Blood tumor mutation burden can predict the clinical response to immune checkpoint inhibitors in advanced non-small cell lung cancer patients

go back to reference Peters S, Gettinger S, Johnson ML, Janne PA, Garassino MC, Christoph D, Toh CK, Rizvi NA, Chaft JE, Carcereny Costa E, Patel JD, Chow LQM, Koczywas M, Ho C, Fruh M, van den Heuvel M, Rothenstein J, Reck M, Paz-Ares L, Shepherd FA, Kurata T, Li Z, Qiu J, Kowanetz M, Mocci S, Shankar G, Sandler A, Felip E (2017) Phase II Trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J clin oncol : off J Am Soc Clin Oncol 35(24):2781–2789. https://doi.org/10.1200/jco.2016.71.9476CrossRef Peters S, Gettinger S, Johnson ML, Janne PA, Garassino MC, Christoph D, Toh CK, Rizvi NA, Chaft JE, Carcereny Costa E, Patel JD, Chow LQM, Koczywas M, Ho C, Fruh M, van den Heuvel M, Rothenstein J, Reck M, Paz-Ares L, Shepherd FA, Kurata T, Li Z, Qiu J, Kowanetz M, Mocci S, Shankar G, Sandler A, Felip E (2017) Phase II Trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J clin oncol : off J Am Soc Clin Oncol 35(24):2781–2789. https://​doi.​org/​10.​1200/​jco.​2016.​71.​9476CrossRef

go back to reference Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833. https://doi.org/10.1056/NEJMoa1606774CrossRefPubMed Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833. https://​doi.​org/​10.​1056/​NEJMoa1606774CrossRefPubMed

go back to reference Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639. https://doi.org/10.1056/NEJMoa1507643CrossRefPubMedPubMedCentral Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639. https://​doi.​org/​10.​1056/​NEJMoa1507643CrossRefPubMedPubMedCentral

go back to reference Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135. https://doi.org/10.1056/NEJMoa1504627CrossRefPubMedPubMedCentral Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135. https://​doi.​org/​10.​1056/​NEJMoa1504627CrossRefPubMedPubMedCentral

go back to reference Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G, Jr., Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB, (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550. https://doi.org/10.1016/S0140-6736(15)01281-7CrossRefPubMed Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G, Jr., Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB, (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550. https://​doi.​org/​10.​1016/​S0140-6736(15)01281-7CrossRefPubMed

go back to reference Network NCC NCCN clinical practice guidelines in Oncology: Non-small cell lung cancer (Version 8.2020) Network NCC NCCN clinical practice guidelines in Oncology: Non-small cell lung cancer (Version 8.2020)

go back to reference Vanderwalde A, Spetzler D, Xiao N, Gatalica Z, Marshall J (2018) Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med 7(3):746–756. https://doi.org/10.1002/cam4.1372CrossRefPubMedPubMedCentral Vanderwalde A, Spetzler D, Xiao N, Gatalica Z, Marshall J (2018) Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med 7(3):746–756. https://​doi.​org/​10.​1002/​cam4.​1372CrossRefPubMedPubMedCentral

go back to reference Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS (2015) Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 16(3):257–265. https://doi.org/10.1016/s1470-2045(15)70054-9CrossRefPubMedPubMedCentral Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS (2015) Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 16(3):257–265. https://​doi.​org/​10.​1016/​s1470-2045(15)70054-9CrossRefPubMedPubMedCentral

go back to reference Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567. https://doi.org/10.1038/nature14011CrossRefPubMedPubMedCentral Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567. https://​doi.​org/​10.​1038/​nature14011CrossRefPubMedPubMedCentral

go back to reference Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, Sequist LV, Smith DC, Leming P, Carbone DP, Pinder-Schenck MC, Topalian SL, Hodi FS, Sosman JA, Sznol M, McDermott DF, Pardoll DM, Sankar V, Ahlers CM, Salvati M, Wigginton JM, Hellmann MD, Kollia GD, Gupta AK, Brahmer JR (2015) Overall survival and long-term safety of nivolumab (Anti-Programmed Death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J clin oncol : off j Am Soc Clin Oncol 33(18):2004–2012. https://doi.org/10.1200/jco.2014.58.3708CrossRef Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, Sequist LV, Smith DC, Leming P, Carbone DP, Pinder-Schenck MC, Topalian SL, Hodi FS, Sosman JA, Sznol M, McDermott DF, Pardoll DM, Sankar V, Ahlers CM, Salvati M, Wigginton JM, Hellmann MD, Kollia GD, Gupta AK, Brahmer JR (2015) Overall survival and long-term safety of nivolumab (Anti-Programmed Death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J clin oncol : off j Am Soc Clin Oncol 33(18):2004–2012. https://​doi.​org/​10.​1200/​jco.​2014.​58.​3708CrossRef

go back to reference Mansfield AS, Murphy SJ, Peikert T, Yi ES, Vasmatzis G, Wigle DA, Aubry MC (2016) Heterogeneity of programmed cell death Ligand 1 expression in multifocal lung cancer. Clin cancer res : an off j Am Assoc Cancer Res 22(9):2177–2182. https://doi.org/10.1158/1078-0432.ccr-15-2246CrossRef Mansfield AS, Murphy SJ, Peikert T, Yi ES, Vasmatzis G, Wigle DA, Aubry MC (2016) Heterogeneity of programmed cell death Ligand 1 expression in multifocal lung cancer. Clin cancer res : an off j Am Assoc Cancer Res 22(9):2177–2182. https://​doi.​org/​10.​1158/​1078-0432.​ccr-15-2246CrossRef

go back to reference Patel SP, Kurzrock R (2015) PD-L1 Expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856. https://doi.org/10.1158/1535-7163.mct-14-0983CrossRefPubMed Patel SP, Kurzrock R (2015) PD-L1 Expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856. https://​doi.​org/​10.​1158/​1535-7163.​mct-14-0983CrossRefPubMed

go back to reference Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science (New York, NY) 348(6230):69–74. https://doi.org/10.1126/science.aaa4971CrossRef Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science (New York, NY) 348(6230):69–74. https://​doi.​org/​10.​1126/​science.​aaa4971CrossRef

go back to reference Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, Hodi FS, Martin-Algarra S, Mandal R, Sharfman WH, Bhatia S, Hwu WJ, Gajewski TF, Slingluff CL Jr, Chowell D, Kendall SM, Chang H, Shah R, Kuo F, Morris LGT, Sidhom JW, Schneck JP, Horak CE, Weinhold N, Chan TA (2017) Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171(4):934–949. https://doi.org/10.1016/j.cell.2017.09.028CrossRefPubMedPubMedCentral Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, Hodi FS, Martin-Algarra S, Mandal R, Sharfman WH, Bhatia S, Hwu WJ, Gajewski TF, Slingluff CL Jr, Chowell D, Kendall SM, Chang H, Shah R, Kuo F, Morris LGT, Sidhom JW, Schneck JP, Horak CE, Weinhold N, Chan TA (2017) Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171(4):934–949. https://​doi.​org/​10.​1016/​j.​cell.​2017.​09.​028CrossRefPubMedPubMedCentral

go back to reference Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science (New York, NY) 348(6230):124–128. https://doi.org/10.1126/science.aaa1348CrossRefPubMedCentral Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science (New York, NY) 348(6230):124–128. https://​doi.​org/​10.​1126/​science.​aaa1348CrossRefPubMedCentral

go back to reference Yarchoan M, Hopkins A, Jaffee EM (2017) Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 377(25):2500–2501. https://doi.org/10.1056/NEJMc1713444CrossRefPubMedPubMedCentral Yarchoan M, Hopkins A, Jaffee EM (2017) Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 377(25):2500–2501. https://​doi.​org/​10.​1056/​NEJMc1713444CrossRefPubMedPubMedCentral

go back to reference Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH Jr, Italiano A, Kao S, Piha-Paul SA, Delord JP, McWilliams RR, Fabrizio DA, Aurora-Garg D, Xu L, Jin F, Norwood K, Bang YJ (2020) Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21(10):1353–1365. https://doi.org/10.1016/s1470-2045(20)30445-9CrossRefPubMed Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH Jr, Italiano A, Kao S, Piha-Paul SA, Delord JP, McWilliams RR, Fabrizio DA, Aurora-Garg D, Xu L, Jin F, Norwood K, Bang YJ (2020) Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21(10):1353–1365. https://​doi.​org/​10.​1016/​s1470-2045(20)30445-9CrossRefPubMed

go back to reference Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, Schrock A, Campbell B, Shlien A, Chmielecki J, Huang F, He Y, Sun J, Tabori U, Kennedy M, Lieber DS, Roels S, White J, Otto GA, Ross JS, Garraway L, Miller VA, Stephens PJ, Frampton GM (2017) Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genom med 9(1):34. https://doi.org/10.1186/s13073-017-0424-2CrossRef Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, Schrock A, Campbell B, Shlien A, Chmielecki J, Huang F, He Y, Sun J, Tabori U, Kennedy M, Lieber DS, Roels S, White J, Otto GA, Ross JS, Garraway L, Miller VA, Stephens PJ, Frampton GM (2017) Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genom med 9(1):34. https://​doi.​org/​10.​1186/​s13073-017-0424-2CrossRef

go back to reference Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, Plodkowski A, Long N, Sauter JL, Rekhtman N, Hollmann T, Schalper KA, Gainor JF, Shen R, Ni A, Arbour KC, Merghoub T, Wolchok J, Snyder A, Chaft JE, Kris MG, Rudin CM, Socci ND, Berger MF, Taylor BS, Zehir A, Solit DB, Arcila ME, Ladanyi M, Riely GJ, Schultz N, Hellmann MD (2018) Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J clin oncol : off j Am Soc Clin Oncol 36(7):633–641. https://doi.org/10.1200/JCO.2017.75.3384CrossRef Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, Plodkowski A, Long N, Sauter JL, Rekhtman N, Hollmann T, Schalper KA, Gainor JF, Shen R, Ni A, Arbour KC, Merghoub T, Wolchok J, Snyder A, Chaft JE, Kris MG, Rudin CM, Socci ND, Berger MF, Taylor BS, Zehir A, Solit DB, Arcila ME, Ladanyi M, Riely GJ, Schultz N, Hellmann MD (2018) Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J clin oncol : off j Am Soc Clin Oncol 36(7):633–641. https://​doi.​org/​10.​1200/​JCO.​2017.​75.​3384CrossRef

go back to reference Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, Rittmeyer A, Fehrenbacher L, Otto G, Malboeuf C, Lieber DS, Lipson D, Silterra J, Amler L, Riehl T, Cummings CA, Hegde PS, Sandler A, Ballinger M, Fabrizio D, Mok T, Shames DS (2018) Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 24(9):1441–1448. https://doi.org/10.1038/s41591-018-0134-3CrossRefPubMed Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, Rittmeyer A, Fehrenbacher L, Otto G, Malboeuf C, Lieber DS, Lipson D, Silterra J, Amler L, Riehl T, Cummings CA, Hegde PS, Sandler A, Ballinger M, Fabrizio D, Mok T, Shames DS (2018) Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 24(9):1441–1448. https://​doi.​org/​10.​1038/​s41591-018-0134-3CrossRefPubMed

go back to reference Wang Z, Duan J, Cai S, Han M, Dong H, Zhao J, Zhu B, Wang S, Zhuo M, Sun J, Wang Q, Bai H, Han J, Tian Y, Lu J, Xu T, Zhao X, Wang G, Cao X, Li F, Wang D, Chen Y, Bai Y, Zhao J, Zhao Z, Zhang Y, Xiong L, He J, Gao S, Wang J (2019) Assessment of blood tumor mutational burden as a potential biomarker for immunotherapy in patients with non-small cell lung cancer with use of a next-generation sequencing cancer gene panel. JAMA Oncol 5(5):696–702. https://doi.org/10.1001/jamaoncol.2018.7098CrossRefPubMedPubMedCentral Wang Z, Duan J, Cai S, Han M, Dong H, Zhao J, Zhu B, Wang S, Zhuo M, Sun J, Wang Q, Bai H, Han J, Tian Y, Lu J, Xu T, Zhao X, Wang G, Cao X, Li F, Wang D, Chen Y, Bai Y, Zhao J, Zhao Z, Zhang Y, Xiong L, He J, Gao S, Wang J (2019) Assessment of blood tumor mutational burden as a potential biomarker for immunotherapy in patients with non-small cell lung cancer with use of a next-generation sequencing cancer gene panel. JAMA Oncol 5(5):696–702. https://​doi.​org/​10.​1001/​jamaoncol.​2018.​7098CrossRefPubMedPubMedCentral

go back to reference Li L, Wang Y, Shi W, Zhu M, Liu Z, Luo N, Zeng Y, He Y (2019) Serial ultra-deep sequencing of circulating tumor DNA reveals the clonal evolution in non-small cell lung cancer patients treated with anti-PD1 immunotherapy. Cancer Med 8(18):7669–7678. https://doi.org/10.1002/cam4.2632CrossRefPubMedPubMedCentral Li L, Wang Y, Shi W, Zhu M, Liu Z, Luo N, Zeng Y, He Y (2019) Serial ultra-deep sequencing of circulating tumor DNA reveals the clonal evolution in non-small cell lung cancer patients treated with anti-PD1 immunotherapy. Cancer Med 8(18):7669–7678. https://​doi.​org/​10.​1002/​cam4.​2632CrossRefPubMedPubMedCentral

go back to reference Wang Z, Duan J, Wang G, Zhao J, Xu J, Han J, Zhao Z, Zhao J, Zhu B, Zhuo M, Sun J, Bai H, Wan R, Wang X, Fei K, Wang S, Zhao X, Zhang Y, Huang M, Huang D, Qi C, Gao C, Bai Y, Dong H, Xiong L, Tian Y, Wang D, Xu C, Wang W, Li J, Hu X, Cai S, Wang J (2019) Allele frequency-adjusted blood-based tumor mutational burden as a predictor of overall survival for patients with NSCLC treated With PD-(L)1 inhibitors. J thorac oncol : off publ Int Assoc Stud Lung Cancer. https://doi.org/10.1016/j.jtho.2019.12.001CrossRef Wang Z, Duan J, Wang G, Zhao J, Xu J, Han J, Zhao Z, Zhao J, Zhu B, Zhuo M, Sun J, Bai H, Wan R, Wang X, Fei K, Wang S, Zhao X, Zhang Y, Huang M, Huang D, Qi C, Gao C, Bai Y, Dong H, Xiong L, Tian Y, Wang D, Xu C, Wang W, Li J, Hu X, Cai S, Wang J (2019) Allele frequency-adjusted blood-based tumor mutational burden as a predictor of overall survival for patients with NSCLC treated With PD-(L)1 inhibitors. J thorac oncol : off publ Int Assoc Stud Lung Cancer. https://​doi.​org/​10.​1016/​j.​jtho.​2019.​12.​001CrossRef

go back to reference Chae YK, Davis AA, Agte S, Pan A, Simon NI, Iams WT, Cruz MR, Tamragouri K, Rhee K, Mohindra N, Villaflor V, Park W, Lopes G, Giles FJ (2019) Clinical implications of circulating tumor DNA tumor mutational burden (ctDNA TMB) in non-small cell lung cancer. Oncologist 24(6):820–828. https://doi.org/10.1634/theoncologist.2018-0433CrossRefPubMedPubMedCentral Chae YK, Davis AA, Agte S, Pan A, Simon NI, Iams WT, Cruz MR, Tamragouri K, Rhee K, Mohindra N, Villaflor V, Park W, Lopes G, Giles FJ (2019) Clinical implications of circulating tumor DNA tumor mutational burden (ctDNA TMB) in non-small cell lung cancer. Oncologist 24(6):820–828. https://​doi.​org/​10.​1634/​theoncologist.​2018-0433CrossRefPubMedPubMedCentral

go back to reference Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours revised RECIST. Eur j cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026CrossRefPubMed Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours revised RECIST. Eur j cancer 45(2):228–247. https://​doi.​org/​10.​1016/​j.​ejca.​2008.​10.​026CrossRefPubMed

go back to reference Xie Z, Liu L, Lin X, Xie X, Gu Y, Liu M, Zhang J, Ouyang M, Lizaso A, Zhang H, Feng W, Li B, Han-Zhang H, Chen S, Li S, Zhong N, Liu H, Zhou C, Qin Y (2019) A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung. Modern pathol : off j U S Canad Acad Pathol. https://doi.org/10.1038/s41379-019-0391-9CrossRef Xie Z, Liu L, Lin X, Xie X, Gu Y, Liu M, Zhang J, Ouyang M, Lizaso A, Zhang H, Feng W, Li B, Han-Zhang H, Chen S, Li S, Zhong N, Liu H, Zhou C, Qin Y (2019) A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung. Modern pathol : off j U S Canad Acad Pathol. https://​doi.​org/​10.​1038/​s41379-019-0391-9CrossRef

go back to reference Bantis LE, Nakas CT, Reiser B (2014) Construction of confidence regions in the ROC space after the estimation of the optimal Youden index-based cut-off point. Biometrics 70(1):212–223. https://doi.org/10.1111/biom.12107CrossRefPubMed Bantis LE, Nakas CT, Reiser B (2014) Construction of confidence regions in the ROC space after the estimation of the optimal Youden index-based cut-off point. Biometrics 70(1):212–223. https://​doi.​org/​10.​1111/​biom.​12107CrossRefPubMed

go back to reference Stenzinger A, Endris V, Budczies J, Merkelbach-Bruse S, Kazdal D, Dietmaier W, Pfarr N, Siebolts U, Hummel M, Herold S, Andreas J, Zoche M, Togel L, Rempel E, Maas J, Merino D, Stewart M, Zaoui K, Schlesner M, Glimm H, Frohling S, Allen J, Horst D, Baretton G, Wickenhauser C, Tiemann M, Evert M, Moch H, Kirchner T, Buttner R, Schirmacher P, Jung A, Haller F, Weichert W, Dietel M (2020) Harmonization and standardization of panel-based tumor mutational burden (TMB) measurement: real-world results and recommendations of the QuIP study. J thorac oncol : off publ Int Assoc Stud Lung Cancer. https://doi.org/10.1016/j.jtho.2020.01.023CrossRef Stenzinger A, Endris V, Budczies J, Merkelbach-Bruse S, Kazdal D, Dietmaier W, Pfarr N, Siebolts U, Hummel M, Herold S, Andreas J, Zoche M, Togel L, Rempel E, Maas J, Merino D, Stewart M, Zaoui K, Schlesner M, Glimm H, Frohling S, Allen J, Horst D, Baretton G, Wickenhauser C, Tiemann M, Evert M, Moch H, Kirchner T, Buttner R, Schirmacher P, Jung A, Haller F, Weichert W, Dietel M (2020) Harmonization and standardization of panel-based tumor mutational burden (TMB) measurement: real-world results and recommendations of the QuIP study. J thorac oncol : off publ Int Assoc Stud Lung Cancer. https://​doi.​org/​10.​1016/​j.​jtho.​2020.​01.​023CrossRef

go back to reference Wu HX, Wang ZX, Zhao Q, Wang F, Xu RH (2019) Designing gene panels for tumor mutational burden estimation: the need to shift from “correlation” to “accuracy.” J Immun Cancer 7(1):206. https://doi.org/10.1186/s40425-019-0681-2CrossRef Wu HX, Wang ZX, Zhao Q, Wang F, Xu RH (2019) Designing gene panels for tumor mutational burden estimation: the need to shift from “correlation” to “accuracy.” J Immun Cancer 7(1):206. https://​doi.​org/​10.​1186/​s40425-019-0681-2CrossRef

go back to reference Kazdal D, Endris V, Allgauer M, Kriegsmann M, Leichsenring J, Volckmar AL, Harms A, Kirchner M, Kriegsmann K, Neumann O, Brandt R, Talla SB, Rempel E, Ploeger C, von Winterfeld M, Christopoulos P, Merino DM, Stewart M, Allen J, Bischoff H, Meister M, Muley T, Herth F, Penzel R, Warth A, Winter H, Frohling S, Peters S, Swanton C, Thomas M, Schirmacher P, Budczies J, Stenzinger A (2019) Spatial and temporal heterogeneity of panel-based tumor mutational burden in pulmonary adenocarcinoma: separating biology from technical artifacts. J thorac oncol : off publ Int Assoc Stud Lung Cancer 14(11):1935–1947. https://doi.org/10.1016/j.jtho.2019.07.006CrossRef Kazdal D, Endris V, Allgauer M, Kriegsmann M, Leichsenring J, Volckmar AL, Harms A, Kirchner M, Kriegsmann K, Neumann O, Brandt R, Talla SB, Rempel E, Ploeger C, von Winterfeld M, Christopoulos P, Merino DM, Stewart M, Allen J, Bischoff H, Meister M, Muley T, Herth F, Penzel R, Warth A, Winter H, Frohling S, Peters S, Swanton C, Thomas M, Schirmacher P, Budczies J, Stenzinger A (2019) Spatial and temporal heterogeneity of panel-based tumor mutational burden in pulmonary adenocarcinoma: separating biology from technical artifacts. J thorac oncol : off publ Int Assoc Stud Lung Cancer 14(11):1935–1947. https://​doi.​org/​10.​1016/​j.​jtho.​2019.​07.​006CrossRef

go back to reference Buttner R, Longshore JW, Lopez-Rios F, Merkelbach-Bruse S, Normanno N, Rouleau E, Penault-Llorca F (2019) Implementing TMB measurement in clinical practice: considerations on assay requirements. ESMO open 4(1):e000442. https://doi.org/10.1136/esmoopen-2018-000442CrossRefPubMedPubMedCentral Buttner R, Longshore JW, Lopez-Rios F, Merkelbach-Bruse S, Normanno N, Rouleau E, Penault-Llorca F (2019) Implementing TMB measurement in clinical practice: considerations on assay requirements. ESMO open 4(1):e000442. https://​doi.​org/​10.​1136/​esmoopen-2018-000442CrossRefPubMedPubMedCentral

go back to reference Budczies JAM, Litchfield K et al (2019) Optimizing panel-based tumor mutational burden (TMB) measurement. Ann oncol: off j Eur Soc Med Oncol 30(9):1496–1506CrossRef Budczies JAM, Litchfield K et al (2019) Optimizing panel-based tumor mutational burden (TMB) measurement. Ann oncol: off j Eur Soc Med Oncol 30(9):1496–1506CrossRef

go back to reference Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Dentro S, Taniere P, O’Sullivan B, Lowe HL, Hartley JA, Iles N, Bell H, Ngai Y, Shaw JA, Herrero J, Szallasi Z, Schwarz RF, Stewart A, Quezada SA, Le Quesne J, Van Loo P, Dive C, Hackshaw A, Swanton C (2017) Tracking the evolution of non-small-cell lung cancer. N Engl J Med 376(22):2109–2121. https://doi.org/10.1056/NEJMoa1616288CrossRefPubMed Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Dentro S, Taniere P, O’Sullivan B, Lowe HL, Hartley JA, Iles N, Bell H, Ngai Y, Shaw JA, Herrero J, Szallasi Z, Schwarz RF, Stewart A, Quezada SA, Le Quesne J, Van Loo P, Dive C, Hackshaw A, Swanton C (2017) Tracking the evolution of non-small-cell lung cancer. N Engl J Med 376(22):2109–2121. https://​doi.​org/​10.​1056/​NEJMoa1616288CrossRefPubMed

