Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial)

Zhengyang Yang, Xiao Zhang, Jie Zhang, Jiale Gao, Zhigang Bai, Wei Deng, Guangyong Chen, Yongbo An, Yishan Liu, Qi Wei, Jiagang Han, Ang Li, Gang Liu, Yi Sun, Dalu Kong, Hongwei Yao, Zhongtao Zhang, Zhengyang Yang, Xiao Zhang, Jie Zhang, Jiale Gao, Zhigang Bai, Wei Deng, Guangyong Chen, Yongbo An, Yishan Liu, Qi Wei, Jiagang Han, Ang Li, Gang Liu, Yi Sun, Dalu Kong, Hongwei Yao, Zhongtao Zhang

Abstract

Background: Long course radiotherapy plus neoadjuvant chemotherapy followed by resection (total mesorectal excision, TME) has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1 humanized IgG4 monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. However, the safety and efficacy of long course (neoadjuvant chemoradiotherapy, NCRT) plus tislelizumab followed by TME for LARC is still uncertain.

Methods: This NCRT-PD1-LARC trial will be a prospective, multicenter and phase II clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course NCRT plus tislelizumab followed by TME. This trial will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 7 cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by TME 6-8 weeks after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes.

Discussion: To our knowledge, this trial is the first multicenter clinical trial in China to assess the safety and efficacy of NCRT plus anti-PD1 therapy followed by TME to treat patients with LARC. NCRT followed by TME was recognized as the most recommended treatment against LARC while could not be completely satisfied in clinic. This study expects to provide a solid basis and encouraging outcomes for this promising combination of radiotherapy, chemotherapy and immunotherapy in LARC.

Trial registration: Name of the registry: ClinicalTrials.gov.

Trial registration number: NCT04911517. Date of registration: 23 May 2021. URL of trial registry record: https://www.

Clinicaltrials: gov/ct2/show/NCT04911517?id=BFH-NCRTPD&draw=2&rank=1 .

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study flow chart. (LARC, locally advanced rectal cancer; MRI, magnetic resonance imaging.)
Fig. 2
Fig. 2
Therapeutic timelines and schedule. (PD1, programmed cell death 1; TME, total mesorectal excision.)
Fig. 3
Fig. 3
Calculation formula of the NAR score. (NAR, neoadjuvant rectal; pN, pathologic nodal stage; cT, clinical tumor stage; pT, pathologic tumor stage.)

References

    1. Sung JJY, Chiu H-M, Jung K-W, et al. Increasing Trend in Young-Onset Colorectal Cancer in Asia: More Cancers in Men and More Rectal Cancers. Am J Gastroenterol. 2019;114:322–329. doi: 10.14309/ajg.0000000000000133.
    1. Chen WZ, Chen XD, Ma LL, et al. Impact of Visceral Obesity and Sarcopenia on Short-Term Outcomes After Colorectal Cancer Surgery. Dig Dis Sci. 2018;63:1620–1630. doi: 10.1007/s10620-018-5019-2.
    1. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–132. doi: 10.3322/caac.21338.
    1. Lawler M, Alsina D, Adams RA, et al. Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer. Gut. 2018;67:179–193. doi: 10.1136/gutjnl-2017-315333.
    1. Katsidzira L, Gangaidzo I, Thomson S, et al. The shifting epidemiology of colorectal cancer in sub-Saharan Africa. Lancet Gastroenterol Hepatol. 2017;2:377–383. doi: 10.1016/S2468-1253(16)30183-2.
    1. Zhu J, Liu A, Sun X, et al. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. J Clin Oncol. 2020;38:4231–4239. doi: 10.1200/JCO.20.01932.
    1. Shen Z, Bu Z, Li A, et al. Multicenter study of surgical and oncologic outcomes of extra-levator versus conventional abdominoperineal excision for lower rectal cancer. Eur J Surg Oncol. 2020;46:115–122. doi: 10.1016/j.ejso.2019.08.017.
    1. Hata T, Takahashi H, Sakai D, et al. Neoadjuvant CapeOx therapy followed by sphincter-preserving surgery for lower rectal cancer. Surg Today. 2017;47:1372–1377. doi: 10.1007/s00595-017-1527-5.
    1. Yang Z, Chunhua G, Huayan Y, et al. Anatomical basis for the choice of laparoscopic surgery for low rectal cancer through the pelvic imaging data-a cohort study. World J Surg Oncol. 2018;16:199. doi: 10.1186/s12957-018-1498-z.
    1. Shamseddine A, Zeidan YH, El Husseini Z, et al. Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma. Radiat Oncol. 2020;15:233. doi: 10.1186/s13014-020-01673-6.
    1. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–1740. doi: 10.1056/NEJMoa040694.
    1. Provenzale D, Gupta S, Ahnen DJ, et al. Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;;4:1010–30. doi: 10.6004/jnccn.2016.0108.
    1. Willett CG. Management of Locoregional Rectal Cancer. J Natl Compr Canc Netw. 2018;16:617–619. doi: 10.6004/jnccn.2018.0037.
    1. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results–EORTC 22921. J Clin Oncol. 2005;23:5620–5627. doi: 10.1200/JCO.2005.02.113.
    1. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24:4620–4625. doi: 10.1200/JCO.2006.06.7629.
    1. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–1123. doi: 10.1056/NEJMoa060829.
    1. Wu F, Zhou C, Wu B, et al. Adding Adjuvants to Fluoropyrimidine-based Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: An Option Worthy of Serious Consideration. J Cancer. 2021;12:417–427. doi: 10.7150/jca.48337.
    1. Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019;16:361–375. doi: 10.1038/s41575-019-0126-x.
    1. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–2454. doi: 10.1056/NEJMoa1200690.
    1. Taieb J, Shi Q, Pederson L, et al. Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies. Ann Oncol. 2019;30:1466–1471. doi: 10.1093/annonc/mdz208.
    1. Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26:566–576. doi: 10.1038/s41591-020-0805-8.
    1. Dekker E, Tanis PJ, Vleugels JLA, et al. Colorectal cancer. Lancet. 2019;394:1467–1480. doi: 10.1016/S0140-6736(19)32319-0.
    1. Overman MJ, Lonardi S, Wong KYM, et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018;36:773–779. doi: 10.1200/JCO.2017.76.9901.
    1. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–1191. doi: 10.1016/S1470-2045(17)30422-9.
    1. Cao Y, Li W, Wang Z, et al. Potential and unsolved problems of anti-PD-1/PD-L1 therapy combined with radiotherapy. Tumori . 2020;107(4):282–291. doi: 10.1177/0300891620940382.
    1. Tang H, Liang Y, Anders RA, et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest. 2018;128:580–588. doi: 10.1172/JCI96061.
    1. Huang AC, Postow MA, Orlowski RJ, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545:60–65. doi: 10.1038/nature22079.
    1. Kong Y, Ma Y, Zhao X, et al. Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers. Front Oncol. 2021;11:638873. doi: 10.3389/fonc.2021.638873.
    1. von Moos R, Koeberle D, Schacher S, et al. Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08) Eur J Cancer. 2018;89:82–89. doi: 10.1016/j.ejca.2017.11.005.
    1. Imam I, Hammarstrom K, Sjoblom T, et al. Neoadjuvant rectal (NAR) score: Value evaluating the efficacy of neoadjuvant therapy and prognostic significance after surgery? Radiother Oncol. 2021;157:70–77. doi: 10.1016/j.radonc.2021.01.002.
    1. Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. J Clin Oncol. 2016;34:1510–7. doi: 10.1200/JCO.2015.64.0391.
    1. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95. doi: 10.1186/s40425-017-0300-z.
    1. Kim B-h, Kim JM, Kang GH, et al. Standardized Pathology Report for Colorectal Cancer, 2nd Edition. J Pathol Transl Med. 2020;54(1):1–19. doi: 10.4132/jptm.2019.09.28.
    1. Liu SY, Wu YL. Tislelizumab: an investigational anti-PD-1 antibody for the treatment of advanced non-small cell lung cancer (NSCLC) Expert Opin Investig Drugs. 2020;29:1355–1364. doi: 10.1080/13543784.2020.1833857.
    1. Zhang J, Cai J, Deng Y, et al. Complete response in patients with locally advanced rectal cancer after neoadjuvant treatment with nivolumab. Oncoimmunology. 2019;8:e1663108. doi: 10.1080/2162402X.2019.1663108.
    1. Li Q, Dong Y, Pan Y, et al. Case Report: Clinical Responses to Tislelizumab as a First-Line Therapy for Primary Hepatocellular Carcinoma With B-Cell Indolent Lymphoma. Front Immunol. 2021;12:634559. doi: 10.3389/fimmu.2021.634559.
    1. Wang J, Lu S, Yu X, et al. Tislelizumab Plus Chemotherapy vs Chemotherapy Alone as First-line Treatment for Advanced Squamous Non-Small-Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021;7:709–717. doi: 10.1001/jamaoncol.2021.0366.
    1. Ayez N, Alberda WJ, Burger JW, et al. Is restaging with chest and abdominal CT scan after neoadjuvant chemoradiotherapy for locally advanced rectal cancer necessary? Ann Surg Oncol. 2013;20:155–160. doi: 10.1245/s10434-012-2537-6.
    1. Raldow AC, Chen AB, Russell M, et al. Cost-effectiveness of Short-Course Radiation Therapy vs Long-Course Chemoradiation for Locally Advanced Rectal Cancer. JAMA Netw Open. 2019;2:e192249. doi: 10.1001/jamanetworkopen.2019.2249.
    1. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18:895–903. doi: 10.1016/S1470-2045(17)30380-7.
    1. Derer A, Frey B, Fietkau R, et al. Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. Cancer Immunol Immunother. 2016;65:779–786. doi: 10.1007/s00262-015-1771-8.
    1. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687–695. doi: 10.1172/JCI67313.
    1. Liu Y, Han G, Li H, et al. Camrelizumab combined with FOLFOX as neoadjuvant therapy for resectable locally advanced gastric and gastroesophageal junction adenocarcinoma. J Clin Oncol. 2020;38(15_suppl):4536–36.
    1. Lin ZY, Cai M, Zhang P, et al. Short-course radiotherapy and subsequent CAPOX plus camrelizumab followed by delayed surgery for locally advanced rectal cancer:Short-term results of a phase II trial. J Clin Oncol. 2021;39(3):63–63. doi: 10.1200/JCO.2021.39.3_suppl.63.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir