A Systemic Review of Resistance Mechanisms and Ongoing Clinical Trials in ALK-Rearranged Non-Small Cell Lung Cancer.
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ABSTRACT:
SUBMITTER: Esfahani K
PROVIDER: S-EPMC4104550 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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A Systemic Review of Resistance Mechanisms and Ongoing Clinical Trials in ALK-Rearranged Non-Small Cell Lung Cancer.
Esfahani Khashayar K Agulnik Jason Scott JS Cohen Victor V
Frontiers in oncology 20140721
The identification of oncogenic driver mutations in non-small cell lung cancer (NSCLC) has led to a paradigm shift and the development of specific molecular treatments. Tumors harboring a rearranged EML4-ALK fusion oncogene are highly sensitive to therapy with ALK-targeted inhibitors. Crizotinib is the first approved treatment for advanced lung tumors containing this genetic abnormality. In this mini review, we discuss the existing data on crizotinib as well as ongoing trials involving this medi ...[more]
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Project description:PurposePatients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small-molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those who do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in patients with ALK(+) non-small cell lung cancer (NSCLC).Experimental designWe analyzed tissue obtained from 14 patients with ALK(+) NSCLC showing evidence of radiologic progression while on crizotinib to define mechanisms of intrinsic and acquired resistance to crizotinib.ResultsEleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient showed outgrowth of epidermal growth factor receptor (EGFR) mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient showed the emergence of an ALK gene fusion-negative tumor compared with the baseline sample but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism.ConclusionsCrizotinib resistance in ALK(+) NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers.
| S-EPMC3311875 | biostudies-literature
Project description:Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).
| S-EPMC4079055 | biostudies-literature
Project description:Most anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLCs) are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). However, patients with these cancers invariably relapse, typically within 1 year, because of the development of drug resistance. Herein, we report findings from a series of lung cancer patients (n = 18) with acquired resistance to the ALK TKI crizotinib. In about one-fourth of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain, including new resistance mutations located in the solvent-exposed region of the adenosine triphosphate-binding pocket, as well as amplification of the ALK fusion gene. Next-generation ALK inhibitors, developed to overcome crizotinib resistance, had differing potencies against specific resistance mutations. In addition to secondary ALK mutations and ALK gene amplification, we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in drug-resistant tumors from patients. In a subset of patients, we found evidence of multiple resistance mechanisms developing simultaneously. These results highlight the unique features of TKI resistance in ALK-positive NSCLCs and provide the rationale for pursuing combinatorial therapeutics that are tailored to the precise resistance mechanisms identified in patients who relapse on crizotinib treatment.
| S-EPMC3385512 | biostudies-literature
Project description:Entrectinib is a pan-tyrosine-kinase inhibitor that targets oncogenic rearrangements in NTRK, ROS1 and ALK. The combined results of two clinical trials demonstrated the efficacy of entrectinib in ROS1-rearranged NSCLC. Because the development of drug resistance is inevitable, it would be helpful to determine the mechanisms of entrectinib resistance in a ROS1-rearranged tumor model so that future therapeutic strategies can be developed. Here, we characterized the molecular basis of resistance in entrectinib-resistant ROS1-rearranged HCC78 cells (HCC78ER cells). These cells were analyzed by next-generation sequencing and genetic profiling, which revealed the acquisition of KRAS G12C and the amplification of KRAS and FGF3. However, there were no secondary mutations in the ROS1 kinase domain. We also found that sustained ERK activation was involved in entrectinib resistance, and that combined treatment with selumetinib resensitized HCC78ER cells to entrectinib in cell viability and colony formation assays. Our data suggest that activation of the RAS signaling pathway can cause entrectinib resistance in ROS1-rearranged NSCLC, and is unlikely to be overcome by sequential single agent ROS1-targeting strategies against such tumors. Instead, co-targeting ROS1 and MEK may be an effective strategy for overcoming entrectinib resistance in ROS1-rearranged NSCLC.
| S-EPMC7066105 | biostudies-literature
Project description:Background:We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods:ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results:Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9?months (95% CI: 2.4-5.6) versus 10.3?months (95% CI: 8.6-12.0), P?<?0.001; OS 15.0?months (95% CI: 5.0-24.9) versus 50.0?months (95% CI: 22.9-77.1), P?=?0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6?months (95% CI: 1.3-4.1) versus 6.2?months (95% CI: 1.8-10.5), P?=?0.021; OS 2.0?months (95% CI: 0.0-4.6) versus 9.0?months (95% CI: 6.1-11.9), P?=?0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0?months (95% CI: 2.9-7.2) versus 14.0?months (95% CI: 8.0-20.1), P?<?0.001; OS 17.0?months (95% CI: 6.7-27.3) versus not reached, P?=?0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4?months (95% CI: 0.1-10.7) versus 9.9?months (95% CI: 6.4-13.5), P?=?0.039; OS 7.0?months versus 50.0?months (95% CI: not reached), P?=?0.001). Conclusions:In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
| S-EPMC6225899 | biostudies-literature
Project description:PurposeLorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting.Experimental designResistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance.ResultsDiverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial-mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.ConclusionsThis study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.
| S-EPMC6942925 | biostudies-literature
Project description:Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.
| S-EPMC5050111 | biostudies-literature
Project description:To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion.We conducted a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed.Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared with chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared with chemotherapy-treated mice. Pemetrexed produced superior overall survival compared with docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. In addition, in the EML4-ALK-driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1174L.Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor-naïve disease and support further clinical investigation of HSP90 inhibitors and second-generation ALK inhibitors in tumors with primary or acquired crizotinib resistance.
| S-EPMC3947539 | biostudies-literature
Project description:AIM:To clarify the clinicopathological features in elderly anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS:A retrospective study was performed in 129 ALK rearranged NSCLC patients diagnosed between April 2008 and March 2019 in fifteen Institutions of the Ibaraki prefecture, Japan. RESULTS:Median age of patients was 63 years. In 59 patients aged 65 and older, the proportions of patients with advanced stage and those treated with ALK-tyrosine kinase inhibitor (TKI) were lower than those younger than 65 years. There was no difference in overall survival (OS) between the two age groups. Among the elderly patients, no difference was observed in OS between the patients aged 65-69 and those aged 70 and older. In 89 patients treated with TKI, no significant differences were observed in the progression-free survival of TKIs and OS between patients aged 65 and older and those younger than 65, respectively. CONCLUSION:Evaluation of ALK gene status and TKI treatment are desirable even for elderly patients.
| S-EPMC7439864 | biostudies-literature
Project description:The identification of oncogenic alterations in subsets of patients with non-small cell lung cancer (NSCLC) is transforming clinical care. Genomic rearrangements in anaplastic lymphoma kinase (ALK) are detected in 3% to 7% of patients with NSCLC. The ALK tyrosine kinase inhibitor crizotinib has demonstrated clinical efficacy in ALK-rearranged NSCLC patients and was recently approved by the U.S. Food and Drug Administration. Crizotinib is currently under additional phase III clinical development as both initial and second-line therapy for advanced ALK-rearranged NSCLC. However, new challenges in the diagnosis and treatment of this subset of NSCLC have emerged, including the need to determine the most effective means of diagnosing ALK-rearranged NSCLC and the emergence of acquired drug resistance to crizotinib. In this review, we discuss current strategies for treatment and diagnosis, as well as the current knowledge about mechanisms of acquired resistance to crizotinib. Finally, we discuss the strategies that are underway to clinically overcome acquired drug resistance.
| S-EPMC3477548 | biostudies-literature