTS: Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months. CONCLUSION: We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy. IMPLICATIONS FOR PRACTICE: Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.

6.
Clin Lung Cancer ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31761448

RESUMO

BACKGROUND: Neurotrophin receptor kinase (NTRK) gene fusions (NTRK+) are rare but actionable oncogenic drivers present in a wide variety of solid tumors. However, the clinicopathologic characteristics of NTRK1 fusion-positive non-small-cell lung cancer are largely unknown. MATERIALS AND METHODS: Lung cancer tissue specimens and/or circulating cell-free DNA from patients with lung cancer who had undergone molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory in China were retrospectively reviewed. The laboratory performed NTRK1 fusion detection using hybridization-based targeted next-generation sequencing. The patients' clinical characteristics and treatment history were retrieved from the database for further evaluation. RESULTS: A total of 21,155 Chinese lung cancer cases had undergone molecular profiling from April 2016 to March 2019, including 13,630 adenocarcinoma cases. Of these cases, 12 were positive for NTRK1 fusion, including 10 cases of adenocarcinoma (0.073%), 1 primary sarcomatoid carcinoma, and 1 with an unknown histologic classification. Seven fusion partners (CD74, interferon regulatory factor 2 binding protein 2 [IRF2BP2], lamin A/C [LMNA], PHD finger protein 20 [PHF20], sequestosome 1 [SQSTM1], tropomyosin 3 [TPM3], TPR) were identified. Additionally, 1 unique rearrangement occurred upstream of the transcription start site of BCL9 fused to exon 12 of NTRK1 (intragenic region, BCL9-NTRK1). Of the 12 cases of NTRK1+ lung cancer, 6 had had concurrent activating EGFR mutations and/or had received previous treatment with EGFR tyrosine kinase inhibitors (TKIs), with 2 having concurrent EGFR T790M and 1 additional EGFR C797S. CONCLUSIONS: NTRK1+ lung cancer cases are extremely rare with multiple fusion partners. Additionally, emergence of NTRK1+ fusion might act as a resistance mechanism to EGFR TKIs. When performing comprehensive analysis of acquired resistance to EGFR TKIs, the ability to detect NTRK1 fusions will be important.

7.
Trends Cancer ; 5(11): 677-692, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31735287

RESUMO

Tumor resistance to EGFR tyrosine kinase inhibitors (TKIs) occurs invariably, and receptor tyrosine kinase (RTK) fusions have emerged as rare but actionable resistance mechanisms. In 2015, the detection of RTK fusions as acquired resistance (AR) in two cases was first reported. Subsequently, a survey of FGFR3-TACC3 fusion and other RTK fusions from a large commercial genomic sequencing company database was published, followed by large-scale clinical trials of EGFR TKIs demonstrating the emergence of RTK fusions in AR. However, detailed examination of the AR RTK fusion landscape in non-small-cell lung cancer is lacking. Hence, we conducted a comprehensive review to categorize these fusion events by the generation of EGFR TKIs, the specific RTK fusions and their fusion partners, the founder EGFR mutations, and their methods of detection. To support the actionability and clinical significance of AR RTK fusions we present all available data demonstrating clinical benefit of concurrent dual blockade of the AR RTK fusion and the original EGFR mutation.

8.
J Thorac Oncol ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31712133

RESUMO

INTRODUCTION: The effectiveness of ALK receptor tyrosine kinase (ALK) inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with NSCLC and ALK point mutations using pooled data from two single-arm phase II studies. METHODS: Studies NP28673 and NP28761 enrolled adults with locally advanced/metastatic ALK-positive NSCLC who had progressed on crizotinib. ALK mutation analysis was conducted on cell-free DNA from 187 patients post-crizotinib/pre-alectinib, and from 49 of these patients who subsequently progressed on alectinib. RESULTS: Baseline characteristics were generally balanced across patient subgroups. At baseline, 34 distinct ALK mutations were identified in 48 of 187 patients (25.7%). Median investigator-assessed progression-free survival was longer in patients without ALK single-nucleotide variants (n = 138) versus those with (n = 48): 10.2 months (95% confidence interval [CI]: 8.1-14.3) versus 5.6 months (95% CI: 4.5-10.9), respectively. Sixteen of 32 patients (50%) with ALK resistance mutations to crizotinib achieved an investigator-assessed response to alectinib (all partial responses); most of these ALK mutations were known to be sensitive to alectinib. Analysis of plasma samples obtained post-progression on alectinib revealed that 26 of 49 (53%) samples harbored 16 distinct ALK mutations, with known alectinib-resistance mutations, I1171 T/N/S, G1202R, and V1180L, observed in 15 of 49 (31%) tumors. CONCLUSIONS: Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cell-free DNA in plasma samples may be an alternative noninvasive method for monitoring resistance mutations during therapy.

