Early plasma circulating tumor DNA (ctDNA) changes predict response to first-line pembrolizumab-based therapy in non-small cell lung cancer (NSCLC).
Biagio Ricciuti,Greg Jones,Mariano Severgnini,Joao Victor Machado Alessi,Gonzalo Recondo,Marissa N. Lawrence,Tim Forshew,Christine A. Lydon,Mizuki Nishino,Michael Cheng,Mark M. Awad +10 more
TLDR
In this paper, the authors studied the effect of changes in circulating tumor DNA (ctDNA) levels after initiation of first-line pembrolizumab±chemotherapy in non-small cell lung cancer (NSCLC) patients.Abstract:
BACKGROUND Currently available biomarkers are imperfect in their ability to predict responses to the multiple first-line treatment options available for patients with advanced non-small cell lung cancer (NSCLC). Having an early pharmacodynamic marker of treatment resistance may help redirect patients onto more effective alternative therapies. We sought to determine if changes in circulating tumor DNA (ctDNA) levels after initiation of first-line pembrolizumab±chemotherapy in NSCLC would enable early prediction of response prior to radiological assessment. METHODS Plasma collected from patients with advanced NSCLC prior to and serially after starting first-line pembrolizumab±platinum doublet chemotherapy was analyzed by next-generation sequencing using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes. Early change in ctDNA allele fraction (AF) was correlated with radiographic responses and long-term clinical outcomes. RESULTS Among 62 patients who received first-line pembrolizumab±platinum/pemetrexed and underwent ctDNA assessment, 45 had detectable ctDNA alterations at baseline. The median change in AF at the first follow-up (at a median of 21 days after treatment initiation) was -90.1% (range -100% to +65%) among patients who subsequently had a radiologic response (n=18), -19.9% (range: -100% to +1884%) among stable disease cases (n=15), and +28.8% (range: -100% to +410%) among progressive disease cases (n=12); p=0.003. In addition, there was a significant correlation between the percent change in ctDNA at the first follow-up and the percent change in tumor target lesions from baseline (R=0.66, p<0.001). AF decrease between the pretreatment and first on-treatment blood draw was associated with significantly higher response rate (60.7% vs 5.8%, p=0.0003), and significantly longer median progression-free survival (8.3 vs 3.4 months, HR: 0.29 (95% CI: 0.14 to 0.60), p=0.0007) and median overall survival (26.2 vs 13.2 months, HR: 0.34 (95% CI: 0.15 to 0.75), p=0.008) compared with cases with an AF increase. CONCLUSION In patients with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.read more
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Peripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors.
TL;DR: In this paper, the potential of circulating immune cells, soluble immune and inflammatory molecules, circulating tumor cells and DNA, exosomes, and the blood-based tumor mutational burden, as biomarkers for the prediction of immune responses and clinical benefit from immune checkpoint inhibitors (ICI) treatment in patients with advanced cancer.
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Signed in Blood: Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening.
TL;DR: In this article, the authors review the ways in which circulating tumor DNA assessment can be leveraged to understand the dynamic changes of molecular landscape in cancers, and propose a liquid biopsy-based approach to evaluate ctDNA over tissue DNA.
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Integrating circulating-free DNA (cfDNA) analysis into clinical practice: opportunities and challenges
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Clinical potential of circulating free DNA and circulating tumour cells in patients with metastatic non-small-cell lung cancer treated with pembrolizumab
Patricia Mondelo-Macía,Jorge García-González,Luis León-Mateos,Urbano Anido,Santiago Aguín,Ihab Abdulkader,María Sánchez-Ares,Alicia Abalo,Aitor Rodriguez-Casanova,Aitor Rodriguez-Casanova,Angel Diaz-Lagares,Ramón Manuel Lago-Lestón,Laura Muinelo-Romay,Rafael López-López,Roberto Díaz-Peña +14 more
TL;DR: In this article, the authors explored the value of liquid biopsy analyses, including circulating free DNA (cfDNA) and circulating tumour cells (CTCs), as a prognostic or predictive tool to guide pembrolizumab therapy.
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Comparative Analysis and Isoform-Specific Therapeutic Vulnerabilities of<i>KRAS</i>Mutations in Non–Small Cell Lung Cancer
TL;DR: In this article , the authors developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms, and analyzed clinicopathologic and genomic data from 3,560 patients with non-small cell lung cancer (NSCLC).
References
More filters
Journal ArticleDOI
Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer
Martin Reck,Delvys Rodriguez-Abreu,Andrew G. Robinson,Rina Hui,Tibor Csőszi,Andrea Fülöp,Maya Gottfried,Nir Peled,Ali Tafreshi,Sinead Cuffe,Mary O'Brien,Suman Rao,Katsuyuki Hotta,Melanie A. Leiby,Gregory M. Lubiniecki,Yue Shentu,Reshma A. Rangwala,Julie R. Brahmer +17 more
TL;DR: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express PD-L1 as mentioned in this paper.
Journal ArticleDOI
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin,Vanna Chiarion-Sileni,Rene Gonzalez,Jean-Jacques Grob,C. Lance Cowey,Christopher D. Lao,Dirk Schadendorf,Reinhard Dummer,Michael Smylie,Piotr Rutkowski,Pier Francesco Ferrucci,A. Hill,John Wagstaff,Matteo S. Carlino,John B A G Haanen,Michele Maio,Ivan Marquez-Rodas,Grant A. McArthur,Paolo A. Ascierto,Georgina V. Long,Margaret K. Callahan,Michael A. Postow,Michael A. Postow,Kenneth F. Grossmann,Mario Sznol,Brigitte Dréno,Lars Bastholt,Arvin Yang,Linda Rollin,Christine Horak,F. Stephen Hodi,Jedd D. Wolchok,Jedd D. Wolchok +32 more
TL;DR: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipILimumab alone, and in patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.
Journal ArticleDOI
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Naiyer A. Rizvi,Naiyer A. Rizvi,Matthew D. Hellmann,Matthew D. Hellmann,Alexandra Snyder,Alexandra Snyder,Pia Kvistborg,Vladimir Makarov,Jonathan J. Havel,William Lee,Jianda Yuan,Phillip Wong,Teresa S. Ho,Martin L. Miller,Natasha Rekhtman,Andre L. Moreira,Fawzia Ibrahim,Cameron Bruggeman,Billel Gasmi,Roberta Zappasodi,Yuka Maeda,Chris Sander,Edward B. Garon,Taha Merghoub,Jedd D. Wolchok,Jedd D. Wolchok,Ton N. Schumacher,Timothy A. Chan,Timothy A. Chan +28 more
TL;DR: Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
Journal ArticleDOI
Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer
Leena Gandhi,Delvys Rodriguez-Abreu,Shirish M. Gadgeel,Emilio Esteban,Enriqueta Felip,Flávia De Angelis,Manuel Domine,Philip Clingan,Maximilian J. Hochmair,Steven Francis Powell,Susanna Y.-S. Cheng,Helge Bischoff,Nir Peled,Francesco Grossi,Ross Jennens,Martin Reck,Rina Hui,Edward B. Garon,Michael Boyer,Belén Rubio-Viqueira,Silvia Novello,Takayasu Kurata,Jhanelle E. Gray,John Vida,Ziwen Wei,J. Yang,Harry Raftopoulos,M. Catherine Pietanza,Marina Chiara Garassino +28 more
TL;DR: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum‐based drug resulted in significantly longer overall survival and progression‐free survival than chemotherapy alone.
Journal ArticleDOI
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Jedd D. Wolchok,Vanna Chiarion-Sileni,Rene Gonzalez,Piotr Rutkowski,Jean-Jacques Grob,C. Lance Cowey,Christopher D. Lao,John Wagstaff,Dirk Schadendorf,Pier Francesco Ferrucci,Michael Smylie,Reinhard Dummer,Andrew F. Hill,David Hogg,John B. A. G. Haanen,Matteo S. Carlino,Oliver Bechter,Michele Maio,Ivan Marquez-Rodas,Massimo Guidoboni,Grant A. McArthur,Céleste Lebbé,Paolo A. Ascierto,Georgina V. Long,Jonathan Cebon,Jeffrey A. Sosman,Michael A. Postow,Margaret K. Callahan,Dana Walker,Linda Rollin,Rafia Bhore,F. Stephen Hodi,James Larkin,James Larkin +33 more
TL;DR: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with n ivolumAB alone than with ipil optimumab alone.