Response to Checkpoint Inhibition in Non-Small Cell Lung Cancer with Molecular Driver Alterations

Kauffmann-Guerrero, Diego; Tufman, Amanda; Kahnert, Kathrin; Bollmann, Benjamin A.; Reu, Simone; Syunyaeva, Zulfiya; Schneider, Christian; Manapov, Farkhad; Huber, Rudolf M.; Golpon, Heiko

doi:10.1159/000506842

Cited by 28 publications

(21 citation statements)

References 12 publications

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“…ASCO/CAP/IASLC/AMP guidelines recommend a TAT of 10 working days between sample receipt and reporting of molecular test results [28]; a recent European Expert Group suggests a general timeframe of 5 working days for molecular test results [75]. Delays in TAT can lead to less efficient use of targeted therapies; for example, initiating immunotherapy before mutation test results are received can mean EGFR tyrosine kinase inhibitors are used as second-line versus first-line agents [76,77].…”

Section: Practical Challenges (Turnaround Time Test Complexity Reflex Testing)mentioning

confidence: 99%

The evolving landscape of biomarker testing for non-small cell lung cancer in Europe

et al. 2021

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The discovery of oncogenic driver mutations rendering non-small cell lung cancer (NSCLC) targetable by smallmolecule inhibitors, and the development of immunotherapies, have revolutionised NSCLC treatment. Today, instead of non-selective chemotherapies, all patients with advanced NSCLC eligible for treatment (and increasing numbers with earlier, less extensive disease) require fast and comprehensive screening of biomarkers for first-line patient selection for targeted therapy, chemotherapy, or immunotherapy (with or without chemotherapy). To avoid unnecessary re-biopsies, biomarker screening before first-line treatment should also include markers that are actionable from second-line onwards; PD-L1 expression testing is also mandatory before initiating treatment.Population differences exist in the frequency of oncogenic driver mutations: EGFR mutations are more frequent in Asia than Europe, whereas the converse is true for KRAS mutations. In addition to approved first-line therapies, a number of emerging therapies are being investigated in clinical trials. Guidelines for biomarker testing vary by country, with the number of actionable targets and the requirement for extensive molecular screening strategies expected to increase. To meet diagnostic demands, rapid screening technologies for singledriver mutations have been implemented. Improvements in DNA-and RNA-based next-generation sequencing

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Section: Practical Challenges (Turnaround Time Test Complexity Reflex Testing)mentioning

confidence: 99%

The evolving landscape of biomarker testing for non-small cell lung cancer in Europe

et al. 2021

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“…Mutant KRAS was associated with increases in tumor infiltrating lymphocytes, PD-L1 expression and tumor mutational burden [ 182 , 183 ]. However, while Gianoncelli et al observed no significant differences between KRAS + and non- KRAS NSCLC patients in terms of progression-free or overall survival [ 184 ], Kauffmann-Guerrero et al reported a positive outcome for KRAS mutations in response to immune checkpoint inhibitors [ 185 ]. Molecular diversity within KRAS + NSCLC patients offers an attractive biological explanation for such discrepancy in results [ 186 ].…”

Section: New Optimism For Targeting Kras Mutatimentioning

confidence: 99%

Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future

Uras

Moll

Casanova

2020

IJMS

106

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Lung cancer is the most frequent cancer with an aggressive clinical course and high mortality rates. Most cases are diagnosed at advanced stages when treatment options are limited and the efficacy of chemotherapy is poor. The disease has a complex and heterogeneous background with non-small-cell lung cancer (NSCLC) accounting for 85% of patients and lung adenocarcinoma being the most common histological subtype. Almost 30% of adenocarcinomas of the lung are driven by an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. The ability to inhibit the oncogenic KRAS has been the holy grail of cancer research and the search for inhibitors is immensely ongoing as KRAS-mutated tumors are among the most aggressive and refractory to treatment. Therapeutic strategies tailored for KRAS+ NSCLC rely on the blockage of KRAS functional output, cellular dependencies, metabolic features, KRAS membrane associations, direct targeting of KRAS and immunotherapy. In this review, we provide an update on the most recent advances in anti-KRAS therapy for lung tumors with mechanistic insights into biological diversity and potential clinical implications.

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“…In addition, it has been shown that alterations in certain genes, such as KRAS, TP53, MET, ARID1A and others are enriched in immunotherapy responsive patients. Thus, their identi cation could lead to such treatment option (80)(81)(82).…”

Section: Immunotherapy Biomarkersmentioning

confidence: 99%

A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience

Özdoğan¹,

Papadopoulou²,

Tsoulos³

et al. 2020

Preprint

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Background: Tumor molecular profile is of great importance for the detection of biomarkers of response to targeted treatment due to the increased availability, with concomitant reduction of cost, of Next Generation Sequencing technology (NGS). In parallel to targeted therapies’, immunotherapies are also evolving, revolutionizing cancer therapy, with Programmed Death-ligand 1 (PD-L1), Microsatellite Instability (MSI), and Tumor Mutational Burden (TMB) analysis being the biomarkers employed most commonly.Methods: In the present study, a 161 gene NGS panel, containing the majority of clinically significant genes for cancer treatment selection, was used for tumor molecular profile analysis. A variety of tumor types have been analyzed, including aggressive and hard to treat cancers such as pancreatic cancer. Besides, the clinical utility of immunotherapy biomarkers (TMB, MSI, PD-L1), was also studied.Results: Molecular profile analysis was conducted in 610 cancer patients, while in 393 of them a at least one biomarker for immunotherapy response was requested. At least one actionable alteration was detected in 77.70% of the patients. 54.59% of them received information related to on-label or off-label treatment (Tiers 1A.1, 1A.2, 2B, and 2C.1) and 21.31% received a variant that could be used for clinical trial inclusion. The addition to immunotherapy biomarker to targeted biomarkers’ analysis in 191 cases increased the number of patients with an on-label treatment recommendation by 22.40%, while an option for on-label or off-label treatment was provided in 71.35% of the cases. Conclusions: Tumor molecular profile analysis by NGS is a first-tier methodology for a variety of tumor types, which provides critical information for treatment decision making in cancer patients. Importantly, simultaneous analysis for targeted therapy and immunotherapy biomarkers could lead to a better tumor characterization and provide actionable information in the majority of patients. Moreover, our results indicate that one in two patients is eligible for ICI treatment based on the biomarkers’ analysis. However, when these analyses are performed, the challenge is their implementation in clinical practice. Multidisciplinary patient management is critical to the refinement of the strategy incorporating such information.

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Response to Checkpoint Inhibition in Non-Small Cell Lung Cancer with Molecular Driver Alterations

Cited by 28 publications

References 12 publications

The evolving landscape of biomarker testing for non-small cell lung cancer in Europe

The evolving landscape of biomarker testing for non-small cell lung cancer in Europe

Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future

A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience

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