Plasma Predictive Features in Treating EGFR-Mutated Non-Small Cell Lung Cancer

Christi M J Steendam, G D Marijn Veerman, Melinda A Pruis, Peggy Atmodimedjo, Marthe S Paats, Cor van der Leest, Jan H von der Thüsen, David C Y Yick, Esther Oomen-de Hoop, Stijn L W Koolen, Winand N M Dinjens, Ron H N van Schaik, Ron H J Mathijssen, Joachim G J V Aerts, Hendrikus Jan Dubbink, Anne-Marie C Dingemans, Christi M J Steendam, G D Marijn Veerman, Melinda A Pruis, Peggy Atmodimedjo, Marthe S Paats, Cor van der Leest, Jan H von der Thüsen, David C Y Yick, Esther Oomen-de Hoop, Stijn L W Koolen, Winand N M Dinjens, Ron H N van Schaik, Ron H J Mathijssen, Joachim G J V Aerts, Hendrikus Jan Dubbink, Anne-Marie C Dingemans

Abstract

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the preferred treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC), not all patients benefit. We therefore explored the impact of the presence of mutations found in cell-free DNA (cfDNA) and TKI plasma concentrations during treatment on progression-free survival (PFS). In the prospective START-TKI study blood samples from 41 patients with EGFR-mutated NSCLC treated with EGFR-TKIs were available. Next generation sequencing (NGS) on cfDNA was performed, and plasma TKI concentrations were measured. Patients without complete plasma conversion of EGFR mutation at week 6 had a significantly shorter PFS (5.5 vs. 17.0 months, p = 0.002) and OS (14.0 vs. 25.5 months, p = 0.003) compared to patients with plasma conversion. In thirteen (second line) osimertinib-treated patients with a (plasma or tissue) concomitant TP53 mutation at baseline, PFS was significantly shorter compared to six wild-type cases; 8.8 vs. 18.8 months, p = 0.017. Erlotinib Cmean decrease of ≥10% in the second tertile of treatment was also associated with a significantly shorter PFS; 8.9 vs. 23.6 months, p = 0.037. We obtained evidence that absence of plasma loss of the primary EGFR mutation, isolated plasma p.T790M loss after six weeks, baseline concomitant TP53 mutations, and erlotinib Cmean decrease during treatment are probably related to worse outcome.

Keywords: EGFR; NSCLC; T790M mutation; TKI; TP53 mutation; cfDNA; pharmacokinetics; plasma conversion.

Conflict of interest statement

The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. C.S. reports financial activities outside the submitted work: advisory board Boehringer Ingelheim, travel and symposia expenses from Roche, Lilly. C.L. reports financial activities outside the submitted work: BMS, Boeringer Ingelheim, MSD, Roche, Abbvie, AstraZeneca. S.K. reports financial activities outside the submitted work: lecture for Roche. W.D. reports financial activities outside the submitted work: Speakers and advisory honoraria from Roche, Bristol-Myers Squibb, Amgen, Bayer, AstraZeneca, Novartis. R.M. reports financial activities outside the submitted work: grants from The Dutch Cancer Society (KWF), Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Pamgene (and other), Pfizer, Prostakan, Novartis (and personal fees), Roche, Servier (and personal fees). J.A. reports financial activities outside the submitted work: MSD, BMS, Boehringer Ingelheim, Amphera, Eli-Lilly, Takeda, Bayer, Roche, AstraZeneca. Intellectual property: licensed patent on allogenic tumor cell lysate, pending patent on combination imunotherapy in cancer and biomarker for immunotherapy. H.D. reports grants, personal fees and non-financial support from AstraZeneca with regard to the Work Under Consideration for Publication and personal fees from AbbVie, Janssen, Pfizer, Lilly, PGDx, MSD outside the submitted work. A.D. reports financial activities outside the submitted work: Attended advisory boards and/or provided lectures for: Roche, Eli Lilly, Boehringer Ingelheim, Astra Zeneca, Pfizer, BMS, Amgen, Novartis, MSD, Takeda, Pharmamar. Received research support from BMS, AbbVie, Amgen. M.V., M.P., P.A., M.P., J.T., D.Y., E.O., and R.S. declare no conflict of interest.

Figures

Figure 1
Figure 1
Plasma conversion of the primary epidermal growth factor receptor (EGFR) mutation in relation to progression-free survival (PFS) and overall survival (OS): (a) PFS and plasma conversion at week 6; (b) PFS and plasma conversion at week 12; (c) OS and plasma conversion at week 6; (d) OS and plasma conversion at week 12.
Figure 2
Figure 2
PFS category distribution and plasma conversion in time.
Figure 3
Figure 3
Variant allele frequency (VAF) of the primary EGFR mutation in time, by plasma conversion status. (a) Patients with complete plasma conversion; (b) patients without complete plasma conversion.
Figure 4
Figure 4
(a) Relative change in erlotinib Cmean during treatment. Treatment period is divided in tertiles; (b) progression-free survival based on the erlotinib Cmean in the second tertile compared to the first tertile. The first (red-line) group has a decrease of less than 10% or an increase in Cmean. The second (blue-line) group has a decrease of at least 10% in erlotinib Cmean. Cmean = mean plasma concentration.

References

    1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492.
    1. Ramalingam S.S., Vansteenkiste J., Planchard D., Cho B.C., Gray J.E., Ohe Y., Zhou C., Reungwetwattana T., Cheng Y., Chewaskulyong B., et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N. Engl. J. Med. 2020;382:41–50. doi: 10.1056/NEJMoa1913662.
    1. Soria J.C., Ohe Y., Vansteenkiste J., Reungwetwattana T., Chewaskulyong B., Lee K.H., Dechaphunkul A., Imamura F., Nogami N., Kurata T., et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 2018;378:113–125. doi: 10.1056/NEJMoa1713137.
    1. Hsu W.H., Yang J.C., Mok T.S., Loong H.H. Overview of current systemic management of EGFR-mutant NSCLC. Ann. Oncol. 2018;29:i3–i9. doi: 10.1093/annonc/mdx702.
    1. Kim Y., Lee B., Shim J.H., Lee S.H., Park W.Y., Choi Y.L., Sun J.M., Ahn J.S., Ahn M.J., Park K. Concurrent genetic alterations predict the progression to target therapy in EGFR-mutated advanced NSCLC. J. Thorac. Oncol. 2019;14:193–202. doi: 10.1016/j.jtho.2018.10.150.
    1. Chang S.C., Lai Y.C., Chang C.Y., Huang L.K., Chen S.J., Tan K.T., Yu P.N., Lai J.I. Concomitant genetic alterations are associated with worse clinical outcome in EGFR mutant NSCLC patients treated with tyrosine kinase inhibitors. Transl. Oncol. 2019;12:1425–1431. doi: 10.1016/j.tranon.2019.07.008.
    1. Jiao X.D., Qin B.D., You P., Cai J., Zang Y.S. The prognostic value of tp53 and its correlation with EGFR mutation in advanced non-small cell lung cancer, an analysis based on cbioportal data base. Lung Cancer. 2018;123:70–75. doi: 10.1016/j.lungcan.2018.07.003.
    1. Canale M., Petracci E., Delmonte A., Chiadini E., Dazzi C., Papi M., Capelli L., Casanova C., De Luigi N., Mariotti M., et al. Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors. Clin. Cancer Res. 2017;23:2195–2202. doi: 10.1158/1078-0432.CCR-16-0966.
    1. Labbe C., Cabanero M., Korpanty G.J., Tomasini P., Doherty M.K., Mascaux C., Jao K., Pitcher B., Wang R., Pintilie M., et al. Prognostic and predictive effects of tp53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC) Lung Cancer. 2017;111:23–29. doi: 10.1016/j.lungcan.2017.06.014.
    1. Hou H., Qin K., Liang Y., Zhang C., Liu D., Jiang H., Liu K., Zhu J., Lv H., Li T., et al. Concurrent tp53 mutations predict poor outcomes of EGFR-tki treatments in chinese patients with advanced NSCLC. Cancer Manag. Res. 2019;11:5665–5675. doi: 10.2147/CMAR.S201513.
    1. Verheijen R.B., Yu H., Schellens J.H.M., Beijnen J.H., Steeghs N., Huitema A.D.R. Practical recommendations for therapeutic drug monitoring of kinase inhibitors in oncology. Clin. Pharmacol. Ther. 2017;102:765–776. doi: 10.1002/cpt.787.
    1. Veerman G.D.M., Hussaarts K., Jansman F.G.A., Koolen S.W.L., van Leeuwen R.W.F., Mathijssen R.H.J. Clinical implications of food-drug interactions with small-molecule kinase inhibitors. Lancet Oncol. 2020;21:e265–e279. doi: 10.1016/S1470-2045(20)30069-3.
    1. Hussaarts K., Veerman G.D.M., Jansman F.G.A., van Gelder T., Mathijssen R.H.J., van Leeuwen R.W.F. Clinically relevant drug interactions with multikinase inhibitors: A review. Ther. Adv. Med. Oncol. 2019;11:1758835918818347. doi: 10.1177/1758835918818347.
    1. Brown K., Comisar C., Witjes H., Maringwa J., de Greef R., Vishwanathan K., Cantarini M., Cox E. Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer. Br. J. Clin. Pharmacol. 2017;83:1216–1226. doi: 10.1111/bcp.13223.
    1. Hidalgo M., Siu L.L., Nemunaitis J., Rizzo J., Hammond L.A., Takimoto C., Eckhardt S.G., Tolcher A., Britten C.D., Denis L., et al. Phase i and pharmacologic study of osi-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J. Clin. Oncol. 2001;19:3267–3279. doi: 10.1200/JCO.2001.19.13.3267.
    1. Lankheet N.A., Knapen L.M., Schellens J.H., Beijnen J.H., Steeghs N., Huitema A.D. Plasma concentrations of tyrosine kinase inhibitors imatinib, erlotinib, and sunitinib in routine clinical outpatient cancer care. Ther. Drug Monit. 2014;36:326–334. doi: 10.1097/FTD.0000000000000004.
    1. Lu J.F., Eppler S.M., Wolf J., Hamilton M., Rakhit A., Bruno R., Lum B.L. Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin. Pharmacol. Ther. 2006;80:136–145. doi: 10.1016/j.clpt.2006.04.007.
    1. Ahluwalia M.S., Becker K., Levy B.P. Epidermal growth factor receptor tyrosine kinase inhibitors for central nervous system metastases from non-small cell lung cancer. Oncologist. 2018;23:1199–1209. doi: 10.1634/theoncologist.2017-0572.
    1. Wu Y.L., Ahn M.J., Garassino M.C., Han J.Y., Katakami N., Kim H.R., Hodge R., Kaur P., Brown A.P., Ghiorghiu D., et al. Cns efficacy of osimertinib in patients with t790m-positive advanced non-small-cell lung cancer: Data from a randomized phase iii trial (aura3) J. Clin. Oncol. 2018;36:2702–2709. doi: 10.1200/JCO.2018.77.9363.
    1. Crowley E., Di Nicolantonio F., Loupakis F., Bardelli A. Liquid biopsy: Monitoring cancer-genetics in the blood. Nat. Rev. Clin. Oncol. 2013;10:472–484. doi: 10.1038/nrclinonc.2013.110.
    1. Rolfo C., Mack P.C., Scagliotti G.V., Baas P., Barlesi F., Bivona T.G., Herbst R.S., Mok T.S., Peled N., Pirker R., et al. Liquid biopsy for advanced non-small cell lung cancer (NSCLC): A statement paper from the IASLC. J. Thorac. Oncol. 2018;13:1248–1268. doi: 10.1016/j.jtho.2018.05.030.
    1. Dagogo-Jack I., Shaw A.T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 2018;15:81–94. doi: 10.1038/nrclinonc.2017.166.
    1. Oxnard G.R., Thress K.S., Alden R.S., Lawrance R., Paweletz C.P., Cantarini M., Yang J.C., Barrett J.C., Jänne P.A. Association between plasma genotyping and outcomes of treatment with osimertinib (azd9291) in advanced non-small-cell lung cancer. J. Clin. Oncol. 2016;34:3375–3382. doi: 10.1200/JCO.2016.66.7162.
    1. Akamatsu H., Koh Y., Okamoto I., Fujimoto D., Bessho A., Azuma K., Morita S., Yamamoto N., Nakagawa K. Clinical significance of monitoring EGFR mutation in plasma using multiplexed digital pcr in EGFR mutated patients treated with afatinib (west japan oncology group 8114LTR study) Lung Cancer. 2019;131:128–133. doi: 10.1016/j.lungcan.2019.03.021.
    1. Ebert E.B.F., McCulloch T., Hansen K.H., Linnet H., Sorensen B., Meldgaard P. Clearing of circulating tumour DNA predicts clinical response to first line tyrosine kinase inhibitors in advanced epidermal growth factor receptor mutated non-small cell lung cancer. Lung Cancer. 2020;141:37–43. doi: 10.1016/j.lungcan.2019.12.016.
    1. Buder A., Hochmair M.J., Setinek U., Pirker R., Filipits M. EGFR mutation tracking predicts survival in advanced EGFR-mutated non-small cell lung cancer patients treated with osimertinib. Transl. Lung Cancer Res. 2020;9:239–245. doi: 10.21037/tlcr.2020.03.02.
    1. Buttitta F., Felicioni L., Lorito A.D., Cortellini A., Irtelli L., Brocco D., Marino P.D., Traisci D., D’Ostilio N., Paolo A.D., et al. Early prediction of resistance to tyrosine kinase inhibitors by plasma monitoring of EGFR mutations in NSCLC: A new algorithm for patient selection and personalized treatment. Oncotarget. 2020;11:982–991. doi: 10.18632/oncotarget.27517.
    1. O’Kane G.M., Liu G., Stockley T.L., Shabir M., Zhang T., Law J.H., Le L.W., Sacher A., Shepherd F.A., Bradbury P.A., et al. The presence and variant allele fraction of EGFR mutations in ctdna and development of resistance. Lung Cancer. 2019;131:86–89. doi: 10.1016/j.lungcan.2019.03.019.
    1. Romero A., Serna-Blasco R., Alfaro C., Sánchez-Herrero E., Barquín M., Turpin M.C., Chico S., Sanz-Moreno S., Rodrigez-Festa A., Laza-Briviesca R., et al. Ctdna analysis reveals different molecular patterns upon disease progression in patients treated with osimertinib. Transl. Lung Cancer Res. 2020;9:532–540. doi: 10.21037/tlcr.2020.04.01.
    1. Oxnard G.R., Hu Y., Mileham K.F., Husain H., Costa D.B., Tracy P., Feeney N., Sholl L.M., Dahlberg S.E., Redig A.J., et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR t790m-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 2018;4:1527–1534. doi: 10.1001/jamaoncol.2018.2969.
    1. Zhao S., Li X., Zhao C., Jiang T., Jia Y., Shi J., He Y., Li J., Zhou F., Gao G., et al. Loss of t790m mutation is associated with early progression to osimertinib in chinese patients with advanced NSCLC who are harboring EGFR t790m. Lung Cancer. 2019;128:33–39. doi: 10.1016/j.lungcan.2018.12.010.
    1. Muller P.A., Vousden K.H. P53 mutations in cancer. Nat. Cell Biol. 2013;15:2–8. doi: 10.1038/ncb2641.
    1. Rivlin N., Brosh R., Oren M., Rotter V. Mutations in the p53 tumor suppressor gene: Important milestones at the various steps of tumorigenesis. Genes Cancer. 2011;2:466–474. doi: 10.1177/1947601911408889.
    1. Aggarwal C., Davis C.W., Mick R., Thompson J.C., Ahmed S., Jeffries S., Bagley S., Gabriel P., Evans T.L., Bauml J.M., et al. Influence of tp53 mutation on survival in patients with advanced EGFR-mutant non-small-cell lung cancer. JCO Precis. Oncol. 2018;2018 doi: 10.1200/PO.18.00107.
