Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations

2022 ◽  
Author(s):  
Aaron C. Tan ◽  
Daniel S. W. Tan
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Braf V600e ◽  
Standards Of Care ◽  
Molecular Testing ◽  
Precision Oncology ◽  
Early Stage Disease ◽  
Molecular Alterations ◽  
Oncogenic Driver ◽  
Exon 20

Lung cancer has traditionally been classified by histology. However, a greater understanding of disease biology and the identification of oncogenic driver alterations has dramatically altered the therapeutic landscape. Consequently, the new classification paradigm of non–small-cell lung cancer is further characterized by molecularly defined subsets actionable with targeted therapies and the treatment landscape is becoming increasingly complex. This review encompasses the current standards of care for targeted therapies in lung cancer with driver molecular alterations. Targeted therapies for EGFR exon 19 deletion and L858R mutations, and ALK and ROS1 rearrangements are well established. However, there is an expanding list of approved targeted therapies including for BRAF V600E, EGFR exon 20 insertion, and KRAS G12C mutations, MET exon 14 alterations, and NTRK and RET rearrangements. In addition, there are numerous other oncogenic drivers, such as HER2 exon 20 insertion mutations, for which there are emerging efficacy data for targeted therapies. The importance of diagnostic molecular testing, intracranial efficacy of novel therapies, the optimal sequencing of therapies, role for targeted therapies in early-stage disease, and future directions for precision oncology approaches to understand tumor evolution and therapeutic resistance are also discussed.

scholarly journals An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer

2020 ◽  
Author(s):  
Athea Vichas ◽  
Naomi T. Nkinsi ◽  
Amanda Riley ◽  
Phoebe C.R. Parrish ◽  
Fujiko Duke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Hippo Pathway ◽  
Spindle Assembly ◽  
Human Lung Cancer ◽  
Precision Oncology ◽  
Cancer Driver ◽  
Molecular Alterations ◽  
Pathway Gene ◽  
Genome Wide

ABSTRACTAdvances in precision oncology have transformed cancer therapy from broadly-applied cytotoxic therapy to personalized treatments based on each tumor’s unique molecular alterations. Here we investigate the oncogene-specific dependencies conferred by lung cancer driver variants of KRAS, EGFR, and RIT1. Integrative analysis of genome-wide CRISPR screens in isogenic cell lines identified shared and unique vulnerabilities of each oncogene. The non-identical landscape of dependencies underscores the importance of genotype-guided therapies to maximize tumor responses. Combining genetic screening data with small molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. This sensitivity may be related to a novel role of RIT1 in mitosis; we find that oncogenic RIT1M90I alters mitotic timing via weakening of the spindle assembly checkpoint. In addition, we uncovered a specific cooperation of mutant RIT1 with loss of Hippo pathway genes. In human lung cancer, RIT1 mutations and amplifications frequently co-occur with loss of Hippo pathway gene expression. These results provide the first genome-wide atlas of oncogenic RIT1-cooperating factors and genetic dependencies and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.

Targeted therapies in cholangiocarcinoma: Assessment of US oncologist practice patterns.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 347-347
Author(s):  
Kinjal Parikh ◽  
Davecia Ragoonath Cameron ◽  
Tristin Abair ◽  
Patrick Kugel ◽  
Arndt Vogel
Keyword(s):  
Clinical Practice ◽  
Targeted Therapies ◽  
Progressive Disease ◽  
Community Setting ◽  
Molecular Testing ◽  
Learning Needs ◽  
Self Awareness ◽  
Multiple Choice Questions ◽  
Molecular Alterations ◽  
Practice Assessment

347 Background: Chemotherapy is a mainstay treatment modality for patients with advanced cholangiocarcinoma (CCA). Recent developments and new approvals have led to changing paradigms, incorporating the use of targeted therapies for patients with progressive disease. Given the need for a greater understanding of the molecular alterations, varying targets, and available and emerging therapies, education is needed to assess knowledge regarding these recent advances in unresectable CCA. The goal of this activity was to increase the knowledge of self-assess the learning needs of oncologists in treating patients with unresectable CCA. Methods: The education included 25 multiple choice questions in a continuing medical education (CME)-certified clinical practice assessment to assess practice gaps. The questions were designed to measure knowledge, competence, confidence, and attitudes of oncologists regarding clinical evidence, role of molecular testing, and place in the treatment paradigm for targeted therapies in unresectable CCA. The self-assessment was made available online to physicians as a learning tool to gain foundational knowledge, as well as receive feedback about their performance as compared to other test-takers, to improve self-awareness of their own personal educational gaps. The activity launched 6/24/20, and data are reported through 8/31/20. Results: A total of 1,009 learners, including 758 physicians, participated in the activity. Of the 104 oncologists that participated, a majority practiced in the community setting, saw patients with a range of cancers, and were not confident about using targeted therapies or recognizing targets for biomarker testing. Oncologists demonstrated the following gaps related to: NGS sequencing and biomarkers: 21% do not use; 32% use upon progressive disease; 35% did not realize that not all panels detect FGFR2 fusions; 20% do not test for biomarkers; 29% and 56% test for IDH or FGFR, respectively; 60% recognize the incidence of IDH1 mutations; Clinical trial (FIGHT202 and ClarIDHy): 45% were able to identify biomarker eligibility for pemigatinib; 9% were able to identify pemigatinib OS outcomes; 30% were able to recognize most common grade 3 AE of pemigatinib; 51% recognized the PFS endpoint with ivosidenib; 34% were able to identify eligibility for ivosidenib; 55% recognized most common AEs of ivosidenib. Conclusions: This CME-certified clinical practice assessment identified gaps in knowledge, competence, and confidence regarding testing and use of targeted therapies and emerging data in patients with unresectable CCA. As new data emerges and the number of targets and targeted therapies expand, continued education remains important to continue to optimize patient care.

Impact of rapid multigene assays with short turnaround time (TAT) on the development of precision medicine for non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9094-9094
Author(s):  
Shingo Matsumoto ◽  
Takaya Ikeda ◽  
Kiyotaka Yoh ◽  
Akira Sugimoto ◽  
Terufumi Kato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Precision Medicine ◽  
Targeted Therapies ◽  
Advanced Nsclc ◽  
Genetic Alterations ◽  
Braf V600e ◽  
Gene Testing ◽  
Genomic Screening ◽  
Nsclc Patients

9094 Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 to identify patients with oncogene drivers and to support the development of novel targeted therapies. Since February 2013 to May 2019 (LC-SCRUM-Asia 1st-phase), single gene testing and/or a targeted NGS assay, Oncomine Comprehensive Assay (OCA), were used for the genomic screening. Since June 2019 to December 2020 (2nd-phase), a multi-gene PCR assay (Amoy 9-in-1 test) and a rapid NGS assay (Genexus/Oncomine Precision Assay [OPA]) were also implemented as rapid multi-gene testing. Results: A total of 10667 Japanese NSCLC patients, including 6826 in the 1st-phase and 3841 in the 2nd-phase, were enrolled in the LC-SCRUM-Asia. Success rate for OCA: 93%, for 9-in-1 test: 98%, for Genexus/OPA: 96%. Median TAT for OCA: 21 days, for 9-in-1 test: 3 days, for Genexus/OPA: 4 days. The frequencies of genetic alterations detected in the 1st-/2nd-phase were EGFR: 17/24%, KRAS: 15/16%, HER2 ex20ins: 4/3%, ALK fusions: 3/3%, RET fusions: 3/2%, ROS1 fusions: 3/2%, MET ex14skip: 2/2%, BRAF V600E: 1/1%, NRG1 fusions: 0/0.2% and NTRK3 fusions: 0.05/0.04%. Overall percent agreement of 9-in-1 test compared with OCA for EGFR/KRAS/HER2/BRAF/MET/ALK/ROS1/RET/NTRK3 alterations was 98%, and that of OPA compared with OCA was 95%. The rate of patients who received targeted therapies as 1st-line treatment was significantly elevated in the 2nd-phase compared with the 1st-phase (510/3841 [13%] vs. 567/6826 [8%], p < 0.001). Through the genomic screening, 1410 (37%) and 1269 (18%) candidate patients for clinical trials of KRAS, HER2, BRAF, MET, ALK, ROS1, RET or TRK-targeted drugs were identified in the 2nd-phase and in the 1st-phase, respectively. The rate of patients who were actually enrolled into the genotype-matched clinical trials were also significantly higher in the 2nd-phase than in the 1st-phase (222 [6%] vs. 186 [3%], p < 0.001). In 1st-line treatments for advanced NSCLC patients, the median progression-free survival was 8.5 months (95% CI, 7.7−9.4) in the 2nd-phase (n = 1839) versus 6.1 months (95% CI, 5.9−6.3) in the 1st-phase (n = 4262) (p < 0.001). Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC.

Immunotherapy and Radiation Therapy for Non-Small Cell Lung Cancer—A Stimulating Partnership

2020 ◽  
Vol 41 (03) ◽  
pp. 360-368
Author(s):  
Ritchell van Dams ◽  
Ye Yuan ◽  
Clifford G. Robinson ◽  
Percy Lee
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Metastatic Disease ◽  
Cell Lung Cancer ◽  
Early Stage ◽  
Locally Advanced ◽  
Small Cell ◽  
Standards Of Care ◽  
Small Cell Lung ◽  
Early Stage Disease

AbstractNon-small cell lung cancer (NSCLC) is the most common subtype of lung cancer and the leading cause of cancer-related death. Although durable local control rates are high after surgical resection or definitive radiotherapy for early-stage disease, a substantial proportion of these patients eventually experience regional and/or distant failure and succumb to their metastatic disease. The discovery of immunotherapeutics and targeted biologics has revolutionized the treatment of locally advanced and metastatic disease, improving progression-free and overall survival when incorporated with the current standards of care. Notably, post-hoc analyses and early clinical trials provide a growing body of evidence to support a synergistic effect between radiation and immunotherapy for the treatment of NSCLC from early-stage to metastatic disease. Radiotherapy appears to be capable of not only potentiating the effect of immunotherapy in targeted lesions, but also eliciting an antitumor response in distant lesions without any direct exposure to radiation. This review explores the biologic basis of immunotherapy, targeted biologics, and radiotherapy as well as the preclinical and clinical data that support the combined use of radioimmunotherapy for early-stage, locally advanced, and metastatic NSCLC.

Matching insurance claims data with EMR molecular status data in non-small cell lung cancer (NSCLC) patients: Understanding real-world molecular testing and prevalence rates at the site and investigator level.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20568-e20568
Author(s):  
Michael Gregory Cushion ◽  
Bhavani Krishnan ◽  
Jeff Paul Hodge ◽  
Jaya Chandra Balusu ◽  
Joseph Wagner ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Real World ◽  
Targeted Therapies ◽  
Claims Data ◽  
Molecular Testing ◽  
Insurance Claims ◽  
Insurance Claims Data ◽  
Nsclc Patients

e20568 Background: Many targeted therapy clinical trials require a somatic gene mutation/alteration for eligibility. We assessed the feasibility of leveraging Real-World Data (RWD) to enrol NSCLC patients into clinical trials. Methods: US insurance claims data were extracted to identify lung cancer patients. These data were matched with EMR data also containing NSCLC patients’ details regarding the occurrence and results of molecular testing for EGFR, ALK, ROS1, JAK2, HER2 and RET somatic alterations, achieving a level of granular detail beyond that available in each individual dataset. A one-year extraction period was applied, with no gender or age restrictions. Results: Results for the matched dataset are summarised in the table below - the overall patient record match was 89.6%. Conclusions: The observed prevalence correlated reasonably well with literature reported prevalence for the molecular biomarkers associated commercially available targeted therapies in NSCLC (EGFR, ALK, ROS1). The sample size for the remaining biomarkers was too small to draw conclusions, though the presence of data correlating to these is of interest, considering that there are no currently approved targeted therapies in NSCLC tailored to these predictive biomarkers. This approach could be expanded upon to recruit patients into targeted therapy clinical trials as the dataset is fully linkable to sites and investigators. With the emergence of broad genomic profiling, the availability of molecular data to support clinical trial enrolment is also expected to grow.[Table: see text]

Patterns of care in ALK+ or ROS1+ non-small cell lung cancer (NSCLC) in community systems.

2020 ◽  
Vol 38 (29_suppl) ◽  
pp. 232-232
Author(s):  
Benjamin Philip Levy ◽  
Breanne Y Farris ◽  
Rebecca R Crawford ◽  
Jeffrey D. Carter ◽  
Tamar Sapir
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Treatment Options ◽  
Patient Centered Care ◽  
Molecular Testing ◽  
Distress Screening ◽  
Patient Centered ◽  
Treatment Practices ◽  
Molecular Tests ◽  
Centered Care

232 Background: For patients who have ALK or ROS1+ NSCLC, targeted therapies have greatly improved treatment options, though challenges personalizing care have hindered effective integration. In a quality improvement (QI) program conducted in 2 community oncology systems, practices involving the use of targeted therapies for NSCLC were assessed. Methods: Between 01-04/2020, retrospective EMR audits of 100 patients with ALK or ROS1+ NSCLC were analyzed for demographics, molecular testing, disease characteristics, treatment history, and shared decision-making (SDM). Surveys were administered to evaluate healthcare professionals’ (HCP; N = 47) challenges and barriers. HCP teams participated in audit-feedback sessions and developed action plans for resolving identified gaps. Results: 64% of HCPs indicated high confidence in utilizing molecular tests to inform treatment and properly sequencing targeted therapies; however, the EMR audit demonstrated challenges efficiently integrating guideline-aligned testing into practice. The mean time from diagnosis to molecular testing results was 22 days and documentation of testing for genetic aberrations other than ALK/ROS1 during work-up were low (Table). Delays in receiving molecular testing results may have presented challenges aligning treatment practices to guidelines as some patients were not receiving frontline targeted therapies (31% ALK+, 24% ROS1+). Additionally, EMR audits suggested sub-optimal use of distress screening (37%), tobacco counseling (38%), quality of life screening (60%), and engagement/documentation of various aspects of SDM (Table) for patient-centered care. Importantly, given the role internalized stigma can play in lung cancer, only 59% of those surveyed indicated that they routinely use tools to identify patients affected by stigma. During audit-feedback sessions, teams identified increased documentation, improved molecular testing/collaboration with pathology team, and provision of patient-centered care, including reduction of smoking-associated stigma as action items. Conclusions: These findings reveal important performance gaps in providing targeted and patient-centered treatment for NSCLC in community settings. These findings may be relevant for future QI programs. [Table: see text]

scholarly journals The Role of Pharmacists in Optimizing Molecular Testing with Evolving Biomarkers and Treatment for Non-Small Cell Lung Cancer

2021 ◽  
pp. 2240-2256
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Small Cell ◽  
Molecular Testing ◽  
Small Cell Lung ◽  
Braf Mutations ◽  
Emerging Therapies ◽  
Oncology Care

Molecular testing and the development of targeted therapies have revolutionized the treatment of non-small cell lung cancer (NSCLC). Despite the advantages of molecular testing in patients with NSCLC and guideline recommendations, there is no specific standard testing method, resulting in variable testing practices based on institution protocol and access. Pharmacists can help to improve coordination of care around appropriate testing as results are important in determining the most appropriate targeted treatment course. The majority of patients with NSCLC are tested for PD-L1, EGFR, ALK, ROS1, and BRAF mutations. These biomarkers and their corresponding targeted therapies are more understood than the remaining biomarkers, such as KRAS, RET, MET exon 14 (METex14), and NTRK. Multiple new and emerging therapies target these latter biomarkers, and this article will focus on these lesser-known biomarkers. As the treatment of NSCLC becomes increasingly biomarker-driven and more therapies are added to the armamentarium for the management of NSCLC, pharmacists will be called upon to assist the oncology care team to optimize NSCLC treatment to improve patient outcomes.

scholarly journals The Landscape of the Advanced NSCLC Treatment Paradigm: Molecular Testing and Actionable Mutations

2021 ◽  
Vol 12 (3) ◽  
Keyword(s):  
Lung Cancer ◽  
Molecular Markers ◽  
Cancer Treatment ◽  
Targeted Therapies ◽  
Advanced Nsclc ◽  
Molecular Testing ◽  
Kras Mutations ◽  
Lung Cancer Treatment ◽  
Treatment Paradigm

At JADPRO Live Virtual 2020, Rasheda Persinger, AGNP-C, explained the current lung cancer treatment landscape, including targeted therapies for EGFR and ALK rearrangements, as well as for BRAF, ROS1, NTRK, RET, MET, and KRAS mutations, and described the different testing modalities for molecular markers.

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