go back to reference Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Gronroos E, Zambrana F, Endozo R, Bi WL, Fennessy FM, Sponer N, Johnson D, Laycock J, Shafi S, Czyzewska-Khan J, Rowan A, Chambers T, Matthews N, Turajlic S, Hiley C, Lee SM, Forster MD, Ahmad T, Falzon M, Borg E, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Hafez D, Naik A, Ganguly A, Kareht S, Shah R, Joseph L, Marie Quinn A, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Oukrif D, Akarca AU, Hartley JA, Lowe HL, Lock S, Iles N, Bell H, Ngai Y, Elgar G, Szallasi Z, Schwarz RF, Herrero J, Stewart A, Quezada SA, Peggs KS, Van Loo P, Dive C, Lin CJ, Rabinowitz M, Aerts H, Hackshaw A, Shaw JA, Zimmermann BG, Swanton C (2017) Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545(7655):446–451. https://doi.org/10.1038/nature22364CrossRefPubMedPubMedCentral Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Gronroos E, Zambrana F, Endozo R, Bi WL, Fennessy FM, Sponer N, Johnson D, Laycock J, Shafi S, Czyzewska-Khan J, Rowan A, Chambers T, Matthews N, Turajlic S, Hiley C, Lee SM, Forster MD, Ahmad T, Falzon M, Borg E, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Hafez D, Naik A, Ganguly A, Kareht S, Shah R, Joseph L, Marie Quinn A, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Oukrif D, Akarca AU, Hartley JA, Lowe HL, Lock S, Iles N, Bell H, Ngai Y, Elgar G, Szallasi Z, Schwarz RF, Herrero J, Stewart A, Quezada SA, Peggs KS, Van Loo P, Dive C, Lin CJ, Rabinowitz M, Aerts H, Hackshaw A, Shaw JA, Zimmermann BG, Swanton C (2017) Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545(7655):446–451. https://​doi.​org/​10.​1038/​nature22364CrossRefPubMedPubMedCentral

go back to reference Zhang Y, Chang L, Yang Y, Fang W, Guan Y, Wu A, Hong S, Zhou H, Chen G, Chen X, Zhao S, Zheng Q, Pan H, Zhang L, Long H, Yang H, Wang X, Wen Z, Wang J, Yang H, Xia X, Zhao Y, Hou X, Ma Y, Zhou T, Zhang Z, Zhan J, Huang Y, Zhao H, Zhou N, Yi X, Zhang L (2019) The correlations of tumor mutational burden among single-region tissue, multi-region tissues and blood in non-small cell lung cancer. J Immun Cancer 7(1):98. https://doi.org/10.1186/s40425-019-0581-5CrossRef Zhang Y, Chang L, Yang Y, Fang W, Guan Y, Wu A, Hong S, Zhou H, Chen G, Chen X, Zhao S, Zheng Q, Pan H, Zhang L, Long H, Yang H, Wang X, Wen Z, Wang J, Yang H, Xia X, Zhao Y, Hou X, Ma Y, Zhou T, Zhang Z, Zhan J, Huang Y, Zhao H, Zhou N, Yi X, Zhang L (2019) The correlations of tumor mutational burden among single-region tissue, multi-region tissues and blood in non-small cell lung cancer. J Immun Cancer 7(1):98. https://​doi.​org/​10.​1186/​s40425-019-0581-5CrossRef

go back to reference Yu H, Chen Z, Ballman KV, Watson MA, Govindan R, Lanc I, Beer DG, Bueno R, Chirieac LR, Chui MH, Chen G, Franklin WA, Gandara DR, Genova C, Brovsky KA, Joshi MM, Merrick DT, Richards WG, Rivard CJ, Harpole DH, Tsao MS, van Bokhoven A, Shepherd FA, Hirsch FR (2019) Correlation of PD-L1 expression with tumor mutation burden and gene signatures for prognosis in early-stage squamous cell lung carcinoma. J thorac oncol : off publ Int Assoc Stud Lung Cancer 14(1):25–36. https://doi.org/10.1016/j.jtho.2018.09.006CrossRef Yu H, Chen Z, Ballman KV, Watson MA, Govindan R, Lanc I, Beer DG, Bueno R, Chirieac LR, Chui MH, Chen G, Franklin WA, Gandara DR, Genova C, Brovsky KA, Joshi MM, Merrick DT, Richards WG, Rivard CJ, Harpole DH, Tsao MS, van Bokhoven A, Shepherd FA, Hirsch FR (2019) Correlation of PD-L1 expression with tumor mutation burden and gene signatures for prognosis in early-stage squamous cell lung carcinoma. J thorac oncol : off publ Int Assoc Stud Lung Cancer 14(1):25–36. https://​doi.​org/​10.​1016/​j.​jtho.​2018.​09.​006CrossRef

go back to reference Singal G, Miller PG, Agarwala V, Li G, Kaushik G, Backenroth D, Gossai A, Frampton GM, Torres AZ, Lehnert EM, Bourque D, O’Connell C, Bowser B, Caron T, Baydur E, Seidl-Rathkopf K, Ivanov I, Alpha-Cobb G, Guria A, He J, Frank S, Nunnally AC, Bailey M, Jaskiw A, Feuchtbaum D, Nussbaum N, Abernethy AP, Miller VA (2019) Association of patient characteristics and tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a clinicogenomic database. JAMA 321(14):1391–1399. https://doi.org/10.1001/jama.2019.3241CrossRefPubMedPubMedCentral Singal G, Miller PG, Agarwala V, Li G, Kaushik G, Backenroth D, Gossai A, Frampton GM, Torres AZ, Lehnert EM, Bourque D, O’Connell C, Bowser B, Caron T, Baydur E, Seidl-Rathkopf K, Ivanov I, Alpha-Cobb G, Guria A, He J, Frank S, Nunnally AC, Bailey M, Jaskiw A, Feuchtbaum D, Nussbaum N, Abernethy AP, Miller VA (2019) Association of patient characteristics and tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a clinicogenomic database. JAMA 321(14):1391–1399. https://​doi.​org/​10.​1001/​jama.​2019.​3241CrossRefPubMedPubMedCentral

go back to reference Marcin Kowanetz WZ, Shames D, Cummings C, Rizvi N, Spira A, Frampton G, Leveque V, Flynn S, Mocci S, Shankar G, Funke R, Ballinger M, Waterkamp D, Chen D, Sandler A, Hampton G, Amler L, Hegde P, Hellmann M (2017) Tumor mutation burden (TMB) is associated with improved efficacy of atezolizumab in 1L and 2L+ NSCLC patients. J Thorac Oncol 12(1):S321-322CrossRef Marcin Kowanetz WZ, Shames D, Cummings C, Rizvi N, Spira A, Frampton G, Leveque V, Flynn S, Mocci S, Shankar G, Funke R, Ballinger M, Waterkamp D, Chen D, Sandler A, Hampton G, Amler L, Hegde P, Hellmann M (2017) Tumor mutation burden (TMB) is associated with improved efficacy of atezolizumab in 1L and 2L+ NSCLC patients. J Thorac Oncol 12(1):S321-322CrossRef

go back to reference Singal GMP, Agarwala V et al (2017) Analyzing biomarkers of cancer immunotherapy (CIT) response using a real-world clinicogenomic database. Ann oncol: off j Eur Soc Med Oncol 28:v403–v427CrossRef Singal GMP, Agarwala V et al (2017) Analyzing biomarkers of cancer immunotherapy (CIT) response using a real-world clinicogenomic database. Ann oncol: off j Eur Soc Med Oncol 28:v403–v427CrossRef

go back to reference Kowanetz MZW, Shames D et al (2017) OA20.01 Tumor Mutation burden (TMB) is associated with improved efficacy of atezolizumab in 1L and 2L+ NSCLC patients. J thorac oncol: off publ Int Assoc Stud Lung Cancer 12:S321–S322CrossRef Kowanetz MZW, Shames D et al (2017) OA20.01 Tumor Mutation burden (TMB) is associated with improved efficacy of atezolizumab in 1L and 2L+ NSCLC patients. J thorac oncol: off publ Int Assoc Stud Lung Cancer 12:S321–S322CrossRef