9.
Lancet Oncol ; 20(12): 1691-1701, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31669155

RESUMO

BACKGROUND: 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). METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Pfizer.

10.
J Thorac Oncol ; 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31669591

RESUMO

INTRODUCTION: The current standard initial therapy for advanced ALK receptor tyrosine kinase (ALK)-positive NSCLC is a second-generation ALK tyrosine kinase inhibitor (TKI) such as alectinib. The optimal next-line therapy after failure of a second-generation ALK TKI remains to be established; however, standard options include the third-generation ALK TKI lorlatinib or platinum/pemetrexed-based chemotherapy. The efficacy of platinum/pemetrexed-based chemotherapy has not been evaluated in cases that are refractory to second-generation TKIs. METHODS: This was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to one or more second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy. RESULTS: Among 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11 of 37 patients; 95% confidence interval [CI]: 15.9% - 47.0%), with median duration of response of 6.4 months (95% CI: 1.6 months - not reached). The median progression-free survival for the entire cohort was 4.3 months (95% CI: 2.9 - 5.8 months). Progression-free survival was longer in patients who received platinum/pemetrexed in combination with an ALK TKI compared to those who received platinum/pemetrexed alone (6.8 months vs. 3.2 months, respectively; hazard ratio = 0.33; p = 0.025). CONCLUSIONS: Platinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition.

12.
J Thorac Oncol ; 14(8): 1354-1359, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31128291
13.
J Clin Oncol ; 37(16): 1370-1379, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30892989

RESUMO

PURPOSE: Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non-small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients. PATIENTS AND METHODS: Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non-small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation-focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status. RESULTS: Approximately one quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without ALK mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with ALK mutations (62% v 32% [plasma]; 69% v 27% [tissue]). Progression-free survival was similar in patients with and without ALK mutations on the basis of plasma genotyping (median, 7.3 months v 5.5 months; hazard ratio, 0.81) but significantly longer in patients with ALK mutations identified by tissue genotyping (median, 11.0 months v 5.4 months; hazard ratio, 0.47). CONCLUSION: In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.

14.
Lung Cancer ; 130: 201-207, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30885345

RESUMO

The incidence of CNS metastasis at the time of diagnosis of and during the natural disease history of advanced ROS1+ NSCLC is largely unknown. It is generally believed that the incidence of CNS metastasis is lower in ROS1+ NSCLC than ALK+ NSCLC as ROS1 fusions are regarded as a less powerful driver mutation than ALK fusions in ALK+ NSCLC based on the longer progression-free survival of ROS1+ NSCLC patients than ALK+ NSCLC patients treated with crizotinib. Here we reviewed the incidence of CNS metastasis from prospective clinical trials and retrospective case series from primarily single institution. The incidence of CNS metastasis in ROS1+ NSCLC patients at the time of diagnosis ranged from 20% to mid 30% while the incidence of CNS metastasis can be as high as in the mid 50% range post-crizotinib indicating CNS metastasis is indeed a major morbidity for ROS1+ NSCLC patients throughout the course of treatment. To date 22 fusion partners in ROS1+ NSCLC have been reported in the literature and one report has indicated CD74-ROS1 fusion variant increased the predilection for CNS metastasis than non-CD74-ROS1 fusion variants. We reviewed reported intra-cranial activity of all preclinical and clinical development stage ROS1 TKIs and pemetrexed-based chemotherapy in ROS1+ NSCLC patients. While several ROS1 TKIs (i.e. entrectinib, cabozantinib, lorlatinib, repotrectinib) have reported intra-cranial response rates, there is no literature reporting on the intra-cranial activity of pemetrexed-based chemotherapy in ROS1+ NSCLC patients. In summary, better understanding the high incidence of CNS metastasis in ROS1+ NSCLC patients, how certain ROS1 fusion variant may increase the incidence of CNS metastasis, and any intra-cranial efficacy data of pemetrexed in ROS1+ NSCLC are all urgently needed.

15.
Lung Cancer (Auckl) ; 10: 21-26, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881166

RESUMO

Exploring resistance mechanisms in patients with EGFR-mutant non-small-cell lung cancer (NSCLC) upon disease progression on EGFR tyrosine kinase inhibitors (TKIs) has been an area of great interest as it may lead to effective next-line treatment strategies. Here we report a case of emergent MET amplification detected in a tumor sample from a patient with NSCLC harboring EGFR L858R mutation after disease progression on erlotinib. The patient subsequently had a sustained partial response to a combination of full-dose osimertinib and crizotinib with excellent tolerance but eventually had central nervous system (CNS) progression. Comprehensive genomic profiling performed on the resected brain sample continued to demonstrate MET amplification as an acquired resistance mechanism. A review of literature shows several groups have utilized similar combination regimens (erlotinib or osimertinib + crizotinib or cabozantinib), albeit with various dosing to target MET alterations in patients with EGFR-mutant NSCLC. As more actionable resistance mechanisms are identified, we envision combination TKI therapy will be readily adopted in clinical practice. Our case report adds to a growing body of evidence that combination osimertinib and crizotinib should be recommended to EGFR-mutant NSCLC patients with emergent MET amplification as acquired resistance. More importantly, as crizotinib has limited brain penetration, developing next-generation MET inhibitors with better CNS activity is urgently needed.

17.
J Thorac Oncol ; 14(2): 255-264, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30368012

RESUMO

INTRODUCTION: Genomic profiling informs selection of matched targeted therapies as part of routine clinical care in NSCLC. Tissue biopsy is the criterion standard; however, genomic profiling of blood-derived circulating tumor DNA (ctDNA) has emerged as a minimally invasive alternative. METHODS: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 1552 patients with NSCLC. RESULTS: Evidence of ctDNA was detected in 80% of samples, and in 86% of these cases, at least one reportable genomic alteration (GA) was detected. Frequently altered genes were tumor protein p53 gene (TP53) (59%), EGFR (25%), and KRAS (17%). Comparative analysis with a tissue genomic database (N = 21,500) showed similar frequencies of GAs per gene, although KRAS mutation and EGFR T790M were more frequent in tissue and ctDNA, respectively (both p < 0.0001), likely reflecting the use of liquid versus tissue biopsy after relapse during targeted therapy. In temporally matched ctDNA and tissue samples from 33 patients with evidence of ctDNA in their blood, 64% of GAs detected in tissue were also detected in ctDNA, including 78% of short variants (58 of 74) and 100% of rearrangements (four of four), but only 16% of amplifications (four of 25). CONCLUSIONS: Genomic profiling of ctDNA detected clinically relevant GAs in a significant subset of NSCLC cases. Most alterations detected in matched tissue were also detected in ctDNA. These results suggest the utility of ctDNA testing in advanced NSCLC as a complementary approach to tissue testing. Blood-based ctDNA testing may be particularly useful at the time of progression during targeted therapy.

18.
Lung Cancer (Auckl) ; 9: 111-116, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30519133

RESUMO

ALK-rearranged lung cancer defines a distinctive molecular cohort of patients whose outcomes are significantly improved by the availability of ALK inhibitors. Thus, it is imperative for clinicians to screen appropriate patients for this driver mutation with a molecular testing platform capable of capturing all ALK fusions. Here, we report a novel VKORC1L1-ALK fusion and an ALK T1151K resistance mutation detected in a lung cancer patient who had been on crizotinib for over 8 years. Alectinib induced a dramatic response in this patient demonstrating its clinical activity against T1151K. This case illustrates the importance of performing repeat biopsy to explore mechanism(s) of resistance when patients experience disease progression on an ALK inhibitor. The approach has a direct therapeutic impact particularly when an ALK resistance mutation is identified.

19.
Lancet Oncol ; 19(12): 1654-1667, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30413378

RESUMO

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Pfizer.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Rearranjo Gênico , Humanos , Lactamas Macrocíclicas/efeitos adversos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Fatores de Tempo , Carga Tumoral
20.
Lung Cancer ; 124: 86-89, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30268485

RESUMO

Non-small cell lung cancer (NSCLC) has emerged as a paradigm for clinical application of precision medicine as optimal therapy is commonly chosen based on genomic biomarkers identified in a patient's tumor sample. Recurrent driver alterations are well described, however, a need to continually identify rare variants remains clinically relevant. We identified an incident case of advanced NSCLC with a PDGFR-α N848 K activation loop mutation with no other concurrent oncogenic drivers. Amino acid sequence alignment confirmed homology to the imatinib-sensitive KIT N822 K activation loop mutation observed in GIST. The patient achieved a 2-year response to single agent imatinib that is ongoing. While PDGFR-α N848 K is rare among public sequencing databases our cases strongly suggests functional relevance and highlights the importance of studying rare variants in NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Carcinoma Pulmonar de Células não Pequenas/genética , Fumar Cigarros , Feminino , Humanos , Neoplasias Pulmonares/genética , Estadiamento de Neoplasias , Pneumonectomia , Intervalo Livre de Progressão , Indução de Remissão
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA