RADIANCE - Radiochemotherapy with or without Durvalumab in the treatment of anal squamous cell carcinoma: A randomized multicenter phase II trial

Daniel Martin; Panagiotis Balermpas; Johannes Gollrad; Christian Weiß; Chiara Valentini; Martin Stuschke; Henning Schäfer; Christoph Henckenberens; Jürgen Debus; David Krug; Thomas Kuhnt; Thomas Brunner; Tilman Bostel; Rita Engenhart-Cabillic; Ursula Nestle; Stephanie Combs; Claus Belka; Matthias Hautmann; Guido Hildebrandt; Cihan Gani; Bülent Polat; Claus Rödel; Emmanouil Fokas

doi:10.1016/j.ctro.2020.04.010

RADIANCE - Radiochemotherapy with or without Durvalumab in the treatment of anal squamous cell carcinoma: A randomized multicenter phase II trial

Clin Transl Radiat Oncol. 2020 May 1:23:43-49. doi: 10.1016/j.ctro.2020.04.010. eCollection 2020 Jul.

Authors

Daniel Martin^{1

2

3

4}, Panagiotis Balermpas⁵, Johannes Gollrad⁶, Christian Weiß⁷, Chiara Valentini⁸, Martin Stuschke⁹, Henning Schäfer¹⁰, Christoph Henckenberens¹¹, Jürgen Debus¹², David Krug¹³, Thomas Kuhnt¹⁴, Thomas Brunner¹⁵, Tilman Bostel¹⁶, Rita Engenhart-Cabillic¹⁷, Ursula Nestle¹⁸, Stephanie Combs¹⁹, Claus Belka²⁰, Matthias Hautmann²¹, Guido Hildebrandt²², Cihan Gani²³, Bülent Polat²⁴, Claus Rödel^{1

2

3

4}, Emmanouil Fokas^{1

2

3

4}

Affiliations

¹ Department of Radiotherapy and Oncology, University of Frankfurt, Germany.
² Frankfurt Cancer Institute (FCI), Frankfurt, Germany.
³ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ German Cancer Consortium (DKTK), partner site, Frankfurt a. M., Germany.
⁵ Department of Radiation Oncology, University Hospital Zürich, Switzerland.
⁶ Department of Radiotherapy and Oncology, Charité University Hospital Berlin, Germany.
⁷ Department of Radiotherapy and Oncology, Community Hospital Darmstadt, Germany.
⁸ Department of Radiotherapy and Oncology, University Hospital Dresden, Germany.
⁹ Department of Radiotherapy, University Hospital Essen, Germany.
¹⁰ Department of Radiotherapy, University Hospital Freiburg, Germany.
¹¹ Department of Radiotherapy, University Hospital Hannover, Germany.
¹² Department of Radiology and Radiotherapy, University Hospital Heidelberg, Germany.
¹³ Department of Radiotherapy, University Hospital Schleswig Holstein, Kiel, Germany.
¹⁴ Department of Radiotherapy, University Hospital Leipzig, Germany.
¹⁵ Department of Radiotherapy, University Hospital Magdeburg, Germany.
¹⁶ Department of Radiation Oncology, University Hospital Mainz, Germany.
¹⁷ Department of Radiotherapy Radiation Oncology, University Hospital Marburg, Germany.
¹⁸ Department of Radiation Oncology, Hospital Maria Hilf, Mönchengladbach, Germany.
¹⁹ Department of Radiation Oncology, Technical University of Munich (TUM), Germany.
²⁰ Department of Radiation Oncology, University Hospital LMU Munich, Germany.
²¹ Department of Radiotherapy,University Hospital Regensburg, Germany.
²² Department of Radiotherapy,University Hospital Rostock, Germany.
²³ Department of Radiation Oncology,University Hospital Tübingen, Germany.
²⁴ Department of Radiation Oncology, University of Würzburg, Germany.

Abstract

Purpose: Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. The 3-year disease-free survival (DFS) in patients with locally-advanced disease is approximately 60% after primary radiochemotherapy (RCT). There is a strong rationale for combining immunotherapy with RCT in patients with ASCC due to its association with human papilloma virus (HPV) infection.

Methods/design: RADIANCE is an investigator initiated, prospective, multicenter, randomized phase II trial testing the addition of Durvalumab, a PD-L1 immune checkpoint inhibitor, to standard RCT in 178 patients with locally advanced ASCC (T2 ≥ 4 cm Nany, cT3-4 and/or cN+). In the control arm, patients will be treated with standard mitomycin C (MMC)/5-fluorouracil (5-FU)-based RCT. Intensity-modulated radiotherapy (IMRT) will be applied as follows: PTV_A (primary tumor) T1-T2 < 4 cm N+: 28 × 1.9 Gy = 53.2 Gy; or T2 ≥ 4 cm, T3-4 Nany: 31 × 1.9 Gy = 58.9 Gy; PTV_N (involved node): 28 × 1.8 Gy = 50.4 Gy ; and PTV_Elec (elective node): 28 × 1.43 Gy = 40.0 Gy over a period of 5,5-6 weeks. Concomitant chemotherapy will be administered using MMC with 5-FU during weeks 1 and 5 of radiotherapy (MMC 12 mg/m², day 1 [maximum single dose 20 mg]; 5-FU 1000 mg/m² days 1-4 and 29-32). In the experimental arm, Durvalmab (1500 mg absolute dose, intravenously) will be combined with the same RCT as in the control arm. Immunotherapy with Durvalumab will start 14 days before initiation of standard RCT, administered every four weeks (q4w) thereafter for a total of twelve doses. The primary endpoint is disease-free survival (DFS) after 3 years.

Discussion: As ASCC is considered an immunogenically "hot" tumor due to its association with HPV infection, the combination of RCT with Durvalumab may improve tumor control and long-term clinical outcome in this patient collective compared to RCT alone.

Keywords: 5-FU, 5-fluorouracil; ASCC, anal squamous cell carcinoma; Anal cancer; CT, computed tomography; DFS, disease-free survival; Disease-free survival; Durvalumab; Immunotherapy; MMC, mitomycin C; MRI, magnetic resonance imaging; OS, overall survival; PD-1, programmed death receptor 1; PD-L1, programmed death receptor ligand 1; Phase 2; RCT, radiochemotherapy; RT, radiotherapy; Radiochemotherapy; cCR, clinical complete response.