scholarly journals The KRAS G12C mutation in NSCLC: from target to resistance

2021 ◽  
Author(s):  
Alfredo Addeo ◽  
Giuseppe Luigi Banna ◽  
Alex Friedlaender
Keyword(s):  
Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Relative Survival ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Driver Mutations ◽  
Kras Mutations ◽  
Secondary Resistance ◽  
Cancer Types ◽  
Oncogenic Driver

Lung cancer represents the most common form of cancer accounting for 1.8 million deaths globally in 2020.The 5-year relative survival rate for lung cancer is lower than many other leading cancer types. Over the last decade the treatment for advanced and metastatic non small cell lung cancer have dramatically improved due to the development of immune checkpoint inhibitors and the identification of targetable driver mutations. Recently, potentially effective inhibitors of a hitherto untargetable oncogenic driver mutation in NSCLC, Kirsten Rat Sarcoma (KRAS) have been developed. KRAS mutations are found in 20-25% of NSCLC and represent the most frequent mutation. The mutation is almost exclusively detected in adenocarcinoma and is found among smokers 90% of the time. Along with the development of new drugs that have been showing promising activity, resistance mechanisms have begun to be clarified. The aim of this review is to unwrap the biology of KRAS in NSCLC with a specific focus on primary and secondary resistance mechanisms and their possible clinical implications.

scholarly journals Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 804
Author(s):  
David König ◽  
Spasenija Savic Prince ◽  
Sacha I. Rothschild
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
New Drugs ◽  
Small Cell Lung ◽  
Comprehensive Overview ◽  
Kras Mutations ◽  
Anaplastic Lymphoma ◽  
Oncogenic Driver

Due to groundbreaking developments and continuous progress, the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) has become an exciting, but increasingly challenging task. This applies, in particular, to the subgroup of NSCLC with oncogenic driver alterations. While the treatment of epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC with various tyrosine kinase inhibitors (TKIs) is well-established, new targets have been identified in the last few years and new TKIs introduced in clinical practice. Even for KRAS mutations, considered for a long time as an “un-targetable” alteration, promising new drugs are emerging. The detection and in-depth molecular analysis of resistance mechanisms has further fueled the development of new therapeutic strategies. The objective of this review is to give a comprehensive overview on the current landscape of targetable oncogenic alterations in NSCLC.

scholarly journals Treating KRAS-mutant NSCLC: latest evidence and clinical consequences

2017 ◽  
Vol 9 (9) ◽  
pp. 589-597 ◽  
Author(s):  
Pilar Garrido ◽  
María Eugenia Olmedo ◽  
Ana Gómez ◽  
Luis Paz Ares ◽  
Fernando López-Ríos ◽  
...  
Keyword(s):  
Small Molecules ◽  
Checkpoint Inhibitors ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Mutation Status ◽  
Comprehensive Genomic Profiling ◽  
Clinical Consequences ◽  
Oncogenic Driver ◽  
Prognostic Implications

KRAS mutations represent one of the most prevalent oncogenic driver mutations in non-small cell lung cancer (NSCLC). For many years we have unsuccessfully addressed KRAS mutation as a unique disease. The recent widespread use of comprehensive genomic profiling has identified different subgroups with prognostic implications. Moreover, recent data recognizing the distinct biology and therapeutic vulnerabilities of different KRAS subgroups have allowed us to explore different treatment approaches. Small molecules that selectively inhibit KRAS G12C or use of immune checkpoint inhibitors based on co-mutation status are some examples which anticipate that personalized treatment for this challenging disease is finally on the horizon.

scholarly journals Lights and Shadows in Immuno-Oncology Drug Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 691
Author(s):  
Milana Bergamino Sirvén ◽  
Sonia Pernas ◽  
Maggie C. U. Cheang
Keyword(s):  
Drug Development ◽  
Checkpoint Inhibitors ◽  
Late Phase ◽  
New Drugs ◽  
Successful Outcome ◽  
Different Types ◽  
Cancer Types ◽  
Clinical Trial Designs ◽  
Oncology Drug Development ◽  
Critical Aspects

The rapidly evolving landscape of immuno-oncology (IO) is redefining the treatment of a number of cancer types. IO treatments are becoming increasingly complex, with different types of drugs emerging beyond checkpoint inhibitors. However, many of the new drugs either do not progress from phase I-II clinical trials or even fail in late-phase trials. We have identified at least five areas in the development of promising IO treatments that should be redefined for more efficient designs and accelerated approvals. Here we review those critical aspects of IO drug development that could be optimized for more successful outcome rates in all cancer types. It is important to focus our efforts on the mechanisms of action, types of response and adverse events of these novel agents. The use of appropriate clinical trial designs with robust biomarkers of response and surrogate endpoints will undoubtedly facilitate the development and subsequent approval of these drugs. Further research is also needed to establish biomarker-driven strategies to select which patients may benefit from immunotherapy and identify potential mechanisms of resistance.

Driver mutations to predict for poorer outcomes in non-small cell lung cancer patients treated with concurrent chemoradiation and consolidation durvalumab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8528-8528
Author(s):  
Yufei Liu ◽  
Zhe Zhang ◽  
Waree Rinsurongkawong ◽  
Xiuning Le ◽  
Carl Michael Gay ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Mutation Status

8528 Background: The use of durvalumab after chemoradiation in locally advanced non-small cell lung cancer (NSCLC) patients significantly improves overall survival. However, it is unclear whether this benefit applies to all genetic subtypes of lung cancer. We hypothesize that patients with driver mutation NSCLC may derive less benefit from consolidation durvalumab. Methods: Using the Genomic Marker-Guided Therapy Initiative (GEMINI) database at MD Anderson, we identified 134 patients who were treated with chemoradiation followed by durvalumab for NSCLC. We segregated patients with driver mutations to targetable (EGFR, ALK translocation, ROS1 fusion, MET exon 14 skipping, RET fusion, and/or BRAF) (N = 24) and those driven by canonical KRAS mutations (N = 26). The rest (N = 84) had none of these mutations. We gathered demographic, treatment, and outcome data and compared progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. We used multivariate regression analysis to account for demographic and treatment variables. Results: For our cohort, median age at diagnosis was 64.8, 52% were female (n = 70), and median follow up was 1.5 years. 86% of patients have a history of smoking (n = 115). 21% had squamous cell histology (n = 28). 2 patients had stage IIA disease, 6 had stage IIB, 48 had stage IIIA, 56 had stage IIIB, 13 had stage IIIC, and 9 had stage IV. 73 patients had progression after durvalumab and 37 patients died. Patients with driver mutations had significantly worse median PFS compared to those without driver mutations (8.9 mo vs 26.6 mo; HR 2.62 p < 0.001). Patients with KRAS mutations had particularly poor PFS (Median 7.9 mo, HR 3.34, p < 0.001), while patients with targetable driver mutations trended to worse PFS (Median 14.5 mo, HR 1.96, p = 0.056). The median OS for the cohort was 4.8 yrs with no significant differences based on driver mutation status. On multivariate analysis, only driver mutation status was associated with PFS, but not OS. For patients with first progression, we found the targetable driver group to have significantly improved time to second objective progression (PFS2) compared to the KRAS (HR 0.28, p = 0.011) or non-mutated group (HR 0.38, p = 0.025). All patients in the targetable driver group received targeted therapy after first progression. Conclusions: Our results suggest that patients with driver mutations have worse PFS compared to patients without these mutations after chemoradiation. However, patients with targetable oncogene driver mutations have significantly improved prognosis after initial progression compared to the other groups, likely due to targeted therapy, suggesting that these therapies, including novel approaches towards KRAS mutants, should be further explored in this setting.

scholarly journals Molecular profile of KRAS G12C-mutant colorectal and non-small-cell lung cancer

2020 ◽  
Author(s):  
Luiz H. Araujo ◽  
Bianca Souza ◽  
Laura Leite ◽  
Sabrina Parma ◽  
Natália Lopes ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Driver Mutations ◽  
Molecular Profile ◽  
Common Mutation ◽  
Small Cell Lung ◽  
The South ◽  
Kras Mutations

Abstract Background: KRAS is the most frequently mutated oncogene in cancer, however efforts to develop targeted therapies have been largely unsuccessful. Recently, two small-molecule inhibitors, AMG 510 and MRTX849, have shown promising activity in KRAS G12C-mutant solid tumors. The current study aims to assess the molecular profile of KRAS G12C in colorectal (CRC) and non-small-cell lung cancer (NSCLC) tested in a clinical certified laboratory.Methods: CRC and NSCLC samples submitted for KRAS testing between 2017 and 2019 were reviewed. CRC samples were tested for KRAS and NRAS by pyrosequencing, while NSCLC samples were submitted to next generation sequencing of KRAS, NRAS, EGFR, and BRAF. Results: The dataset comprised 4,897 CRC and 4,686 NSCLC samples. Among CRC samples, KRAS was mutated in 2,354 (48.1%). Most frequent codon 12 mutations were G12D in 731 samples (15.2%) and G12V in 462 (9.6%), followed by G12C in 167 (3.4%). KRAS mutations were more frequent in females than males (p=0.003), however this difference was exclusive of non-G12C mutants (p<0.001). KRAS mutation frequency was lower in the South and North regions (p=0.003), but again KRAS G12C did not differ significantly (p=0.80). In NSCLC, KRAS mutations were found in 1,004 samples (21.4%). As opposed to CRC samples, G12C was the most common mutation in KRAS, in 346 cases (7.4%). The frequency of KRAS G12C was higher in the South and Southeast regions (p=0.012), and lower in patients younger than 50 years (p<0.001). KRAS G12C mutations were largely mutually exclusive with other driver mutations; only 11 NSCLC (3.2%) and 3 CRC (1.8%) cases had relevant co-mutations. Conclusions: KRAS G12C presents in frequencies higher than several other driver mutations, represent a large volume of patients in absolute numbers. KRAS testing should be considered in all CRC and NSCLC patients, independently of clinical or demographic characteristics.

scholarly journals First-Line Therapies for Metastatic Lung Adenocarcinoma Without a Driver Mutation

2018 ◽  
Vol 14 (9) ◽  
pp. 529-535 ◽  
Author(s):  
J. Nicholas Bodor ◽  
Vineela Kasireddy ◽  
Hossein Borghaei
Keyword(s):  
Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Driver Mutation ◽  
Driver Mutations ◽  
First Line ◽  
Histologic Subtype ◽  
First Line Therapy ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Common Histologic Subtype

Lung cancer is the leading cause of cancer-related death worldwide. The majority of these cancers are non–small-cell lung cancer, of which adenocarcinoma is the most common histologic subtype. Most patients are diagnosed at advanced stages when systemic treatment is needed. Whereas prognosis has improved for patients with targetable driver mutations, the majority of patients do not possess tumors with such molecular mutations. Platinum-based chemotherapy has traditionally been the mainstay of treatment, although in recent years immunotherapy has emerged as a treatment option and can result in robust and durable treatment responses in a subset of patients. Recent clinical trials on novel immunotherapy combinations and immunochemotherapy combinations may broaden the number of patients that may benefit from checkpoint inhibitors and elicit responses in those who otherwise may not have experienced a response to monotherapy with an immunotherapy drug. This review will outline the currently available therapies for the first-line treatment of metastatic adenocarcinoma that do not possess a driver mutation and provide a recommended approach and algorithm by which to select the best first-line therapy.

scholarly journals CMET-18. IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi55-vi55
Author(s):  
Adam Lauko ◽  
Assad Ali ◽  
Soumya Sagar ◽  
Addison Barnett ◽  
Hong Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Checkpoint Inhibitors ◽  
Care Center ◽  
Tertiary Care ◽  
Wild Type ◽  
Chi Square ◽  
Kras Mutations ◽  
Mutational Status

Abstract BACKGROUND Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.

Clinical outcomes of various resistance mechanisms of osimertinib in Chinese advanced non-small cell lung cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20530-e20530
Author(s):  
Puyuan Xing ◽  
Li Junling ◽  
Xuezhi Hao ◽  
Yuxin Mu ◽  
Shouzheng Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Kras Mutations

e20530 Background: Increasing efforts have been invested in elucidating the resistance mechanisms to osimertinib. Major resistance mechanisms include but not limited to acquired EGFR mutations, predominantly C797, mutations in bypass pathways and small cell lung cancer (SCLC) transformation. However, no study has comprehensively investigated clinical outcomes of various mechanisms of resistance. Methods: 103 T790M positive advanced Chinese non-small cell lung cancer (NSCLC) patients who progressed on 1st generation EGFR-TKI were enrolled. Targeted sequencing, using a panel consisting of 168 lung cancer related genes, was performed on paired plasma samples collected prior to osimertinib and after the development of disease progression (PD) to profile mutation spectrum. 7 patients with no mutation detected at PD were excluded from analyses. Results: Major acquired mutations included 25% EGFR mutations, predominantly C797 and L792, 16% MET amplification, 8% TP53 mutations, 4% KRAS mutations, 4% RET fusions, 4% ERBB2 amplification and 6.25% RB1 mutations. Acquired RB1 mutation may indicate the possibility of SCLC transformation. Approximately, 30% of patients with no known resistance mechanisms at PD. In this cohort, we had 61 patients with 19 deletion and 35 patients with EGFR L858R prior to the initiation of osimertinib. We revealed patients with 19del acquired more mutations ( p= 0.014) and were more likely to acquire mutations in MAP/PI3Kpathway ( p= 0.04) and TP53 at PD ( p= 0.021). On the other hand, acquired ERBB2 amplifications were only detected in L858R-mutant patients ( p= 0.047). Furthermore, 36 patients preserved T790M and 60 patients lost T790M at PD. Our data revealed patients retaining T790M, often associated with activation of bypass signaling pathways or continued EGFR activation through tertiary mutations, had a longer progression-free survival (PFS) ( p= 0.047) and overall survival (OS) ( p= 0.04) comparing to patients with T790M loss, often with diverse and EGFR-independent mechanisms. We also show that patients with acquired C797S had significantly longer PFS ( p= 0.031), while patients with acquired MET amplifications had significantly shorter PFS ( p= 0.033). Conclusions: Collectively, we revealed differential clinical outcomes associated with various resistance mechanisms, representing an important step in advancing the understanding of resistance mechanisms of osimertinib.

scholarly journals Rapidly changing treatment algorithms for metastatic nonsquamous non-small-cell lung cancer

2018 ◽  
Vol 25 ◽  
pp. 68 ◽  
Author(s):  
B. Melosky
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Treatment Algorithm ◽  
Small Cell ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Treatment Algorithms

Background The treatment paradigm for metastatic nonsquamous non-small-cell lung cancer (nsclc) continues to change. Algorithms published only 6 months ago are outdated today and are dramatically different from those published a few years ago. New driver mutations continue to be identified, and the development of therapies to inhibit oncogenic addiction is ongoing. Patient survival is improving as treatments become more personalized and effective.Methods This review looks at the outcomes of recent trials and discusses treatment options for patients with metastatic nsclc of nonsquamous histology. Algorithms continue to change quickly, and an attempt is made to keep the paradigm current and applicable into the near future.Results Treatment algorithms for nsclc tumours with EGFR mutations, ALK rearrangements, and ROS1 rearrangements, and for wild-type tumours are presented. A future algorithm based on new immunotherapy data is proposed.Conclusions The treatment algorithm for EGFR mutation is changing with the proven efficacy of osimertinib for the acquired T790M mutation. All patients taking first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors must be tested. The treatment algorithm for ALK rearrangement has changed with the proven superiority of alectinib compared with crizotinib in the first-line setting. The approval of crizotinib for ROS1 rearrangements now means that patients also must be tested for that mutation. The biomarker for checkpoint inhibitors continues to be PD-L1 by immunohistochemistry stain, but whether testing will be necessary for patient selection if chemotherapy combinations are implemented will be determined soon.

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