Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer

K Haslett, P Koh, A Hudson, W D Ryder, S Falk, D Mullan, B Taylor, R Califano, F Blackhall, C Faivre-Finn, K Haslett, P Koh, A Hudson, W D Ryder, S Falk, D Mullan, B Taylor, R Califano, F Blackhall, C Faivre-Finn

Abstract

Background: The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating treatment response. Selumetinib inhibits MEK and enhances effects of radiotherapy in preclinical studies.

Patients and methods: Single-arm, single-centre, open-label phase I trial. Patients with stage III NSCLC unsuitable for concurrent chemo-radiotherapy, or stage IV with dominant thoracic symptoms, were recruited to a dose-finding stage (Fibonacci 3 + 3 design; maximum number = 18) then an expanded cohort (n = 15). Oral selumetinib was administered twice daily (starting dose 50 mg) commencing 7 days prior to thoracic radiotherapy, then with radiotherapy (6-6.5 weeks; 60-66 Gy/30-33 fractions). The primary objective was to determine the recommended phase II dose (RP2D) of selumetinib in combination with thoracic radiotherapy.

Results: 21 patients were enrolled (06/2010-02/2015). Median age: 62y (range 50-73). M:F ratio 12(57%):9(43%). ECOG PS 0:1, 7(33%):14(67%). Stage III 16(76%); IV 5(24%). Median GTV 64 cm3 (range 1-224 cm3). 15 patients comprised the expanded cohort at starting dose. All 21 patients completed thoracic radiotherapy as planned and received induction chemotherapy. 13 (62%) patients received the full dose of selumetinib.In the starting cohort no enhanced radiotherapy-related toxicity was seen. Two patients had dose-limiting toxicity (1x grade 3 diarrhoea/fatigue and 1x pulmonary embolism). Commonest grade 3-4 adverse events: lymphopaenia (19/21 patients) and hypertension (7/21 patients). One patient developed grade 3 oesophagitis. No patients developed grade ≥3 radiation pneumonitis. Two patients were alive at the time of analysis (24 and 26 months follow-up, respectively). Main cause of first disease progression: distant metastases ± locoregional progression (12/21 [57.1%] patients). Six patients had confirmed/suspected pneumocystis jiroveci pneumonia.

Conclusion: We report poor outcome and severe lymphopenia in most patients treated with thoracic radiotherapy and selumetinib at RP2D in combination, contributing to confirmed/clinically suspected pneumocystis jiroveci pneumonia. These results suggest that this combination should not be pursued in a phase II trial.ClinicalTrials.gov reference: NCT01146756.

Keywords: Lung cancer; MEK inhibitor; NSCLC; Phase I; Selumetinib; Thoracic radiotherapy.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

© 2021 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.

Figures

Fig. 1
Fig. 1
A) Overall survival B) Progression-free survival.

References

    1. Bradley J.D. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187–199. doi: 10.1016/S1470-2045(14)71207-0.
    1. Bentzen S.M., Harari P.M., Bernier J. Exploitable mechanisms for combining drugs with radiation: concepts, achievements and future directions. Nat Rev Clin Oncol. 2007;4(3):172–180. doi: 10.1038/ncponc0744.
    1. Dai Y. Synergistic effects of crizotinib and radiotherapy in experimental EML4–ALK fusion positive lung cancer. Radiother Oncol. 2015;114(2):173–181. doi: 10.1016/j.radonc.2014.12.009.
    1. Chinnaiyan P. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by Erlotinib (Tarceva) Cancer Res. 2005;65(8):3328–3335. doi: 10.1158/0008-5472.CAN-04-3547.
    1. Das A.K. Non–small cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Res. 2006;66(19):9601–9608. doi: 10.1158/0008-5472.CAN-06-2627.
    1. Koh P.K., Faivre-Finn C., Blackhall F.H., De Ruysscher D. Targeted agents in non-small cell lung cancer (NSCLC): Clinical developments and rationale for the combination with thoracic radiotherapy. Cancer Treat Rev. 2012;38(6):626–640. doi: 10.1016/j.ctrv.2011.11.003.
    1. Simone C.B., 2nd, Burri S.H., Heinzerling J.H. Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies. Transl Lung Cancer Res. 2015;4(5):545–552. doi: 10.3978/j.issn.2218-6751.2015.10.05.
    1. Wan J. Unexpected high lung toxicity from radiation pneumonitis in a phase I/II trial of concurrent erlotinib with limited field radiation for intermediate prognosis patients with stage III or inoperable stage IIB non–small-cell lung cancer(NSCLC) Int J Radiat Oncol*Biol*Phys. 2009;75(3):S110. doi: 10.1016/j.ijrobp.2009.07.267.
    1. Bhardwaj B., Revannasiddaiah S., Bhardwaj H., Balusu S., Shwaiki A. Molecular targeted therapy to improve radiotherapeutic outcomes for non-small cell lung carcinoma. Ann Transl Med. 2016;4(3):50. doi: 10.3978/j.issn.2305-5839.2015.10.35.
    1. Chung E.J. In vitro and In vivo radiosensitization with AZD6244 (ARRY-142886), an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 kinase. Clin Cancer Res. 2009;15(9):3050–3057. doi: 10.1158/1078-0432.CCR-08-2954.
    1. Hayes D.N. Phase II efficacy and pharmacogenomic study of selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res. 2012;18(7):2056–2065. doi: 10.1158/1078-0432.CCR-11-0563.
    1. Eisenhauer E.A. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Green M.R. Endpoints for multimodal clinical trials in Stage III non-small cell lung cancer (NSCLC): a consensus report. Lung Cancer. 1994;11:S11–S13. doi: 10.1016/0169-5002(94)91859-7.
    1. Adizie J.B. Stage III non-small cell lung cancer management in England. Clin Oncol. 2019;31(10):688–696. doi: 10.1016/j.clon.2019.07.020.
    1. Harrow S., Hanna G.G., Faivre-Finn C., McDonald F., Chalmers A.J. The challenges faced in developing novel drug radiation combinations in non-small cell lung cancer. Clin Oncol. 2016;28(11):720–725. doi: 10.1016/j.clon.2016.08.004.
    1. Sharma R.A. Clinical development of new drug–radiotherapy combinations. Nat Rev Clin Oncol. 2016;13(10):627–642. doi: 10.1038/nrclinonc.2016.79.
    1. Hallqvist A. Concurrent cetuximab and radiotherapy after docetaxel–cisplatin induction chemotherapy in stage III NSCLC: Satellite—A phase II study from the Swedish Lung Cancer Study Group. Lung Cancer. 2011;71(2):166–172. doi: 10.1016/j.lungcan.2010.05.011.
    1. Blumenschein G.R., Jr. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non–small-cell lung cancer: RTOG 0324. J Clinc Oncol. 2011;29(17):2312–2318. doi: 10.1200/JCO.2010.31.7875.
    1. Ready N. Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thoracic Oncol. 2010;5(9):1382–1390. doi: 10.1097/JTO.0b013e3181eba657.
    1. Rothschild S., Bucher S.E., Bernier J., Aebersold D.M., Zouhair A., Ries G., Lombrieser N., Lippuner T., Lütolf U.M., Glanzmann C., Ciernik I.F. Gefitinib in combination with irradiation with or without cisplatin in patients with inoperable Stage III non–small cell lung cancer: a phase I trial. Int J Radiat Oncol*Biol*Phys. 2011;80(1):126–132. doi: 10.1016/j.ijrobp.2010.01.048.
    1. Zhao Y. A phase I/II study of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic radiation therapy for non–small-cell lung cancer: north central cancer treatment group (NCCTG)-N0321. J Thoracic Oncol. 2015;10(1):172–180. doi: 10.1097/JTO.0000000000000383.
    1. Sarkaria J.N. Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer. J Thoracic Oncol. 2007;2(8):751–757. doi: 10.1097/JTO.0b013e3180cc2587.
    1. Deutsch E. Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer. Ann Oncol. 2015;26(6):1223–1229. doi: 10.1093/annonc/mdv105.
    1. Iacovelli R., Palazzo A., Mezi S., Morano F., Naso G., Cortesi E. Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy. A meta-analysis of published trials. Acta Oncol. 2012;51(7):873–879. doi: 10.3109/0284186X.2012.705019.
    1. Bristow R.G. Combining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology. Lancet Oncol. 2018;19(5):e240–e251. doi: 10.1016/S1470-2045(18)30096-2.
    1. Sugiyama M. Evaluation of 3'-deoxy-3'-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice. J Nuclear Med. 2004;45(10):1754–1758.
    1. Ullrich R.T. Early detection of erlotinib treatment response in NSCLC by 3'-deoxy-3'-[F]-fluoro-L-thymidine ([F]FLT) positron emission tomography (PET) PLoS ONE. 2008;3(12) doi: 10.1371/journal.pone.0003908.
    1. Yeh T.C. Biological Characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007;13(5):1576–1583. doi: 10.1158/1078-0432.CCR-06-1150.
    1. Davies B.R. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo , pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther. 2007;6(8):2209–2219. doi: 10.1158/1535-7163.MCT-07-0231.
    1. Christodoulou M., McCloskey P., Stones N., Bayman N., Burt P., Chittalia A., Harris M., Lee L., Pemberton L., Sheikh H., Swindell R., Faivre-Finn C. Investigation of a Patient Reported Outcome tool to assess radiotherapy-related toxicity prospectively in patients with lung cancer. Radiother Oncol. 2014;112(2):244–249. doi: 10.1016/j.radonc.2014.07.008.
    1. Abravan A., Faivre-Finn C., Kennedy J., McWilliam A., van Herk M. Radiotherapy-related lymphopenia affects overall survival in patients with lung cancer. J Thoracic Oncol. 2020;15(10):1624–1635. doi: 10.1016/j.jtho.2020.06.008.
    1. Tang C., Liao Z., Gomez D., Levy L., Zhuang Y., Gebremichael R.A., Hong D.S., Komaki R., Welsh J.W. Lymphopenia association with gross tumor volume and lung v5 and its effects on non-small cell lung cancer patient outcomes. Int J Radiat Oncol*Biol*Phys. 2014;89(5):1084–1091. doi: 10.1016/j.ijrobp.2014.04.025.
    1. Diehl A., Yarchoan M., Hopkins A., Jaffee E., Grossman S.A. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget. 2017;8(69):114268–114280. doi: 10.18632/oncotarget.23217.
    1. Chen D., Patel R.R., Verma V., Ramapriyan R., Barsoumian H.B., Cortez M.A., Welsh J.W. Interaction between lymphopenia, radiotherapy technique, dosimetry, and survival outcomes in lung cancer patients receiving combined immunotherapy and radiotherapy. Radiother Oncol. 2020;150:114–120. doi: 10.1016/j.radonc.2020.05.051.
    1. Walls G.M. CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer. Clin Transl Radiat Oncol. 2020;25:61–66. doi: 10.1016/j.ctro.2020.09.006.

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