    1. Lu H.Y., Qin J., Han N., Lei L., Xie F., Li C. EGFR, KRAS, BRAF, PTEN, and PIK3CA mutation in plasma of small cell lung cancer patients. OncoTargets Ther. 2018;11:2217–2226. doi: 10.2147/OTT.S159612.
    1. Seki Y., Fujiwara Y., Kohno T., Yoshida K., Goto Y., Horinouchi H., Kanda S., Nokihara H., Yamamoto N., Kuwano K., et al. Circulating cell-free plasma tumour DNA shows a higher incidence of EGFR mutations in patients with extrathoracic disease progression. ESMO Open. 2018;3:e000292. doi: 10.1136/esmoopen-2017-000292.
    1. Hu Y., Ulrich B.C., Supplee J., Kuang Y., Lizotte P.H., Feeney N.B., Guibert N.M., Awad M.M., Wong K.K., Jänne P.A., et al. False-positive plasma genotyping due to clonal hematopoiesis. Clin. Cancer Res. 2018;24:4437–4443. doi: 10.1158/1078-0432.CCR-18-0143.
    1. Rolfo C., Cardona A.F., Cristofanilli M., Paz-Ares L., Diaz Mochon J.J., Duran I., Raez L.E., Russo A., Lorente J.A., Malapelle U., et al. Challenges and opportunities of cfdna analysis implementation in clinical practice: Perspective of the international society of liquid biopsy (ISLB) Crit. Rev. Oncol. Hematol. 2020;151:102978. doi: 10.1016/j.critrevonc.2020.102978.
    1. Steendam C.M.J., Atmodimedjo P., De Jonge E., Paats M.S., Van der Leest C., Oomen-de Hoop E., Jansen M.P.H.M., Del Re M., Von der Thüsen J.H., Dinjens W.N.M., et al. Plasma cell-free DNA testing of patients with EGFR mutant non–small-cell lung cancer: Droplet digital PCR versus next-generation sequencing compared with tissue-based results. JCO Precis. Oncol. 2019;3:1–9. doi: 10.1200/PO.18.00401.
    1. Pruis M.A., Geurts-Giele W.R.R., von der T.J.H., Meijssen I.C., Dinjens W.N.M., Aerts J., Dingemans A.M.C., Lolkema M.P., Paats M.S., Dubbink H.J. Highly accurate DNA-based detection and treatment results of met exon 14 skipping mutations in lung cancer. Lung Cancer. 2020;140:46–54. doi: 10.1016/j.lungcan.2019.11.010.
    1. Veerman G.D.M., Lam M.H., Mathijssen R.H.J., Koolen S.L.W., de Bruijn P. Quantification of afatinib, alectinib, crizotinib and osimertinib in human plasma by liquid chromatography/triple-quadrupole mass spectrometry; focusing on the stability of osimertinib. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2019;1113:37–44. doi: 10.1016/j.jchromb.2019.03.011.
    1. Braal C.L., Veerman G.D.M., Peric R., Aerts J., Mathijssen R.H.J., Koolen S.L.W., de Bruijn P. Quantification of the tyrosine kinase inhibitor erlotinib in human scalp hair by liquid chromatography-tandem mass spectrometry: Pitfalls for clinical application. J. Pharm. Biomed. Anal. 2019;172:175–182. doi: 10.1016/j.jpba.2019.04.031.
    1. Veerman G.D.M., Hussaarts K., Peric R., Oomen-de Hoop E., Landa K.D., van der Leest C.H., Broerse S.D., Rutten H.B., Belderbos H.N.A., Steendam C.M.J., et al. Influence of cow’s milk and esomeprazole on the absorption of erlotinib: A randomized, crossover pharmacokinetic study in lung cancer patients. Clin. Pharmacokinet. 2020 doi: 10.1007/s40262-020-00910-1. Epub ahead of print.
    1. National Institute of Health Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE) [(accessed on 1 December 2019)]; Available online: .

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner