Early [18]FDG PET/CT scan predicts tumor response in head and neck squamous cell cancer patients treated with erlotinib adjusted per smoking status

Mercedes Porosnicu, Anderson O'Brien Cox, Joshua D Waltonen, Paul M Bunch, Ralph D'Agostino, Thomas W Lycan, Richard Taylor, Dan W Williams 3rd, Xiaofei Chen, Kirtikar Shukla, Brian E Kouri, Tiffany Walker, Gregory Kucera, Hafiz S Patwa, Christopher A Sullivan, J Dale Browne, Cristina M Furdui, Mercedes Porosnicu, Anderson O'Brien Cox, Joshua D Waltonen, Paul M Bunch, Ralph D'Agostino, Thomas W Lycan, Richard Taylor, Dan W Williams 3rd, Xiaofei Chen, Kirtikar Shukla, Brian E Kouri, Tiffany Walker, Gregory Kucera, Hafiz S Patwa, Christopher A Sullivan, J Dale Browne, Cristina M Furdui

Abstract

Translational relevance: Evaluation of targeted therapies is urgently needed for the majority of patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) who progress after immunochemotherapy. Erlotinib, a targeted inhibitor of epidermal growth factor receptor pathway, lacks FDA approval in HNSCC due to inadequate tumor response. This study identifies two potential avenues to improve tumor response to erlotinib among patients with HNSCC. For the first time, this study shows that an increased erlotinib dose of 300 mg in smokers is well-tolerated and produces similar plasma drug concentration as the regular dose of 150 mg in non-smokers, with increased study-specific defined tumor response. The study also highlights the opportunity for improved patient selection for erlotinib treatment by demonstrating that early in-treatment [18]FDG PET/CT is a potential predictor of tumor response, with robust statistical correlations between metabolic changes on early in-treatment PET (4-7 days through treatment) and anatomic response measured by end-of-treatment CT.

Purpose: Patients with advanced HNSCC failing immunochemotherapy have no standard treatment options. Accelerating the investigation of targeted drug therapies is imperative. Treatment with erlotinib produced low response rates in HNSCC. This study investigates the possibility of improved treatment response through patient smoking status-based erlotinib dose optimization, and through early in-treatment [18]FDG PET evaluation to differentiate responders from non-responders.

Experimental design: In this window-of-opportunity study, patients with operable HNSCC received neoadjuvant erlotinib with dose determined by smoking status: 150 mg (E150) for non-smokers and 300 mg (E300) for active smokers. Plasma erlotinib levels were measured using mass spectrometry. Patients underwent PET/CT before treatment, between days 4-7 of treatment, and before surgery (post-treatment). Response was measured by diagnostic CT and was defined as decrease in maximum tumor diameter by ≥ 20% (responders), 10-19% (minimum-responders), and < 10% (non-responders).

Results: Nineteen patients completed treatment, ten of whom were smokers. There were eleven responders, five minimum-responders, and three non-responders. Tumor response and plasma erlotinib levels were similar between the E150 and E300 patient groups. The percentage change on early PET/CT and post-treatment PET/CT compared to pre-treatment PET/CT were significantly correlated with the radiologic response on post-treatment CTs: R=0.63, p=0.0041 and R=0.71, p=0.00094, respectively.

Conclusion: This pilot study suggests that early in-treatment PET/CT can predict response to erlotinib, and treatment with erlotinib dose adjusted according to smoking status is well-tolerated and may improve treatment response in HNSCC. These findings could help optimize erlotinib treatment in HNSCC and should be further investigated.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT00601913, identifier NCT00601913.

Keywords: [18FDG] PET/CT; erlotinib; head and neck cancer; smokers; women in science.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Copyright © 2022 Porosnicu, O’Brien Cox, Waltonen, Bunch, D’Agostino, Lycan, Taylor, Williams, Chen, Shukla, Kouri, Walker, Kucera, Patwa, Sullivan, Browne and Furdui.

Figures

Figure 1
Figure 1
Percent tumor response by patient and dose (A) and by plasma erlotinib measured by LC/MS/MS analysis (B). N = 19; 10 patients received erlotinib at 300 mg PO daily (cyan in panel A and panel B) and 9 received erlotinib 150 mg PO daily (pink in panel A and panel B).
Figure 2
Figure 2
Correlation of percent change in tumor diameter with percent change in PET/CT SUV. (A) Contrast-enhanced neck CT and PET/CT images obtained in an 82 year-old female patient with OC T4N0M0, former smoker, treated with erlotinib dose of 150 mg. (B) Contrast-enhanced neck CT and PET/CT images obtained in a 55 year-old male patient with OC T2N2bM0, active smoker, treated with erlotinib dose of 300 mg. (C) - (F) Pearson correlation analysis of tumor diameter percent change with the percent change in SUV at early in-treatment PET/CT (C and E, 19 patients) and at post-treatment PET/CT (D and F, 18 patients). Panels (C) and (D) present the analysis across the smokers and non-smokers combined, while panels (E) and (F) show correlation analysis for each group. .

