Phase I/II trial of Durvalumab plus Tremelimumab and stereotactic body radiotherapy for metastatic head and neck carcinoma

Houda Bahig, Francine Aubin, John Stagg, Olguta Gologan, Olivier Ballivy, Eric Bissada, Felix-Phuc Nguyen-Tan, Denis Soulières, Louis Guertin, Edith Filion, Apostolos Christopoulos, Louise Lambert, Mustapha Tehfe, Tareck Ayad, Danielle Charpentier, Rahima Jamal, Philip Wong, Houda Bahig, Francine Aubin, John Stagg, Olguta Gologan, Olivier Ballivy, Eric Bissada, Felix-Phuc Nguyen-Tan, Denis Soulières, Louis Guertin, Edith Filion, Apostolos Christopoulos, Louise Lambert, Mustapha Tehfe, Tareck Ayad, Danielle Charpentier, Rahima Jamal, Philip Wong

Abstract

Background: The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic Body Radiotherapy (SBRT) aims at ablating metastatic lesions and may play a synergistic role with immunotherapy. The purpose of this study is to assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab and tremelimumab in combination with SBRT in metastatic HNSCC.

Method: This is a phase I/II single arm study that will include 35 patients with 2-10 extracranial metastatic lesions. Patients will receive durvalumab (1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75 mg IV Q4W for a total of 4 doses) until progression, unacceptable toxicity or patient withdrawal. SBRT to 2-5 metastases will be administered between cycles 2 and 3 of immunotherapy. The safety of the treatment combination will be evaluated through assessment of TTC-related toxicities, defined as grade 3-5 toxicities based on Common Terminology Criteria for Adverse Events (v 4.03), occurring within 6 weeks from SBRT start, and that are definitely, probably or possibly related to the combination of all treatments. We hypothesize that dual targeting of PD-L1 and CTLA-4 pathways combined with SBRT will lead to < 35% grade 3-5 acute toxicities related to TTC. Progression free survival (PFS) will be the primary endpoint of the phase II portion of this study and will be assessed with radiological exams every 8 weeks using the RECIST version 1.1 criteria.

Discussion: The combination of synergistic dual checkpoints inhibition along with ablative radiation may significantly potentiate the local and systemic disease control. This study constitutes the first clinical trial combining effects of SBRT with dual checkpoint blockade with durvalumab and tremelimumab in the treatment of metastatic HNSCC. If positive, this study would lead to a phase III trial testing this treatment combination against standard of care in metastatic HNSCC.

Trial registration: NCT03283605 . Registration date: September 14, 2017; version 1.

Keywords: Durvalumab; Head and neck cancer; Immunotherapy; Metastatic; SBRT; Tremelimumab.

Conflict of interest statement

Ethics approval and consent to participate

The proposed study has been approved by the Centre Hospitalier de l’Université de Montreal IRB.

Consent for publication

Not applicable.

Competing interests

None.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study schema. HNSCC = head and neck squamous cell carcinoma; SBRT = stereotactic body radiotherapy; PFS = Progression free survival; LC = local control; OS = overall survival
Fig. 2
Fig. 2
Durvalumab (MEDI4736) and tremelimumab administration schedule

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. doi: 10.3322/caac.21332.
    1. Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer. 1993;71(2):452–456. doi: 10.1002/1097-0142(19930115)71:2<452::AID-CNCR2820710228>;2-B.
    1. Ferlito A, Shaha AR, Silver CE, Rinaldo A, Mondin V. Incidence and sites of distant metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec. 2001;63(4):202–207. doi: 10.1159/000055740.
    1. Leon X, Quer M, Orus C, del Prado VM, Lopez M. Distant metastases in head and neck cancer patients who achieved loco-regional control. Head neck. 2000;22(7):680–686. doi: 10.1002/1097-0347(200010)22:7<680::AID-HED7>;2-J.
    1. Dragovic AF, Caudell JJ, Spencer SA, Carroll WR, Nabell LA, Bonner JA. Locoregional failure and the risk of distant metastasis after modern radiotherapy for head and neck cancer. Head Neck. 2013;35(3):381–387. doi: 10.1002/hed.22977.
    1. Seiwert TY, Cohen EE. State-of-the-art management of locally advanced head and neck cancer. Br J Cancer. 2005;92(8):1341–1348. doi: 10.1038/sj.bjc.6602510.
    1. Marur S, Forastiere AA. Head and neck squamous cell carcinoma: update on epidemiology, diagnosis, and treatment. Mayo Clin Proc. 2016;91(3):386–396. doi: 10.1016/j.mayocp.2015.12.017.
    1. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27.
    1. Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, Forastiere AA. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the eastern cooperative oncology group. J Clin Oncol. 2005;23(15):3562–3567. doi: 10.1200/JCO.2005.01.057.
    1. Denaro N, Russi EG, Adamo V, Merlano MC. State-of-the-art and emerging treatment options in the management of head and neck cancer: news from 2013. Oncology. 2014;86(4):212–229. doi: 10.1159/000357712.
    1. Reyes DK, Pienta KJ. The biology and treatment of oligometastatic cancer. Oncotarget. 2015;6(11):8491–8524. doi: 10.18632/oncotarget.3455.
    1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13(1):8–10. doi: 10.1200/JCO.1995.13.1.8.
    1. Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011;8(6):378–382. doi: 10.1038/nrclinonc.2011.44.
    1. Gomez DR, Blumenschein GR, Jr, Lee JJ, Hernandez M, Ye R, Camidge DR, Doebele RC, Skoulidis F, Gaspar LE, Gibbons DL, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17(12):1672–1682. doi: 10.1016/S1470-2045(16)30532-0.
    1. Young ER, Diakos E, Khalid-Raja M, Mehanna H. Resection of subsequent pulmonary metastases from treated head and neck squamous cell carcinoma: systematic review and meta-analysis. Clin Otolaryngol. 2015;40(3):208–218. doi: 10.1111/coa.12348.
    1. Sahgal A, Roberge D, Schellenberg D, Purdie TG, Swaminath A, Pantarotto J, Filion E, Gabos Z, Butler J, Letourneau D, et al. The Canadian Association of Radiation Oncology scope of practice guidelines for lung, liver and spine stereotactic body radiotherapy. Clin Oncol. 2012;24(9):629–639. doi: 10.1016/j.clon.2012.04.006.
    1. Lo SS, Fakiris AJ, Chang EL, Mayr NA, Wang JZ, Papiez L, Teh BS, McGarry RC, Cardenes HR, Timmerman RD. Stereotactic body radiation therapy: a novel treatment modality. Nat Rev Clin Oncol. 2010;7(1):44–54. doi: 10.1038/nrclinonc.2009.188.
    1. Cihan YB. Stereotactic body radiation therapy for treatment of spinal bone metastasis. Asian Pac J Cancer Prev. 2016;17(3):937–938. doi: 10.7314/APJCP.2016.17.3.937.
    1. Nyman J, Johansson KA, Hulten U. Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancer--mature results for medically inoperable patients. Lung Cancer. 2006;51(1):97–103. doi: 10.1016/j.lungcan.2005.08.011.
    1. Onishi H, Kuriyama K, Komiyama T, Tanaka S, Sano N, Marino K, Ikenaga S, Araki T, Uematsu M. Clinical outcomes of stereotactic radiotherapy for stage I non-small cell lung cancer using a novel irradiation technique: patient self-controlled breath-hold and beam switching using a combination of linear accelerator and CT scanner. Lung Cancer. 2004;45(1):45–55. doi: 10.1016/j.lungcan.2004.01.004.
    1. Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, Gomi K, Niibe Y, Karasawa K, Hayakawa K, Takai Y, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac. 2007;2(7 Suppl 3):S94–100. doi: 10.1097/JTO.0b013e318074de34.
    1. Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, Gomi K, Karasawa K, Hayakawa K, Niibe Y, Takai Y, et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery? Int J Radiat Oncol Biol Phys. 2011;81(5):1352–1358. doi: 10.1016/j.ijrobp.2009.07.1751.
    1. Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, Freeman GJ, Ferris RL. Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFNgamma that induce PD-L1 expression in head and neck Cancer. Cancer Res. 2016;76(5):1031–1043. doi: 10.1158/0008-5472.CAN-15-2001.
    1. Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, Levionnois E, Nizard M, Si-Mohamed A, Besnier N, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73(1):128–138. doi: 10.1158/0008-5472.CAN-12-2606.
    1. Ferris RL, Blumenschein G, Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–1867. doi: 10.1056/NEJMoa1602252.
    1. Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956–965. doi: 10.1016/S1470-2045(16)30066-3.
    1. Chow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, Berger R, Eder JP, Burtness B, Lee SH, et al. Antitumor activity of Pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016.
    1. Ezra Cohen DS, Le Tourneau C, Dinis J, Licitra L, Ahn M-J, Soria A, Machiels J-P, Mach N, Mehra R, Burtness B, Zhang P, Cheng J, Swaby R, Harrington KJ. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet Oncol. 2018.
    1. Segal NH, Ou SHI, Balmanoukian AS, Massarelli E, Brahmer JR, Weiss J, Schoffski P, Antonia SJ, Massard C, Zandberg DP, et al. Updated safety and efficacy of durvalumab (MEDI4736), an anti-PD-L 1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. Ann Oncol. 2016;27(suppl_6):949O.
    1. Kvistborg P, Philips D, Kelderman S, Hageman L, Ottensmeier C, Joseph-Pietras D, Welters MJ, van der Burg S, Kapiteijn E, Michielin O, et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci Transl Med. 2014;6(254):254ra128. doi: 10.1126/scitranslmed.3008918.
    1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. doi: 10.1038/nrc3239.
    1. Carbognin L, Pilotto S, Milella M, Vaccaro V, Brunelli M, Calio A, Cuppone F, Sperduti I, Giannarelli D, Chilosi M, et al. Differential activity of Nivolumab, Pembrolizumab and MPDL3280A according to the tumor expression of programmed death-Ligand-1 (PD-L1): sensitivity analysis of trials in melanoma Lung and Genitourinary Cancers. PloS one. 2015;10(6):e0130142. doi: 10.1371/journal.pone.0130142.
    1. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(13):1270–1271. doi: 10.1056/NEJMc1509660.
    1. Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, Narwal R, Steele K, Gu Y, Karakunnel JJ, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299–308. doi: 10.1016/S1470-2045(15)00544-6.
    1. Jill Gilbert CLT, Mehanna H, Fayette J, Goswami T, Emeribe U, JarkowskiIII A, Melillo G, Siu LL. Phase II, randomized, open-label study of durvalumab (MEDI4736) or tremelimumab monotherapy, or durvalumab + tremelimumab, in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CONDOR. Journal for Immuno Therapy of Cancer. 2015;3(Suppl 2):P152. doi: 10.1186/2051-1426-3-S2-P152.
    1. Robert L, Ferris CE, Haddad R, Tahara M, Goswami T, Franks A, Emeribe U, JarkowskiIII A, Melillo G, Licitra L. The phase III EAGLE study (NCT02369874) will investigate the efficacy and safety of durvalumab as monotherapy or in combination with tremelimumab versus SoC. Journal for Immuno Therapy of Cancer. 2015;3(Suppl 2):P150. doi: 10.1186/2051-1426-3-S2-P150.
    1. Demaria S, Bhardwaj N, McBride WH, Formenti SC. Combining radiotherapy and immunotherapy: a revived partnership. Int J Radiat Oncol Biol Phys. 2005;63(3):655–666. doi: 10.1016/j.ijrobp.2005.06.032.
    1. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373–377. doi: 10.1038/nature14292.
    1. Wu CY, Yang LH, Yang HY, Knoff J, Peng S, Lin YH, Wang C, Alvarez RD, Pai SI, Roden RB, et al. Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors. Clin Cancer Res. 2014;20(3):644–657. doi: 10.1158/1078-0432.CCR-13-1334.
    1. Park B, Yee C, Lee KM. The effect of radiation on the immune response to cancers. Int J Mol Sci. 2014;15(1):927–943. doi: 10.3390/ijms15010927.
    1. Tang C, Wang X, Soh H, Seyedin S, Cortez MA, Krishnan S, Massarelli E, Hong D, Naing A, Diab A, et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2(9):831–838. doi: 10.1158/2326-6066.CIR-14-0069.
    1. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687–695. doi: 10.1172/JCI67313.
    1. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925–931. doi: 10.1056/NEJMoa1112824.
    1. Sharabi AB, Nirschl CJ, Kochel CM, Nirschl TR, Francica BJ, Velarde E, Deweese TL, Drake CG. Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol Res. 2015;3(4):345–355. doi: 10.1158/2326-6066.CIR-14-0196.
    1. Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E, Lhuillier C,Vanpouille-Box C, Friedman K, Ferrari de Andrade L, Wucherpfennig KW, Heguy A,Imai N, Gnjatic S, Emerson RO, Zhou XK, Zhang T, Chachoua A, Demaria S. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med. 2018;24(12):1845–51.
    1. Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, Formenti SC. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11(2 Pt 1):728–734.
    1. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379–5388. doi: 10.1158/1078-0432.CCR-09-0265.
    1. Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114(3):589–595. doi: 10.1182/blood-2009-02-206870.
    1. Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 2005;174(12):7516–7523. doi: 10.4049/jimmunol.174.12.7516.
    1. Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology. 2014;3:e28518. doi: 10.4161/onci.28518.
    1. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1(6):365–372. doi: 10.1158/2326-6066.CIR-13-0115.
    1. Lock M, Muinuddin A, Kocha WI, Dinniwell R, Rodrigues G, D'Souza D. Abscopal effects: case report and emerging opportunities. Cureus. 2015;7(10):e344.
    1. Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, Formenti SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer. 2018;18(5):313–22.
    1. Siu LL, Even C, Mesia R, Remenar E, Daste A, Delord JP, Krauss J, Saba NF, Nabell L, Ready NE, et al. Safety and efficacy of Durvalumab with or without Tremelimumab in patients with PD-L1-low/negative recurrent or metastatic HNSCC: the phase 2 CONDOR randomized clinical trial. JAMA oncology. 2018.
    1. Berber B, Ibarra R, Snyder L, Yao M, Fabien J, Milano MT, Katz AW, Goodman K, Stephans K, El-Gazzaz G, et al. Multicentre results of stereotactic body radiotherapy for secondary liver tumours. HPB. 2013;15(11):851–857. doi: 10.1111/hpb.12044.
    1. Wang XS, Rhines LD, Shiu AS, Yang JN, Selek U, Gning I, Liu P, Allen PK, Azeem SS, Brown PD, et al. Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1-2 trial. Lancet Oncol. 2012;13(4):395–402. doi: 10.1016/S1470-2045(11)70384-9.
    1. Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008;70(3):685–692. doi: 10.1016/j.ijrobp.2007.10.053.
    1. Zhao J, Yorke ED, Li L, Kavanagh BD, Li XA, Das S, Miften M, Rimner A, Campbell J, Xue J, et al. Simple factors associated with radiation-induced lung toxicity after stereotactic body radiation therapy of the thorax: a pooled analysis of 88 studies. Int J Radiat Oncol Biol Phys. 2016;95(5):1357–1366. doi: 10.1016/j.ijrobp.2016.03.024.
    1. Filatenkov A, Baker J, Mueller AM, Kenkel J, Ahn GO, Dutt S, Zhang N, Kohrt H, Jensen K, Dejbakhsh-Jones S, et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clinical cancer. 2015;21(16):3727–3739. doi: 10.1158/1078-0432.CCR-14-2824.
    1. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, Adamow M, Kuk D, Panageas KS, Carrera C, Wong P, Quagliarello F, Wubbenhorst B, D'Andrea K, Pauken KE, Herati RS, Staupe RP, Schenkel JM, McGettigan S, Kothari S, George SM, Vonderheide RH, Amaravadi RK, Karakousis GC, Schuchter LM, Xu X, Nathanson KL, Wolchok JD, Gangadhar TC, Wherry EJ. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545(7652):60–65.

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