scholarly journals Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

2013 ◽  
Vol 31 (31) ◽  
pp. 3987-3996 ◽  
Author(s):  
Justin F. Gainor ◽  
Alice T. Shaw
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Anaplastic Lymphoma ◽  
Development Of Resistance ◽  
Tki Resistance ◽  
Alk Positive ◽  
Egfr Mutant

The success of tyrosine kinase inhibitors (TKIs) in select patients with non–small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies.

scholarly journals Canadian perspectives: update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
B. Melosky ◽  
P. Cheema ◽  
J. Agulnik ◽  
R. Albadine ◽  
D. G. Bebb ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Alk Positive

BackgroundInhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update.MethodsClinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive nsclc.ResultsRandomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows:Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALKrearrangement.Treatment-naïve patients with ALK-positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially.Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially.Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially.Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy.Other systemic therapies should be exhausted before immunotherapy is considered.SummaryMultiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALKrearrangement.

scholarly journals Lung Cancer Genotype-Based Therapy and Predictive Biomarkers: Present and Future

2012 ◽  
Vol 136 (12) ◽  
pp. 1482-1491 ◽  
Author(s):  
Philip T. Cagle ◽  
Timothy Craig Allen
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Precision Medicine ◽  
Tyrosine Kinase Inhibitors ◽  
First Generation ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Predictive Biomarkers ◽  
Current Status ◽  
Anaplastic Lymphoma

Context.—The advent of genotype-based therapy and predictive biomarkers for lung cancer has thrust the pathologist into the front lines of precision medicine for this deadly disease. Objective.—To provide the clinical background, current status, and future perspectives of molecular targeted therapy for lung cancer patients, including the pivotal participation of the pathologist. Data Sources.—Data were obtained from review of the pertinent peer-reviewed literature. Conclusions.—First-generation tyrosine kinase inhibitors have produced clinical response in a limited number of non–small cell lung cancers demonstrated to have activating mutations of epidermal growth factor receptor or anaplastic lymphoma kinase rearrangements with fusion partners. Patients treated with first-generation tyrosine kinase inhibitors develop acquired resistance to their therapy. Ongoing investigations of second-generation tyrosine kinase inhibitors and new druggable targets as well as the development of next-generation genotyping and new antibodies for immunohistochemistry promise to significantly expand the pathologist's already crucial role in precision medicine of lung cancer.

scholarly journals Maintained Sensitivity to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Lung Cancer Recurring after Adjuvant Erlotinib or Gefitinib

2011 ◽  
Vol 17 (19) ◽  
pp. 6322-6328 ◽  
Author(s):  
Geoffrey R. Oxnard ◽  
Yelena Y. Janjigian ◽  
Maria E. Arcila ◽  
Camelia S. Sima ◽  
Samantha L. Kass ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutant

scholarly journals Out-of-Pocket Costs for Tyrosine Kinase Inhibitors and Patient Outcomes in EGFR- and ALK-Positive Advanced Non–Small-Cell Lung Cancer

2020 ◽  
pp. OP.20.00692 ◽  
Author(s):  
Bernardo H.L. Goulart ◽  
Joseph M. Unger ◽  
Shasank Chennupati ◽  
Catherine R. Fedorenko ◽  
Scott D. Ramsey
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Alk Positive ◽  
Tki Discontinuation

PURPOSE: We investigated the association of out-of-pocket (OOP) costs for tyrosine kinase inhibitors (TKIs) with overall survival (OS) in epidermal growth factor receptor ( EGFR)- and anaplastic lymphoma kinase ( ALK)-positive advanced non–small-cell lung cancer (NSCLC). We secondarily investigated associations of TKI OOP costs with TKI adherence, duration of therapy (DOT), and TKI discontinuation. METHODS: We used the Hutchinson Institute for Cancer Outcomes Research registry-claims database to identify patients with stage IV EGFR- or ALK-positive NSCLC; ≥ 1 claims for EGFR or ALK TKIs; and ≥ 3-month survival from TKI initiation. We estimated the average monthly TKI OOP costs per patient up to 3 months from TKI initiation, categorizing patients into quartiles of TKI OOP costs (Q1 < Q2 < Q3 < Q4). We conducted landmark analysis at 3 months from TKI initiation to compare Q1-3 v Q4 TKI OOP costs with respect to OS, TKI DOT, TKI adherence, and TKI discontinuation. RESULTS: Seventy-eight and twenty-seven patients comprised the Q1-3 and Q4 groups, respectively. Median monthly TKI OOP costs were $1,431 (Q1-3) v $2,888 (Q4). Compared with Q1-3, Q4 patients had inferior OS (adjusted hazard ratio [HR], 1.85; [95% CI, 1.11 to 3.10], similar TKI DOT (adjusted HR, 1.06; 95% CI, 0.53 to 2.15), decreased TKI adherence (adjusted odds ratio [OR], 0.28; 95% CI, 0.10 to 0.76), and higher TKI discontinuation rate (adjusted OR, 8.75; 95% CI, 2.59 to 29.52). CONCLUSION: Among patients with advanced EGFR- and ALK-positive NSCLC, higher TKI OOP costs are associated with decreased TKI adherence, a higher likelihood of TKI discontinuation, and inferior survival.

ALK resistance mutations and co-occurring genetic alterations to the ALK tyrosine kinase inhibitors in lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20675-e20675 ◽  
Author(s):  
Jin-Ji Yang ◽  
Chi Zhang ◽  
Jun Zhao ◽  
Pingping Dai ◽  
Gen Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Point Mutations ◽  
Resistance Mutation ◽  
Genetic Alterations ◽  
Driver Gene ◽  
Resistance Mutations ◽  
Significant Difference

e20675 Background: Acquired ALK mutations pose a challenge in multiple ALK tyrosine kinase inhibitors (TKIs) for lung cancer. In our study, we examined the profiles of ALK resistance mutations and co-occurring genetic alterations after targeted therapy. Methods: Using targeted gene capture and next-generation sequencing technologies, we analyzed the somatic mutations from174 patients (pts) with post-TKI samples. Among them, 123 pts received first-generation TKI crizotinib only, 51 pts (34 with second-generation TKI, 17 with third-generation TKI) treated with multiple ALK-TKIs. Results: After the treatment of ALK-TKIs, 29% (50/174) patients developed ALK resistance point mutations, including G1202R (22 pts), G1269A (13 pts), L1196M (8 pts), D1203N (5 pts), F1174L (4 pts), I1171T (4 pts), E1210K (4 pts), G1128A (3 pts), F1174C (3 pts), C1156Y (1 pts), G1123S (1 pts), I1171S (1 pts), L1152R (1 pts), and 10 of them had multi-clone. Specifically, G1269A was found a higher proportion in crizotinib group contrast to multi-TKIs cohort (10/24 vs 3/26, p = 0.024). The recalcitrant G1202R was another common resistance mutation, but there was no significant difference between the two groups (p = 0.052). Other concurrent genetic alterations related to clinical response were usually observed in TP53 mutations (46%), furthermore it seemed to be more frequently detected in post-crizotinb compared with multi-TKIs (P = 0.023). Activated bypass signaling may promote tumor progression. In non-ALK resistance point mutations samples (n = 124), co-occurring genomic alterations in EGFR (32/124, p = 0.004) were significantly more enriched in crizotinib group (n = 99). The driver gene mutation may limit crizotinib response. However, EP300 (24%), CDKN2A (12%), TRIM58 (12%), STK11 (12%) or KRAS (8%) mutations were common in the multiple ALK-TKIs group (n = 25). Conclusions: In lung cancer patients, ALK resistance point mutations G1269A was significantly enriched in post-crizotinib, while patients with multiple ALK-TKIs may frequently found G1202R or L1196M. The co-occurring genetic alterations in TP53 or EGFR after the TKIs therapeutic may offer directions for further research and therapy in lung cancer.

Sign in / Sign up

Export Citation Format

Share Document