References

    1. Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G, et al. . Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet (2019) 394(10212):1915–28. doi: 10.1016/S0140-6736(19)32591-7
    1. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. . Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med (2006) 354(6):567–78. doi: 10.1056/NEJMoa053422
    1. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. . Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol (2010) 11(1):21–8. doi: 10.1016/S1470-2045(09)70311-0
    1. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. . Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med (2008) 359(11):1116–27. doi: 10.1056/NEJMoa0802656
    1. Administration USFD . Highlights of prescribing information (2010). Tarceva (erlotinib. Available at: (Accessed 3/13/18).
    1. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol Off J Am Soc Clin Oncol (2004) 22(1):77–85. doi: 10.1200/JCO.2004.06.075
    1. Cohen EE, Halpern AB, Kasza K, Kocherginsky M, Williams R, Vokes EE. Factors associated with clinical benefit from epidermal growth factor receptor inhibitors in recurrent and metastatic squamous cell carcinoma of the head and neck. Oral Oncol (2009) 45(10):e155–160. doi: 10.1016/j.oraloncology.2009.05.637
    1. Clark GM, Zborowski DM, Santabarbara P, Ding K, Whitehead M, Seymour L, et al. . Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the national cancer institute of Canada clinical trials group study BR.21. Clin Lung cancer. (2006) 7(6):389–94. doi: 10.3816/CLC.2006.n.022
    1. Sohn HS, Kwon JW, Shin S, Kim HS, Kim H. Effect of smoking status on progression-free and overall survival in non-small cell lung cancer patients receiving erlotinib or gefitinib: a meta-analysis. J Clin Pharm Ther (2015) 40(6):661–71. doi: 10.1111/jcpt.12332
    1. Lu JF, Eppler SM, Wolf J, Hamilton M, Rakhit A, Bruno R, et al. . 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(2):136–45. doi: 10.1016/j.clpt.2006.04.007
    1. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, et al. . Effects of smoking on the pharmacokinetics of erlotinib Clinical cancer research. an Off J Am Assoc Cancer Res (2006) 12:2166–71.
    1. Smit EF, Wu YL, Gervais R, Zhou C, Felip E, Feng J, et al. . A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS). Lung Cancer (Amsterdam Netherlands) (2016) 99:94–101. doi: 10.1016/j.lungcan.2016.06.019
    1. Li H, Wang S, Takayama K, Harada T, Okamoto I, Iwama E, et al. . Nicotine induces resistance to erlotinib via cross-talk between alpha 1 nAChR and EGFR in the non-small cell lung cancer xenograft model. Lung Cancer (Amsterdam Netherlands). (2015) 88(1):1–8.
    1. Tiseo M, Ippolito M, Scarlattei M, Spadaro P, Cosentino S, Latteri F, et al. . Predictive and prognostic value of early response assessment using 18FDG-PET in advanced non-small cell lung cancer patients treated with erlotinib. Cancer chemotherapy Pharmacol (2014) 73(2):299–307. doi: 10.1007/s00280-013-2356-x
    1. Stefano A, Russo G, Ippolito M, Cosentino S, Mure G, Baldari S, et al. . Evaluation of erlotinib treatment response in non-small cell lung cancer using metabolic and anatomic criteria. Q J Nucl Med Mol Imaging Off Publ Ital Assoc Nucl Med (AIMN) [and] Int Assoc Radiopharmacology (IAR) [and] Section So. (2016) 60(3):264–73.
    1. Vergez S, Delord JP, Thomas F, Rochaix P, Caselles O, Filleron T, et al. . Preclinical and clinical evidence that deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography is a reliable tool for the detection of early molecular responses to erlotinib in head and neck cancer. Clin Cancer Res an Off J Am Assoc Cancer Res (2010) 16(17):4434–45. doi: 10.1158/1078-0432.CCR-09-2795
    1. Bansal N, Mims J, Kuremsky JG, Olex AL, Zhao W, Yin L, et al. . Broad phenotypic changes associated with gain of radiation resistance in head and neck squamous cell cancer. Antioxid Redox Signal (2014) 21(2):221–36. doi: 10.1089/ars.2013.5690
    1. Mims J, Bansal N, Bharadwaj MS, Chen X, Molina AJ, Tsang AW, et al. . Energy metabolism in a matched model of radiation resistance for head and neck squamous cell cancer. Radiat Res (2015) 183(3):291–304. doi: 10.1667/RR13828.1
    1. Schmitz S, Caballero C, Locati LD. Perspectives on window of opportunity trials in head and neck cancer: lessons from the EORTC 90111-24111-NOCI-HNCG study. Eur J Cancer (Oxford Engl 1990). (2018) 104:219–23. doi: 10.1016/j.ejca.2018.07.315
    1. Schmitz S, Duhoux F, Machiels JP. Window of opportunity studies: Do they fulfil our expectations? Cancer Treat Rev (2016) 43:50–7. doi: 10.1016/j.ctrv.2015.12.005
    1. Thomas F, Rochaix P, Benlyazid A, Sarini J, Rives M, Lefebvre JL, et al. . Pilot study of neoadjuvant treatment with erlotinib in nonmetastatic head and neck squamous cell carcinoma. Clin Cancer Res an Off J Am Assoc Cancer Res (2007) 13(23):7086–92. doi: 10.1158/1078-0432.CCR-07-1370
    1. Thomas F, Rochaix P, White-Koning M, Hennebelle I, Sarini J, Benlyazid A, et al. . Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma. Eur J Cancer (Oxford Engl 1990). (2009) 45(13):2316–23. doi: 10.1016/j.ejca.2009.05.007
    1. Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et al. . Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations European Organization for research and treatment of cancer (EORTC) PET study group. Eur J Cancer (Oxford Engl 1990). (1999) 35(13):1773–82. doi: 10.1016/S0959-8049(99)00229-4
    1. Svedberg A, Green H, Vikstrom A, Lundeberg J, Vikingsson S. A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma. J Pharm BioMed Anal (2015) 107:186–95. doi: 10.1016/j.jpba.2014.12.022
    1. Team RC . R: A language and environment for statistical computing. (Vienna, Austria: R foundation for statistical computing; ) (2020).
    1. Wicklam H. ggplot2: Elegant graphics for data analysis. (Berlin/Heidelberg, Germany: Springer-Verlag; ) (2016).
    1. Ferris RL, Kim S, Trivedi S, Srivastava RM, Concha-Benavente F, Heron DE, et al. . Correlation of anti-tumor adaptive immunity with clinical response in a phase II “Window” trial of neoadjuvant cetuximab in patients with resectable stage III-IV head and neck squamous carcinoma (HNSCC). J Clin Oncol (2016) 34(15_suppl):6060–0. doi: 10.1200/JCO.2016.34.15_suppl.6060
    1. Gross ND, Bauman JE, Gooding WE, Denq W, Thomas SM, Wang L, et al. . Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer. Clin Cancer Res an Off J Am Assoc Cancer Res (2014) 20(12):3289–98. doi: 10.1158/1078-0432.CCR-13-3360
    1. William W, Weber R, Lee J, Myers J, Ginsberg L, El-Naggar A, et al. . Randomized trial of a short course of erlotinib 150 to 300 mg daily prior to surgery for squamous cell carcinomas of the head and neck (SCCHN) in current, former, and never smokers: Objective responses and clinical outcomes. J Clin Oncol (2011) 29 (15_suppl), 5520-20.
    1. Day TA, Shirai K, O'Brien PE, Matheus MG, Godwin K, Sood AJ, et al. . Inhibition of mTOR signaling and clinical activity of rapamycin in head and neck cancer in a window of opportunity trial. Clin Cancer Res an Off J Am Assoc Cancer Res (2019) 25(4):1156–64. doi: 10.1158/1078-0432.CCR-18-2024
    1. Schmitz S, Hamoir M, Reychler H, Magremanne M, Weynand B, Lhommel R, et al. . Tumour response and safety of cetuximab in a window pre-operative study in patients with squamous cell carcinoma of the head and neck. Ann Oncol (2013) 24(9):2261–6. doi: 10.1093/annonc/mdt180
    1. Benz MR, Herrmann K, Walter F, Garon EB, Reckamp KL, Figlin R, et al. . (18)F-FDG PET/CT for monitoring treatment responses to the epidermal growth factor receptor inhibitor erlotinib. J Nucl Med (2011) 52(11):1684–9. doi: 10.2967/jnumed.111.095257
    1. Machiels JP, Bossi P, Menis J, Lia M, Fortpied C, Liu Y, et al. . Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN). Ann Oncol (2018) 29(4):985–91. doi: 10.1093/annonc/mdy013
    1. Uppaluri R, Winkler AE, Lin T, Law JH, Haughey BH, Nussenbaum B, et al. . Biomarker and tumor responses of oral cavity squamous cell carcinoma to trametinib: A phase II neoadjuvant window-of-Opportunity clinical trial. Clin Cancer Res an Off J Am Assoc Cancer Res (2017) 23(9):2186–94. doi: 10.1158/1078-0432.CCR-16-1469

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir