Advertisement

Novel Immunological Approaches in the Treatment of Locally Advanced Rectal Cancer

  • Author Footnotes
    # These authors contributed equally as first authors in this work.
    Hideaki Bando
    Correspondence
    Address for correspondence: Hideaki Bando, Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, JPN.
    Footnotes
    # These authors contributed equally as first authors in this work.
    Affiliations
    Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally as first authors in this work.
    Yuichiro Tsukada
    Footnotes
    # These authors contributed equally as first authors in this work.
    Affiliations
    Department of Colorectal Surgery, National Cancer Center Hospital East, Kashiwa, Japan
    Search for articles by this author
  • Masaaki Ito
    Affiliations
    Department of Colorectal Surgery, National Cancer Center Hospital East, Kashiwa, Japan
    Search for articles by this author
  • Takayuki Yoshino
    Affiliations
    Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally as first authors in this work.
Open AccessPublished:October 16, 2021DOI:https://doi.org/10.1016/j.clcc.2021.10.001

      Abstract

      Chemoradiotherapy (CRT) followed by radical surgery is one of the standard therapies for patients with locally advanced rectal cancer (LARC). Various combination therapies have been developed to improve the efficacy of preoperative therapies. One promising approach is the combination of ionizing radiation and immune checkpoint inhibitors (ICIs) because it enhances both local and distal immunogenic efficacy according to several xenograft models. To date, promising short-term efficacy results of 23% to 37.5% of the pathological complete response (pCR) rate have been reported in clinical trials investigating the combination of CRT and ICIs in patients with microsatellite stable (MSS) LARC. In patients with high-level microsatellite instability (MSI-H) LARC, CRT followed by ICI also achieved a 60% (3/5) pCR rate according to the data of the VOLTAGE study, suggesting increased efficacy of ICIs in this subgroup, albeit with a small sample size. In patients with MSS LARC, programmed cell death-ligand 1 tumor proportion score positivity, elevated CD8/effector regulatory T cell ratio, higher immune-score, consensus molecular subtype 1, and higher tumor mutational burden appear to be positive predictors of ICIs efficacy. In addition, various prospective studies combining CRT with ICI, chemotherapy, and target agents are currently being conducted. To confirm the survival benefits of these approaches, confirmatory phase III trials are needed.

      Keywords

      Abbreviations:

      CMS (consensus molecular subtype), CRC (colorectal cancer), CRT (chemoradiotherapy), CTLA-4 (T-lymphocyte-associated protein 4), DFS (disease-free survival), eTreg (effector regulatory T-cell), ICI (immune checkpoint inhibitor), IS (immune-score), LARC (locally advanced rectal cancer), MDSC (myeloid-derived suppressor cell), MSI-H (microsatellite instability-high), MSS (microsatellite stable), NAR score (neoadjuvant rectal score), OS (overall survival), pCR (pathological complete response), PD-1 (programmed cell death-1), PD-L1 (programmed cell death-ligand 1), PFS (progression-free survival), SSS (sphincter-sparing surgery), TGF-β (transforming growth factor-β), TMB (tumor mutational burden), TME (total mesorectal excision), TNT (total neoadjuvant therapy), TPS (tumor proportion score), Treg (regulatory T-cell), TRG (tumor regression grade)

      Introduction

      Standard and Emerging Treatment Strategies for Locally Advanced Rectal Cancer

      Colorectal cancer (CRC) was the third most common cancer in men and the second most common cancer in women worldwide in 2020.
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • et al.
      Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      For patients with locally advanced rectal cancer (LARC) of clinical stage II (T3-4 N0) or stage III (T1-4 N+), preoperative chemoradiotherapy (CRT) using fluoropyrimidine-based chemotherapy plus 50.4 Gy of radiotherapy, followed by total mesorectal excision (TME),
      • Heald R.J.
      • Husband E.M.
      • Ryall R.D.
      The mesorectum in rectal cancer surgery–the clue to pelvic recurrence?.
      ,
      • Lowry A.C.
      • Simmang C.L.
      • Boulos P.
      • et al.
      is one of the standard treatment.
      • Sauer R.
      • Becker H.
      • Hohenberger W.
      • et al.
      Preoperative versus postoperative chemoradiotherapy for rectal cancer.
      Oxaliplatin-based postoperative adjuvant chemotherapy is generally administered if postoperative conditions are favorable. According to previous randomized phase III trials, pathological complete response (pCR) rates of 10% to 15%, 3-year disease-free survival (DFS) rates of 60% to 70%, and overall survival (OS) rates of 70% to 80% have been reported in conventional CRT followed by radical surgery.
      • Bosset J.F.
      • Collette L.
      • Calais G.
      • et al.
      Chemotherapy with preoperative radiotherapy in rectal cancer.
      • Gerard J.P.
      • Conroy T.
      • Bonnetain F.
      • et al.
      Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203.
      • Hofheinz R.D.
      • Wenz F.
      • Post S.
      • et al.
      Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.
      For further improvements in treatment outcome, various new treatment approaches have been investigated.
      Although postoperative adjuvant chemotherapy is associated with the improvement of DFS, poor compliance has been observed.
      • Bosset J.F.
      • Collette L.
      • Calais G.
      • et al.
      Chemotherapy with preoperative radiotherapy in rectal cancer.
      ,
      • Hong Y.S.
      • Nam B.H.
      • Kim K.P.
      • et al.
      Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial.
      For patients with LARC who are at high risk of margin-positive resection, such as those with T4 disease, involved mesorectal fascia, or extramural venous invasion, or patients with clearly node-positive disease, the sequential combination of preoperative chemotherapy and CRT, referred to as total neoadjuvant therapy (TNT), has been a promising approach.
      • Garcia-Aguilar J.
      • Chow O.S.
      • Smith D.D.
      • et al.
      Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial.
      ,
      • Fokas E.
      • Allgauer M.
      • Polat B.
      • et al.
      Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12.
      TNT showed improved compliance with oxaliplatin-based chemotherapy compared to conventional therapy, suggesting improvement in both local and distant control.
      • Cercek A.
      • Roxburgh C.S.D.
      • Strombom P.
      • et al.
      Adoption of total neoadjuvant therapy for locally advanced rectal cancer.
      According to several randomized phase III studies, TNT resulted in significant improvements of pCR, disease-related treatment failure, and DFS compared to conventional CRT followed by TME, and it has become one of the standard approaches for patients with LARC.
      • Bahadoer R.R.
      • Dijkstra E.A.
      • van Etten B.
      • et al.
      Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.
      ,
      • Conroy T.
      • Bosset J.F.
      • Etienne P.L.
      • et al.
      Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.
      The favorable local control achieved with TNT also suggests the possibility of a higher percentage of cases of organ preservation with a minimal or nonsurgical approach.
      • Rullier E.
      • Vendrely V.
      • Asselineau J.
      • et al.
      Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial.
      ,
      • Garcia-Aguilar J.
      • Patil S.
      • Kim J.K.
      • et al.
      Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial.
      Organ preservation with watchful waiting is also considered as an emerging treatment; however, long-term observations for patient survival have not been reported.
      Biomarker-based treatment strategies have not been established for LARC. The microsatellite status of rectal cancer is expected to be mostly microsatellite stable (MSS) because of the low incidence of high-level microsatellite instability (MSI-H) in left-sided colorectal cancer. An MSI-H incidence of 7.8% has been reported in LARC.
      • Meillan N.
      • Vernerey D.
      • Lefèvre J.H.
      • et al.
      Mismatch repair system deficiency is associated with response to neoadjuvant chemoradiation in locally advanced rectal cancer.
      A greater pathologic response and better prognosis following conventional CRT were observed in patients with MSI-H LARC than in those with MSS LARC, although past retrospective analyses have suggested a lower efficacy of oxaliplatin-based induction systemic chemotherapy.
      • Meillan N.
      • Vernerey D.
      • Lefèvre J.H.
      • et al.
      Mismatch repair system deficiency is associated with response to neoadjuvant chemoradiation in locally advanced rectal cancer.
      • de Rosa N.
      • Rodriguez-Bigas M.A.
      • Chang G.J.
      • et al.
      DNA mismatch repair deficiency in rectal cancer: benchmarking its impact on prognosis, neoadjuvant response prediction, and clinical cancer genetics.
      • Cercek A.
      • Dos Santos Fernandes G.
      • Roxburgh C.S.
      • et al.
      Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy.

      Applications of Immune Checkpoint Inhibitors for the Treatment of Rectal Cancer

      Based on our understanding of the importance of immune mechanisms in various types of tumors, immune checkpoint inhibitors (ICIs) have become an important component of cancer therapy. In particular, antibodies that block negative regulators of the immune system, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-ligand 1 (PD-L1), have shown efficacy in the treatment of various solid tumor types.
      • Hodi F.S.
      • O'Day S.J.
      • McDermott D.F.
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      • Kang Y.K.
      • Boku N.
      • Satoh T.
      • et al.
      Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      • Kato K.
      • Cho B.C.
      • Takahashi M.
      • et al.
      Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.
      In CRC, a strong association between the efficacy of ICIs and the presence of MSI-H, albeit a rare subtype, has been reported.
      • Le D.T.
      • Uram J.N.
      • Wang H.
      • et al.
      PD-1 blockade in tumors with mismatch-repair deficiency.
      For patients with MSS CRC, the Dutch NICHE trial indicated a promising pathological response of 27% (4/15), with 3 major pathological responses and 1 partial response by neoadjuvant anti-CTLA-4 antibody ipilimumab plus anti-PD-1 antibody nivolumab in patients with clinical stage I-III MSS CRC.
      • Chalabi M.
      • Fanchi L.F.
      • Dijkstra K.K.
      • et al.
      Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.
      However, limited efficacy of ICIs has been reported in patients with advanced or metastatic CRC. Therefore, investigations of various immunotherapy combinations that improve the efficacy of immunologic therapy in this subtype have been initiated.
      • Eng C.
      • Kim T.W.
      • Bendell J.
      • et al.
      Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.
      ,
      • Fukuoka S.
      • Hara H.
      • Takahashi N.
      • et al.
      Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603).
      One promising approach is to combine ICIs with ionizing radiation, since radiation may enhance the action of ICIs through several mechanisms (immunogenic effects), including increased tumor antigen release, activation of the innate immune pathway, increased T cell infiltration, augmented antigen presentation, and modulation of immunosuppressive cells.
      • Deng L.
      • Liang H.
      • Burnette B.
      • et al.
      Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice.
      ,
      • Dovedi S.J.
      • Adlard A.L.
      • Lipowska-Bhalla G.
      • et al.
      Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.
      On the other hand, several studies have suggested an immunosuppressive effect of radiation, such as direct killing of lymphocytes, increased transforming growth factor (TGF) β, enhancements of myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs).
      • Barcellos-Hoff M.H.
      • Derynck R.
      • Tsang M.L.
      • Weatherbee J.A.
      Transforming growth factor-beta activation in irradiated murine mammary gland.
      ,
      • Wei J.
      • Montalvo-Ortiz W.
      • Yu L.
      • et al.
      Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses.
      (Figure 1) The optimal combination of radiation dose (long-course or short-course) and ICIs (concurrent or sequential) has not been established. In in vivo analysis, the sequential combination of an anti-PD-1 antibody and radiation to melanoma and breast carcinoma xenografts increased the proportion of tumor antigen complexes and major histocompatibility complex molecules, enhanced lymph node cross-presentation, and increased T cell tumor infiltration.
      • Sharabi A.B.
      • Nirschl C.J.
      • Kochel C.M.
      • et al.
      Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen.
      Blockade of the PD-1 pathway after local tumor irradiation also resulted in the expansion of polyfunctional intratumoral CD8+ T cells, decrease in intratumoral dysfunctional CD8+ T cells, expansion of reprogrammable CD8+ T cells, and induction of potent out-of-field (abscopal) responses.
      • Wei J.
      • Montalvo-Ortiz W.
      • Yu L.
      • et al.
      Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses.
      Although limited efficacy of radiation plus ICIs for out-of-field tumor shrinkage have been reported in patients with metastatic CRC,
      • Monjazeb A.M.
      • Giobbie-Hurder A.
      • Lako A.
      • et al.
      A randomized trial of combined PD-L1 and CTLA-4 inhibition with targeted low-dose or hypofractionated radiation for patients with metastatic colorectal cancer.
      ,
      • Segal N.H.
      • Cercek A.
      • Ku G.
      • et al.
      Phase II single-arm study of durvalumab and tremelimumab with concurrent radiotherapy in patients with mismatch repair-proficient metastatic colorectal cancer.
      the efficacy of this combined approach in non-metastatic cases have not been elucidated. Recently, significant improvements in both progression-free survival (PFS) and OS have been reported with the sequential combination of conventional platinum-based CRT plus consolidation anti-PD-L1 antibody in patients with locally advanced unresectable non-small cell lung cancer.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      ,
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      In addition, significant improvement in DFS has been reported with the sequential combination of neoadjuvant chemoradiotherapy and radical surgery followed by adjuvant anti-PD-1 antibody in patients with esophageal cancer.
      • Kelly R.J.
      • Ajani J.A.
      • Kuzdzal J.
      • et al.
      Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
      Investigations regarding use of the combination of CRT and ICIs in patients with LARC have been started.
      Fig.ure 1
      Fig.ure 1Local radiation therapy induces immunogenic effects, including increased tumor antigen release, activation of the innate immune pathway, increased T cell infiltration, augmented antigen presentation, and modulation of immunosuppressive cells. Conversely, local radiation enhances immunosuppressive effect, such as direct killing of lymphocytes, increased transforming growth factor (TGF) β, increase in myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs), anergy, and immunosenescence.
      The clinical developments of combination CRT and ICIs should be examined separately based on the MSI status because MSS and MSI-H LARC have different response to immunotherapy, CRT, and systemic chemotherapy. Currently, investigators mainly focus on MSS LARC as they expect that the combination of CRT and ICIs can overcome the ‘immune-cold’ tumor microenvironment and improve efficacy in patients with MSS LARC.

      Reported Clinical Trials

      VOLTAGE Study

      Several short-term results of the combination of CRT and ICI in patients with LARC have been reported since 2020. The first report on the efficacy and safety of CRT plus ICIs was reported in Japan. EPOC 1504 VOLTAGE (cohort A) is a proof-of-concept, nonrandomized phase I/II trial (NCT02948348) (Table 1).
      • Yuki S.
      • Bando H.
      • Tsukada Y.
      • et al.
      Short-term results of VOLTAGE-A: nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer.
      Patients with clinical stage T3–4 N0-2 LARC were treated with capecitabine (825 mg/m2 twice daily)-based CRT at a dose of 50.4 Gy, followed by 5 cycles of nivolumab monotherapy (240 mg every 2 weeks) and subsequent TME at 12 weeks after the last dose of CRT. The primary endpoint for patients with MSS LARC was the pCR rate using the American Joint Committee on Cancer guidelines for the evaluation of tumor regression grade (TRG), as determined by an independent central pathology assessment committee.
      Table 1Reported Clinical Trials of Combination Chemoradiotherapy With Immune-Checkpoint Inhibitor for Patients With Locally Advanced Rectal Cancer
      TreatmentPrimary EndpointNT FactorN Factor (%)pCR RateDFSOS
      VOLTAGE (Cohort A)

      NCT02921256
      Cape/RT (50.4 Gy) →Nivolumab →TME

      (→FOLFOX/CAPOX)
      pCR rate37 (MSS)T1-2, 0%

      T3, 87.2%

      T4, 12.8%
      N0, 76.9%

      N+, 23.1%
      30%NRNR
      5 (MSI-H)T1-2, 0%

      T3, 100%

      T4, 0%
      N0, 67%

      N+, 33%
      60%NRNR
      NRG-GI002

      NCT02921256
      FOLFOX6 →Cape/RT (50.4 Gy) +Pembrolizumab →TMENAR score90T1-2, 4.4%

      T3, 74.4%

      T4, 21.1%
      N0, 22.2%

      N+, 77.8%
      31.9%NRNR
      FOLFOX6→Cape/RT →TME95T1-2, 5.3%

      T3, 71.6%

      T4, 23.2%
      N0, 23.2%

      N+, 76.8%
      29.4%NRNR
      AVANA

      NCT03854799
      Cape/RT (50.4 Gy) +Avelumab →TMEpCR rate101T1-2, 11%

      T3, 73%

      T4, 16%
      N0, 6%

      N+, 94%
      23%NRNR
      AVERECTAL

      NCT03503630
      SCRT (25 Gy) →FOLFOX +Avelumab →TMEpCR rate40T1-2, 5%

      T3, 85%

      T4, 5%
      N0, 5%

      N+, 95%
      37.5%NRNR
      Abbreviations: pCR = pathological complete response; DFS = disease-free survival; OS = overall survival; Cape = capecitabine; RT = radiotherapy; TME = total mesorectal excision; FOLFOX = oxaliplatin plus 5-FU; CAPOX = oxaliplatin plus capecitabine; MSS = microsatellite stable; MSI-H = microsatellite instability-high; NR = not reported; NAR score = neoadjuvant rectal score; SCRT = short-course radiotherapy.
      In phase I, 3 patients with MSS LARC received full courses of both CRT and nivolumab without dose modification and underwent radical surgical resection. No dose-limiting toxicity was observed. In phase II, 30% (11/37) of patients with pCR were centrally confirmed in the primary MSS cohort, and the primary endpoint of this study was met. In the exploratory MSI-H cohort, 60% (3/5) of the patients with pCR were centrally confirmed. The median neoadjuvant rectal (NAR) scores of patients with MSS and MSI-H LARC were 8.4 (0.0-50.4) and 0.9 (0.9-20.4), respectively. While immune-related severe adverse events were observed in three patients (grade 3 myasthenia, grade 3 interstitial nephritis, and grade 2 peripheral motor neuropathy), all patients recovered fully and underwent radical surgery. No treatment-related deaths were observed. As of January 2020, 4 patients with MSS LARC experienced recurrence (2 local and 2 distant), and no patients with MSI-H LARC experienced recurrence after a median of 22.5 months and 6.6 months, respectively.

      NRG-GI002 Study

      The NRG-GI002 study is the first randomized phase II clinical trial to assess the efficacy and safety of additional pembolizumab during and after neoadjuvant chemoradiotherapy performed by NRG Oncology in the United States (NCT02921256) (Table 1).
      • Rahma O.E.
      • Yothers G.
      • Hong T.S.
      • et al.
      Use of total neoadjuvant therapy for locally advanced rectal cancer: initial results from the pembrolizumab arm of a phase 2 randomized clinical trial.
      Patients with clinical stage II or III LARC who met at least one of the following criteria: distal location (≤ 5 cm from the anal verge), bulky disease (any clinical T4 or evidence that the tumor is within 3 mm of the mesorectal fascia), high risk of metastatic disease with 4 or more involved regional lymph nodes (clinical N2), or not a candidate for sphincter-sparing surgery (SSS). Patients were randomized (1:1) into neoadjuvant FOLFOX for 6 cycles, followed by CRT (825 mg/m2 capecitabine twice daily with 50.4 Gy), with or without concurrent pembrolizumab (200 mg every 3 weeks) for up to 6 doses. TME was performed 8 to 12 weeks after the last dose of radiotherapy. The primary endpoint was the NAR score, that incorporates a weighted combination of the pre-CRT cT-category, and post-CRT ypT and ypN categories. The NAR score was developed by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and NRG Oncology, and was associated with better OS.
      • Valentini V.
      • van Stiphout R.G.
      • Lammering G.
      • et al.
      Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials.
      ,
      • George T.J.
      • Allegra C.J.
      • Yothers G.
      Neoadjuvant rectal (NAR) score: a new surrogate endpoint in rectal cancer clinical trials.
      A total of 185 patients were randomized into the control arm (n = 95) or pembrolizumab arm (n = 90). Of the 138 patients with resected tumors, 137 had complete pathologic assessment and a valid NAR score. The mean NAR score was 11.53 in the pembrolizumab arm versus 14.08 in the control arm (P = .26), and the primary endpoint of this study was not met. The pCR rate was 31.9% in the pembrolizumab group and 29.4% in the control arm (P = .75). The clinical complete response rates were 13.9% and 13.6% in the pembrolizumab arm and in the control arm, respectively (P = .95). The percentage of patients who underwent SSS was 59.4% in the pembrolizumab arm versus 71.0% in the control arm (P = .15). Grade 3 to 4 adverse events were slightly increased in the pembrolizumab arm (48.2%) versus the control arm (37.3%) during chemoradiotherapy. Investigators concluded that the concurrent addition of pembrolizumab to CRT as part of TNT was not sufficient to support further study.

      AVANA Study

      The Italian GONO group performed a multicenter, single-arm phase II AVANA study to investigate the role of avelumab in combination with preoperative CRT in patients with LARC (NCT03854799) (Table 1).
      • Salvatore L.
      • Bensi M.
      • Corallo S.
      • et al.
      Phase II study of preoperative chemoradiotherapy plus avelumab in patients with locally advanced rectal cancer: the AVANA study.
      Patients with resectable LARC received standard preoperative CRT (825 mg/m2 capecitabine twice daily with 50.4 Gy) plus concurrent 6 cycles of avelumab (10 mg/kg every 2 weeks). Resectable LARC was defined by the presence of at least one of the following features: clinical N-positive, clinical T4, high-risk clinical T3. Surgery with TME was performed 8 to 10 weeks after the last CRT dose. The primary endpoint was the pCR.
      A total of 101 patients with resectable LARC were enrolled in the study. At baseline, 94 (93%) and 16 (16%) patients had clinical N-positive and clinical T4 LARC, respectively. Of the 100 patients evaluated for pathological response, 23 (23%) achieved a pCR and 60 (60%) achieved a major pathological response. The primary endpoints were met. The rates of grade 3 to 4 non-immune and immune-related adverse events were 8% and 4%, respectively. Investigators concluded that the concurrent combinations of CRT and avelumab showed promising activity and a feasible safety profile.

      AVERECTAL Study

      A multicenter, phase II AVERECTAL study was also conducted in the United States, France, and Jordan (NCT03503630) (Table 1).
      • Shamseddine A.
      • Zeidan Y.H.
      • Bouferraa Y.
      • Turfa R.
      • Kattan J.
      • Mukherji D.
      • et al.
      SO-30 Efficacy and safety of neoadjuvant short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma: averectal study.
      The efficacy and safety of short-course radiotherapy (SCRT) (25 Gy in 5 fractions), followed by 6 cycles of mFOLFOX-6 plus avelumab, and TME 3 to 4 weeks after the last dose were evaluated in patients with LARC. The primary endpoint of this study was the pCR rate.
      In the first stage, the feasibility of study treatment was investigated for the first 13 patients.
      • Shamseddine A.
      • Zeidan Y.H.
      • 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.
      With the inclusion of the patients in the second stage, a total of 44 patients were recruited and 40 patients completed at least 1 treatment cycle and surgery, with a median follow-up period of 13.2 (range, 3.6-31.9) months. Since 15 of 40 (37.5%) patients achieved TRG 0 (pCR), the primary endpoint of this study was met. In addition, 12/40 (30%) patients had a near-complete response with TRG 1 (<10% viable cells in the tumor bed). In total, 27/40 patients (67.5%) had a major pathologic response rate (TRG 0 and 1). Regarding safety, 43 of 242 (17.7%) adverse events were serious.

      Biomarkers of Efficacy of Chemoradiotherapy Plus Immune-Checkpoint Inhibitors

      To investigate patients in whom higher efficacy of treatment may be achieved by CRT plus ICIs, various biomarker analyses have been performed. In the VOLTAGE study, biomarker analyses using serially collected tumor and blood samples have been reported.
      • Inamori K.
      • Togashi Y.
      • Bando H.
      • et al.
      Translational research of VOLTAGE-A: efficacy predictors of preoperative chemoradiotherapy and consolidation nivolumab in patients with both microsatellite stable and microsatellite instability-high locally advanced rectal cancer.
      In 38 patients with MSS who underwent surgery, pCR rates of 67% (6/9) and 17% (5/29) (P = .009) were observed in those with positive and negative PD-L1 tumor proportion score (TPS), respectively. In 24 patients with MSS, pre-CRT samples were analyzed by flow cytometry; pCR rates of 78% (7/9) and 13% (2/15) (P =.003) were observed in patients with higher and lower CD8+ / effector regulatory T (CD8/eTreg) cell ratios, respectively. A pCR rate of 100% (5/5) was observed in patients with PD-L1 TPS positivity and a higher CD8/eTreg ratio. In contrast, a pCR rate of 8% (1/12) was observed in patients with PD-L1 TPS negative and a lower CD8/eTreg ratio. Of 21 patients with MSS LARC whose consensus molecular subtype (CMS) was analyzable, those with the CMS1 (MSI-immune) subtype achieved pCR at rates of 100%. The tumor mutational burden (TMB) in patients with MSI-H LARC was significantly higher than that in patients with MSS LARC. In patients with MSS LARC, TMB was significantly higher in patients with TRG 0 to 1 than in those with TRG 2 to 3.
      In the AVERECTAL study, preliminary immune-score (IS) results have been reported.
      • Shamseddine A.
      • Zeidan Y.H.
      • Bouferraa Y.
      • Turfa R.
      • Kattan J.
      • Mukherji D.
      • et al.
      SO-30 Efficacy and safety of neoadjuvant short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma: averectal study.
      Significantly higher IS was observed in patients with TRG 0 compared to those with TRG 2 (P = .045), suggesting that a higher pCR rate can be predicted using IS.

      Other On-Going Clinical Trials

      Currently, many clinical trials investigating the combination of CRT and ICIs are ongoing (Table 2). In the nivolumab-based developments, VOLTAGE (cohort D, NCT02921256), CHINOREC (NCT04124601), and the US trial (NCT04751370) are investigating the safety and efficacies of standard CRT and ipilimumab+nivolumab combination in both MSS and MSI-H LARC patients. A trial conducted in Israel also investigated the combination of standard CRT and FOLFOX+nivolumab in patients with LARC (NCT03921684). Moreover, based on the promising response of nivolumab plus regorafenib in metastatic MSS CRC,
      • Fukuoka S.
      • Hara H.
      • Takahashi N.
      • et al.
      Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603).
      studies investigating the efficacy of nivolumab plus regorafenib after SCRT (25 Gy) are ongoing (NCT04503694).
      Table 2On-Going Clinical Trials of Combination Chemoradiotherapy With Immune-Checkpoint Inhibitor for Patients With Locally Advanced Rectal Cancer
      CountryTreatmentMicrosatellite StatusNPrimary Endpoint
      VOLTAGE (Cohort D)

      NCT02921256
      JapanCape/RT (50.4 Gy) →Ipilimumab+Nivolumab →TME

      (→FOLFOX/CAPOX)
      MSS/MSI-H25Safety and pCR rate
      CHINOREC

      NCT04124601
      AustriaCape/RT (50 Gy) →Ipilimumab+Nivolumab →TME vs.

      Cape/RT (50 Gy)→TME
      MSS/MSI-H80Safety and tolerability
      NCT04751370USAIpilimumab+Nivolumab →SCRT (25 Gy) →TMEMSI-H31pCR rate
      NCT03921684IsraelCape/RT (50.4 Gy) →FOLFOX+Nivolumab →TMEMSS/MSI-H29Safety and pCR rate
      REGINA

      NCT04503694
      BelgiumSCRT (25 Gy) +Nivolumab+Regrafenib →TMEMSS/MSI-H60pCR rate
      Keynote-981 (PEMREC)

      NCT04109755
      SwitzerlandSCRT (25 Gy) +Pembrolizumab →Pemubrolizumab →TMEMSS25TRG using Mandard regression grade
      NCT04357587USACape/RT (50.4 Gy) +Pembrolizumab →TMEMSI-H10Safety and feasibility
      NSABP FR-2

      NCT03102047
      USAStandard CRT →Durvalumab →TMEMSS44NAR Score
      PAMDORA

      NCT04083365
      ItalyCape/RT (50.4 Gy) →Durvalumab →TMEMSS/MSI-H60pCR rate using Mandard regression grade
      PRIME-RT

      NCT04621370
      UKSCRT (25 Gy) +Durvalumab →FOLFOX +Durvalumab →TME

      Cape/RT (50 Gy) +Durvalumab →FOLFOX +Durvalumab →TME
      MSS/MSI-H48pCR/cCR
      DUREC

      NCT04293419
      SpainFOLFOX +Durvalumab →Cape/RT (50.4 Gy) +Durvalumab →Durvalumab →TMEMSS/MSI-H58pCR rate
      R-IMMUNE

      NCT03127007
      Belgium5-FU/RT (50 Gy) +Atezolizumab →TMEMSS/MSI-H54Safety and pCR rate
      TARZAN

      NCT04017455
      NetherlandsStandard CRT →Atezilizumab+Bevacizumab →TMEMSS/MSI-H38pCR rate
      NCT03299660Australia5-FU or Cape/RT (50.4 Gy) +Avelumab →TMEMSS/MSI-H45pCR rate
      Abbreviations: Cape = capecitabine; RT = radiotherapy; TME = total mesorectal excision; MSS = microsatellite stable; MSI-H = microsatellite instability-high; pCR = pathological complete response; SCRT = short-course radiotherapy; FOLFOX = oxaliplatin plus 5-FU; TRG = tumor regression grade; NAR = neoadjuvant rectal; cCR = clinical complete response.
      Among recent developments in pembrolizumab-based therapies, the Keynote-981 (PEMREC) study investigated the concurrent and sequential combination of pembrolizumab and SCRT (25 Gy) (NCT04109755). Keynote-981 also monitored circulating tumor DNA before, during, and after study treatment. Additionally, a small study investigating the use of standard CRT plus pembrolizumab for MSI-H LARC is ongoing (NCT04357587).
      Among developments in durvalumab-based therapies, NSABP FR-2 (NCT03102047) and PAMDORA (NCT04083365) investigated the efficacy and safety of standard CRT followed by durvalumab in patients with LARC. Additionally, PRIME-RT (NCT04621370) and DUREC (NCT04293419) investigated the efficacy and safety of TNT plus durvalumab.
      Among developments in atezolizumab-based therapies, the R-IMMUNE study investigated the efficacy and safety of concurrent standard 5-FU/RT (50 Gy) plus atezolizumab in patients with LARC (NCT03127007). The TARZAN study investigated the efficacy of standard CRT followed by atezolizumab plus bevacizumab in patients with LARC (NCT04017455).
      An Australian trial is currently ongoing to investigate the efficacy of concurrent standard CRT plus avelumab in patients with LARC (NCT03299660).

      Discussion

      CRT followed by radical surgery is one the standard therapies for patients with LARC. However, further developments are expected to improve both local and distant control. While immunotherapy has been established as a standard treatment in patients with metastatic MSI-H CRC, it has been largely ineffective in patients with MSS CRC. To evaluate whether the combination of CRT and ICIs can improve efficacy in patients with MSS LARC, various clinical trials have been conducted. In addition, several studies also ascertained the efficacy of CRT and ICIs in patients with MSI-H LARC, although small samples have been included. As there are fundamental differences in biology and response to treatment between MSS and MSI-H LARC, clinical evaluation of combination of CRT, systemic chemotherapies, and ICIs in these groups should be conducted separately.
      Since population-based meta-analyses have suggested that pCR can be a strong surrogate for both local and distant tumor control and can serve as a good predictor of favorable survival in patients with LARC,
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ,
      • Martin S.T.
      • Heneghan H.M.
      • Winter D.C.
      Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer.
      most early phase II trials used the pCR rate as the primary endpoint to determine further developments. The short-term efficacy results of 23% to 37.5% of the pCR rate suggested promising signals of CRT plus ICIs in patients with MSS LARC. As systemic failure is a critical factor in the survival of patients with LARC, long-term follow up to evaluate the DFS and OS is important. So far, there were only 4 patients (10.8%, 4/37) with MSS LARC with recurrence (local recurrence in 2 patients and distal recurrence in 2) after a median follow-up of 22.5 months in the Japanese VOLTAGE study, suggesting promising long-term local and distant control by CRT plus ICIs.
      Although the toxicities resulting from the combination of ICIs are generally mild, immune-related adverse events have been reported, including grade 3 myasthenia, grade 3 interstitial nephritis, grade 2 peripheral motor neuropathy, grade 3 hyperthyroidism, and grade 3 diarrhea. The balance between efficacy and toxicity is important in the evaluation of the clinical developments of ICIs for MSS LARC.
      When ICIs are combined with CRT, either concurrent or sequential combinations can be expected. While there is no evidence to suggest whether concurrent or sequential combination of ICIs is a better strategy, the NRG-GI002 study reported that preoperative FOLFOX followed by CRT with concurrent pembrolizumab did not improve pCR rates compared with FOLFOX followed by CRT (31.9% vs. 29.4%, P= .75). An in-vivo analysis showed that administration of anti-PD-1 after local irradiation preferentially expanded polyfunctional CD8+ effector T-cells in both primary and distal tumors. Conversely, administration of anti-PD-1 before irradiation almost completely abrogated systemic immunity, which was associated with increased radiosensitivity and death of CD8+ T cells. The subsequent reduction of polyfunctional effector CD8+ T cells at the irradiated tumor site generated a suboptimal systemic antitumor response and the loss of abscopal responses.
      • Wei J.
      • Montalvo-Ortiz W.
      • Yu L.
      • et al.
      Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses.
      Therefore, sequential combination of CRT followed by ICIs might be better than ICIs followed by CRT or concurrent combination.
      In patients with MSI-H LARC, CRT followed by nivolumab and surgery achieved a 60% (3/5) pCR rate in the VOLTAGE study, suggesting increased efficacy of ICIs in this subgroup, albeit with a small sample size. Although the number of patients with MSI-H LARC was small due to the low incidence of left-sided MSI-H CRC, including rectal cancer,
      • Meillan N.
      • Vernerey D.
      • Lefèvre J.H.
      • et al.
      Mismatch repair system deficiency is associated with response to neoadjuvant chemoradiation in locally advanced rectal cancer.
      ,
      • de Rosa N.
      • Rodriguez-Bigas M.A.
      • Chang G.J.
      • et al.
      DNA mismatch repair deficiency in rectal cancer: benchmarking its impact on prognosis, neoadjuvant response prediction, and clinical cancer genetics.
      the promising pCR rate suggested that CRT plus ICIs have the potential to become a favorable treatment option in this population. Several clinical trials investigating the efficacy of CRT plus ICIs in patients with MSI-H LARC are ongoing (NCT04751370, NCT04357587) (Table 2).
      According to the biomarker analysis in the VOLTAGE study, PD-L1 TPS-positive and elevated CD8/eTreg ratios were predictors of efficacy of CRT plus ICI combinations. Additionally, in patients with both positive PD-L1 expression and high CD8/eTreg ratios, the highest pCR rate (100%, 5/5) was observed. In the AVERECTAL study, IS was significantly higher in patients with pCR than in those with non-pCR populations. High estimates of efficacy were also observed in MSS LARC patients with CMS1 and higher TMB in the VOLTAGE study. As CMS1 is associated with gene expression of diffuse immune infiltrate
      • Guinney J.
      • Dienstmann R.
      • Wang X.
      • et al.
      The consensus molecular subtypes of colorectal cancer.
      and higher TMB is associated with a high frequency of neoantigens,
      • Yarchoan M.
      • Hopkins A.
      • Jaffee E.M.
      Tumor mutational burden and response rate to PD-1 inhibition.
      patients with MSS LARC with these markers might be expected to experience a higher efficacy similar to that observed in MSI-H LARC.
      As MSS LARC is a generally “immune-cold” cancer, strong enhancement of the immune system and careful patient selection are keys for future development. The combination of ICIs may overcome the “immune-cold” situations. Currently, 2 clinical trials (NCT02921256, NCT04124601) investigating the safety and efficacy of standard CRT and ipilimumab +nivolumab combination in patients with MSS LARC are ongoing. Furthermore, PD-L1 TPS, CD8 lymphocytes elevation in TILs, high IS, CMS1, and higher TMB are potential predictive markers for MSS LARC. Therefore, clinical trials investigating combination therapy of ICIs for biomarker-selected populations may be a promising strategy for future studies.
      In conclusion, the combination of preoperative CRT and ICIs before radical surgery may be associated with increased immunotherapy efficacy with only mild toxicities in both patients with MSS and MSI-H LARC, as indicated by the promising pCR and NAR scores. In patients with MSS LARC, PD-L1 TPS positivity, elevated CD8/eTreg ratio, higher IS, CMS 1, and higher TMB appear to be positive predictors of ICI efficacy.

      Acknowledgments

      We would like to thank Editage (www.editage.com) for English language editing. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      References

        • Sung H.
        • Ferlay J.
        • Siegel R.L.
        • et al.
        Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2021; 71: 209-249
        • Heald R.J.
        • Husband E.M.
        • Ryall R.D.
        The mesorectum in rectal cancer surgery–the clue to pelvic recurrence?.
        Br J Surg. 1982; 69: 613-616
        • Lowry A.C.
        • Simmang C.L.
        • Boulos P.
        • et al.
        Consensus statement of definitions for anorectal physiology and rectal cancer: report of the Tripartite Consensus Conference on Definitions for Anorectal Physiology and Rectal Cancer, Washington, D.C.44. 2001: 915-919 (May 1, 1999Dis Colon Rectum)
        • Sauer R.
        • Becker H.
        • Hohenberger W.
        • et al.
        Preoperative versus postoperative chemoradiotherapy for rectal cancer.
        N Engl J Med. 2004; 351: 1731-1740
        • Bosset J.F.
        • Collette L.
        • Calais G.
        • et al.
        Chemotherapy with preoperative radiotherapy in rectal cancer.
        N Engl J Med. 2006; 355: 1114-1123
        • Gerard J.P.
        • 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
        • Hofheinz R.D.
        • Wenz F.
        • Post S.
        • et al.
        Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.
        Lancet Oncol. 2012; 13: 579-588
        • Hong Y.S.
        • Nam B.H.
        • Kim K.P.
        • et al.
        Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial.
        Lancet Oncol. 2014; 15: 1245-1253
        • Garcia-Aguilar J.
        • Chow O.S.
        • Smith D.D.
        • et al.
        Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial.
        Lancet Oncol. 2015; 16: 957-966
        • Fokas E.
        • Allgauer M.
        • Polat B.
        • et al.
        Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12.
        J Clin Oncol. 2019; 37: 3212-3222
        • Cercek A.
        • Roxburgh C.S.D.
        • Strombom P.
        • et al.
        Adoption of total neoadjuvant therapy for locally advanced rectal cancer.
        JAMA Oncol. 2018; 4e180071
        • Bahadoer R.R.
        • Dijkstra E.A.
        • van Etten B.
        • et al.
        Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.
        Lancet Oncol. 2021; 22: 29-42
        • Conroy T.
        • Bosset J.F.
        • Etienne P.L.
        • et al.
        Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.
        Lancet Oncol. 2021; 22: 702-715
        • Rullier E.
        • Vendrely V.
        • Asselineau J.
        • et al.
        Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial.
        Lancet Gastroenterol Hepatol. 2020; 5: 465-474
        • Garcia-Aguilar J.
        • Patil S.
        • Kim J.K.
        • et al.
        Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial.
        J Clin Oncol. 2020; 38: 4008
        • Meillan N.
        • Vernerey D.
        • Lefèvre J.H.
        • et al.
        Mismatch repair system deficiency is associated with response to neoadjuvant chemoradiation in locally advanced rectal cancer.
        Int J Radiat Oncol Biol Phys. 2019; 105: 824-833
        • de Rosa N.
        • Rodriguez-Bigas M.A.
        • Chang G.J.
        • et al.
        DNA mismatch repair deficiency in rectal cancer: benchmarking its impact on prognosis, neoadjuvant response prediction, and clinical cancer genetics.
        J Clin Oncol. 2016; 34: 3039-3046
        • Cercek A.
        • Dos Santos Fernandes G.
        • Roxburgh C.S.
        • et al.
        Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy.
        Clin Cancer Res. 2020; 26: 3271-3279
        • Hodi F.S.
        • O'Day S.J.
        • McDermott D.F.
        • et al.
        Improved survival with ipilimumab in patients with metastatic melanoma.
        N Engl J Med. 2010; 363: 711-723
        • Kang Y.K.
        • Boku N.
        • Satoh T.
        • et al.
        Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet. 2017; 390: 2461-2471
        • Kato K.
        • Cho B.C.
        • Takahashi M.
        • et al.
        Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.
        Lancet Oncol. 2019; 20: 1506-1517
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N Engl J Med. 2015; 372: 2509-2520
        • Chalabi M.
        • Fanchi L.F.
        • Dijkstra K.K.
        • et al.
        Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.
        Nat Med. 2020; 26: 566-576
        • Eng C.
        • Kim T.W.
        • Bendell J.
        • et al.
        Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.
        Lancet Oncol. 2019; 20: 849-861
        • Fukuoka S.
        • Hara H.
        • Takahashi N.
        • et al.
        Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603).
        J Clin Oncol. 2020; 38: 2053-2061 JCO1903296
        • 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
        • Dovedi S.J.
        • Adlard A.L.
        • Lipowska-Bhalla G.
        • et al.
        Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.
        Cancer Res. 2014; 74: 5458-5468
        • Barcellos-Hoff M.H.
        • Derynck R.
        • Tsang M.L.
        • Weatherbee J.A.
        Transforming growth factor-beta activation in irradiated murine mammary gland.
        J Clin Invest. 1994; 93: 892-899
        • Wei J.
        • Montalvo-Ortiz W.
        • Yu L.
        • et al.
        Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses.
        Sci Immunol. 2021; 6
        • Sharabi A.B.
        • Nirschl C.J.
        • Kochel C.M.
        • et al.
        Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen.
        Cancer Immunol Res. 2015; 3: 345-355
        • Monjazeb A.M.
        • Giobbie-Hurder A.
        • Lako A.
        • et al.
        A randomized trial of combined PD-L1 and CTLA-4 inhibition with targeted low-dose or hypofractionated radiation for patients with metastatic colorectal cancer.
        Clin Cancer Res. 2021; 27: 2470-2480
        • Segal N.H.
        • Cercek A.
        • Ku G.
        • et al.
        Phase II single-arm study of durvalumab and tremelimumab with concurrent radiotherapy in patients with mismatch repair-proficient metastatic colorectal cancer.
        Clin Cancer Res. 2021; 27: 2200-2208
        • Antonia S.J.
        • Villegas A.
        • Daniel D.
        • et al.
        Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
        N Engl J Med. 2017; 377: 1919-1929
        • Antonia S.J.
        • Villegas A.
        • Daniel D.
        • et al.
        Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
        N Engl J Med. 2018; 379: 2342-2350
        • Kelly R.J.
        • Ajani J.A.
        • Kuzdzal J.
        • et al.
        Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
        N Engl J Med. 2021; 384: 1191-1203
        • Yuki S.
        • Bando H.
        • Tsukada Y.
        • et al.
        Short-term results of VOLTAGE-A: nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer.
        J Clin Oncol. 2020; 38
        • Rahma O.E.
        • Yothers G.
        • Hong T.S.
        • et al.
        Use of total neoadjuvant therapy for locally advanced rectal cancer: initial results from the pembrolizumab arm of a phase 2 randomized clinical trial.
        JAMA Oncol. 2021; 7: 1225-1230
        • Valentini V.
        • van Stiphout R.G.
        • Lammering G.
        • et al.
        Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials.
        J Clin Oncol. 2011; 29: 3163-3172
        • George T.J.
        • Allegra C.J.
        • Yothers G.
        Neoadjuvant rectal (NAR) score: a new surrogate endpoint in rectal cancer clinical trials.
        Curr Colorectal Cancer Rep. 2015; 11: 275-280
        • Salvatore L.
        • Bensi M.
        • Corallo S.
        • et al.
        Phase II study of preoperative chemoradiotherapy plus avelumab in patients with locally advanced rectal cancer: the AVANA study.
        J Clin Oncol. 2021; : 39
        • Shamseddine A.
        • Zeidan Y.H.
        • Bouferraa Y.
        • Turfa R.
        • Kattan J.
        • Mukherji D.
        • et al.
        SO-30 Efficacy and safety of neoadjuvant short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma: averectal study.
        Ann Oncol. 2021; 32: S215
        • Shamseddine A.
        • Zeidan Y.H.
        • 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
        • Inamori K.
        • Togashi Y.
        • Bando H.
        • et al.
        Translational research of VOLTAGE-A: efficacy predictors of preoperative chemoradiotherapy and consolidation nivolumab in patients with both microsatellite stable and microsatellite instability-high locally advanced rectal cancer.
        J Clin Oncol. 2021; : 39
        • Maas M.
        • Nelemans P.J.
        • Valentini V.
        • et al.
        Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
        Lancet Oncol. 2010; 11: 835-844
        • Martin S.T.
        • Heneghan H.M.
        • Winter D.C.
        Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer.
        Br J Surg. 2012; 99: 918-928
        • Guinney J.
        • Dienstmann R.
        • Wang X.
        • et al.
        The consensus molecular subtypes of colorectal cancer.
        Nat Med. 2015; 21: 1350-1356
        • Yarchoan M.
        • Hopkins A.
        • Jaffee E.M.
        Tumor mutational burden and response rate to PD-1 inhibition.
        N Engl J Med. 2017; 377: 2500-2501