scholarly journals Chemotherapy Should Be Combined With Checkpoint Inhibitors in the Treatment of Patients With Stage IV EGFR-Mutant NSCLC Whose Disease Has Progressed on All Available Tyrosine Kinase Inhibitors

2021 ◽  
Vol 16 (10) ◽  
pp. 1622-1626
Author(s):  
Fei Zhou ◽  
Caicun Zhou
2021 ◽  
Vol 22 (2) ◽  
pp. 493
Author(s):  
Christos Vallilas ◽  
Panagiotis Sarantis ◽  
Anastasios Kyriazoglou ◽  
Evangelos Koustas ◽  
Stamatios Theocharis ◽  
...  

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).


2013 ◽  
Vol 31 (31) ◽  
pp. 3987-3996 ◽  
Author(s):  
Justin F. Gainor ◽  
Alice T. Shaw

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.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21142-e21142
Author(s):  
Moushumi Suryavanshi ◽  
Sakshi Mattoo ◽  
Sanjeev Kumar Sharma ◽  
Anurag Mehta ◽  
Ullas Batra

e21142 Background: Different molecular mechanisms of on target and off target primary and secondary resistance have been observed in EGFR mutant NSCLC patients after first(1st), second(2nd) and third (3rd) generation of tyrosine kinase inhibitors(TKIs). Next generation sequencing(NGS) offers a comprehensive method of detecting these mechanisms to decide next line of treatment. Methods: We retrospectively analyzed 430 samples of NSCLC for primary and secondary resistance to 1st, 2nd and 3rd TKIs. NGS was performed using thermofischer Ion Torrent Oncomine Focus 52 gene Assay. These cases were divided into 4 groups.1)Primary resistance to first and second generation TKIs 2)Primary resistance to 3rd generation TKI 3)Secondary resistance to 1st and 2nd generation TKI 4) Secondary resistance to 3rd generation TKI.Last group was further subgrouped into A when 3rd generation TKI was offered as second line after 1st or 2nd generation TKIs on detection of T790M and subgroup B when it was given as first line. Results: Group1 had 13 cases. There were 2 cases of complex EGFR exon 19 mutation p.Glu746_Leu747delinsValPro, 4 cases of EGFR exon 20 insertion, 1 case of dual EGFR L833V & H835L mutation, 2 cases with EGFR amplification with EGFR exon 19 del and PIK3CA C420_P421del along with EGFR exon 19 del. Four cases had no additional abnormality. Group 2 had 5 cases:1 case had L858R and E709A dual mutation, 2 cases had KRAS G13C and KRAS G12V along with EGFR exon 19 del. One case had EGFR amplification and one case had MET amplification along with EGFR exon 19 del respectively.Group 3 had 34 cases including 10 cases of EGFR L858R and 24 cases of exon 19 deletion.T790M mutation was detected in 8 patients, MET amplification in 7 cases,one case had both T790M and MET amplification. One case lost the primary EGFR exon 19 del. Others mutations detected were KRAS G13C, PIK3CA H1047R, TP53 R213Q and TP53 C242fs. Group3 had 15 cases with 7 cases in subgroup A and 9 cases in subgroup B. In subgroup A T790M mutation was lost in 6 out of 7 cases.One case which lost T790M developed ALK translocation.One case of EGFR exon 19 del retained EGFR T790M with EGFR C797S in cis allele. Other mutations detected were PIK3CA E542K and KRAS G12C. In subgroup B one case showed EGFR C797S(both cis and trans) besides the primary EGFR exon 19 del. One case showed BRAF G469A along with EGFR exon 19 del. Other mutations detected were CTNNB1 D32N, KRAS G12V, and PIK3CA E542K. Conclusions: Primary and secondary acquired resistance is unavoidable in EGFR mutant advanced NSCLC on any generation of TKIs. NGS offers an advantage in diagnosing mechanism of resistance for further choice of therapy.


2016 ◽  
Vol 21 (8) ◽  
pp. 964-973 ◽  
Author(s):  
Meghan Campo ◽  
Hani Al‐Halabi ◽  
Melin Khandekar ◽  
Alice T. Shaw ◽  
Lecia V. Sequist ◽  
...  

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