A Study to Assess the Ability of Stereotactic Radiotherapy to Restore the Efficacy of Immunotherapy in Patients With Metastatic Cancer.

This study aims at enrolling patients with solid tumors at metastatic stage, considered long responders to immunotherapy (\> 6 months) and displaying disease progression. In this study, the investigator wants to evaluate specific modalities of stereotactic radiotherapy, with 3 sessions, each of 8 Gy, lasting 20 minutes and spaced 72 hours apart (Day 1, Day 4, Day 7). The radiotherapy device itself is not the subject of this study and will be used in accordance with its CE mark and indications. The objective of the study is to assess the ability of stereotactic radiotherapy to restore the lost efficacy of immunotherapy. In particular, the abscopal effect will be assessed, i.e. the action of irradiating a particular target lesion and observing an effect on other distant metastases.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. Male or female, 18 years of age or older,
2. Patient with a metastatic solid tumor,
3. Patient with at least one target lesion (for radiotherapy) together with other secondary lesions that must be measurable,
4. Measurable disease according to RECIST 1.1 and iRECIST criteria,
5. Patient undergoing anti-PD1 immunotherapy as part of standard of care treatment,
6. Disease progression with immunotherapy (progression assessed by iRECIST criteria) but having received at least 6 months of immunotherapy,
7. Performance Status (PS) of 0 or 1,
8. Patient eligible for stereotactic radiotherapy,
9. Patient affiliated to or benefiting from a social security scheme,
10. Patient having been informed of the investigation and having signed the informed consent form prior to any study-specific procedures,
11. Patient willing and able to undergo all examinations and procedures in accordance with the clinical investigation plan.

Exclusion Criteria:

1. Patient having received previous radiotherapy since the start of immunotherapy,
2. Patient for whom first disease progression (pre-inclusion stage) is not confirmed secondarily (inclusion stage),
3. Patient with an active implantable medical device (e.g. pacemaker) or an active medical device worn on the body that could interact adversely with stereotactic radiotherapy treatment,
4. Patient with hematological cancer,
5. Symptomatic patient requiring a rapid change of systemic line according to the investigator's judgment,
6. Concurrent participation in another clinical trial, or patient having received an investigational product within 30 days prior to inclusion,
7. Pregnant or breast-feeding women,
8. Patient under legal protection.

• RESULTBorghaei 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. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27. PMID 26412456
• RESULTDewan 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 Sep 1;15(17):5379-88. doi: 10.1158/1078-0432.CCR-09-0265. Epub 2009 Aug 25. PMID 19706802
• RESULTDoyen J, Besse B, Texier M, Bonnet N, Levy A. PD-1 iNhibitor and chemotherapy with concurrent IRradiation at VAried tumor sites in advanced Non-small cell lung cAncer: the Prospective Randomized Phase 3 NIRVANA-Lung Trial. Clin Lung Cancer. 2022 May;23(3):e252-e256. doi: 10.1016/j.cllc.2021.10.008. Epub 2021 Oct 24. PMID 34810130
• RESULTBrahmer 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. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31. PMID 26028407
• RESULTFunck-Brentano E, Baghad B, Fort M, Aouidad I, Roger A, Beauchet A, Otmezguine Y, Blom A, Longvert C, Boru B, Saiag P. Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy. Int J Cancer. 2020 Sep 15;147(6):1707-1714. doi: 10.1002/ijc.32934. Epub 2020 Feb 28. PMID 32083739
• Levy A, Khalifa J, Martin E, Botticella A, Quevrin C, Lavaud P, Aldea M, Besse B, Planchard D, Barlesi F, Deutsch E, Massabeau C, Doyen J, Le Pechoux C. Stereotactic body radiotherapy for extra-cranial oligoprogressive or oligorecurrent small-cell lung cancer. Clin Transl Radiat Oncol. 2023 May 3;41:100637. doi: 10.1016/j.ctro.2023.100637. eCollection 2023 Jul.