Panning for gold in a dry creek?—the ongoing search for role of immunotherapy in mismatch repair proficient rectal cancer

Background

National Comprehensive Cancer Network (NCCN) guidelines endorse a “total neoadjuvant therapy” (TNT) approach to the treatment of locally advanced rectal cancer (LARC) (1). LARC delineates clinical stage II (T3–T4, node-negative) or stage III (node-positive) tumors (2). All patients with colorectal cancer should receive universal testing for high microsatellite instability (MSI-H) and/or deficiency of mismatch repair (dMMR) proteins (3). While patients with dMMR/MSI-H disease have shown exceptional responsiveness to immune checkpoint inhibitors (ICI), this subset represents only roughly 3% of all patients with rectal tumors (4). The efficacy of immunotherapy in the mismatch repair proficient (pMMR) population has not been validated by robust clinical trial data thus far. For this reason, evolving from the neoadjuvant chemoradiotherapy (CRT) that previously defined standard of care in LARC, TNT for pMMR LARC includes the additional administration of a 12–16-week course of oxaliplatin-based chemotherapy before total mesorectal excision (TME). The TNT strategy aims to enhance tumor regression and increase the likelihood of sphincter-preserving resections. A 2023 update of mature results from the UNICANCER GI trial, PRODIGE 23, indicates TNT may even improve overall survival (5). For those with complete clinical response (CCR) to neoadjuvant treatment and no evidence of residual disease—on digital rectal examination (DRE), rectal magnetic resonance imaging (MRI), and direct endoscopic evaluation—the NCCN additionally endorses appropriateness of a non-operative “watch-and-wait” approach following careful discussion with patients of their risk tolerance and with an experienced multidisciplinary team review. The prospect of minimizing the need for radical resections, or surgery altogether, underscores the significance of identifying predictive biomarkers of responsiveness to already-existing therapies, and the ongoing development of novel therapeutics.

The focus of this editorial commentary is the single-arm phase 2 trial by Li et al. [2024] conducted at Peking University Cancer Hospital and Institute, with short-term findings recently published in JAMA Surgery (6). In this study, 25 patients with pMMR LARC—determined “high-risk” based on either clinical T3c staging or higher, extramural venous invasion, N2 staging, or positive mesorectal fascia margin based on MRI—underwent a TNT-like regimen. Induction chemotherapy consisted of three cycles capecitabine and oxaliplatin (CAPOX) with the anti-programmed cell death 1 (anti-PD-1) ICI camrelizumab, followed by long-course CRT, and in the absence of disease progression, two cycles of consolidation chemotherapy prior to surgery with CAPOX. Tumor response was assessed 2 weeks prior to CRT, consolidation chemotherapy, and intended surgery. The primary endpoint was the rate of pathologic complete response (pCR), while secondary end points included adverse events during neoadjuvant treatment, 3-year disease-free survival (DFS), and 30-day surgical complication rate. Of the cohort of 25 patients, one did not receive CRT due to myelosuppression, two chose to defer consolidation treatment after CRT and underwent surgery, and of the 12 that achieved CCR, four opted for a watch-and-wait approach rather than surgery.

Primary endpoint of trial

By nature of its single-arm design and small sample size, this phase 2 trial is not powered to compare efficacy of this neoadjuvant regimen including immunotherapy to standard TNT regimens. Nevertheless, a cursory comparison unfortunately does not reveal significant deviations from published pCR rates in larger-scale phase 3 clinical trials assessing standard TNT for pMMR LARC, making it unlikely that additional data from a larger sample size would be practice-changing. Perhaps the most comparable patient population to this phase 2 study by Li et al. can be found in the RAPIDO trial comparing TNT to prior standard of care, long-course CRT. Recruitment into RAPIDO necessitated the presence of at least one of the following “high-risk” features of LARC: clinical T4a-, T4b-, or N2-staging, extramural vascular invasion, involved mesorectal fascia or enlarged lateral lymph nodes. While Li et al. report a pCR rate of 33.3% (seven of 21 participants), the RAPIDO trial reported a pCR rate of 28% in their TNT arm (n=462), which included short course CRT followed by CAPOX for six cycles, or nine cycles of FOLFOX-4, prior to resection (7). As outlined in Table 1, published pCR rates from other phase 3 trials have ranged from 17% to 28% (8-10). These rates stand in stark contrast to reported data from early phase trials in the dMMR setting, including the Memorial Sloan Kettering Cancer Center-based phase 2 trial using dostarlimab in mismatch repair-deficient stage II or III rectal adenocarcinoma where all participants (n=12) exhibited CCR (11). An update by Cercek from this NCT04165772 trial was presented at the American Society of Clinical Oncology (ASCO) 2024 annual meeting, further corroborating the high efficacy of this immunotherapeutic regimen in dMMR and also presenting new data describing its durability (12). Of the 47 patients enrolled onto the study, 41 completed 6 months of dostarlimab, and 100% of these participants achieved a CCR. Additionally, for 20 patients, this clinical complete response was sustained greater than 12 months from the first treatment, with a median follow-up of 28.9 months (95% CI: 22.9–37.1), satisfying their second co-primary endpoint.

Generalizability of trial findings

In considering the generalizability of these findings by Li et al. to real-world management of LARC, particularly in the United States, there are numerous challenges. The first pertains to patient selection. Of the 25 patients recruited to the trial, two had a tumor mutational burden (TMB) of >100—which is not typical of patients with pMMR rectal cancer—and one had MSI-H cancer. An additional concern relates to selection of the investigational drug. Camrelizumab is a monoclonal antibody targeting the PD-1 receptor, developed by Jiangsu Hengrui Medicine Co., Ltd. (Lianyungang, China) (13). In China, it is currently approved for the treatment of hepatocellular carcinoma, Hodgkin’s lymphoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma, and non-small cell lung cancer (14). It is not yet approved for use by the U.S. Food and Drug Administration (FDA), however, was granted Orphan Drug Designation for advanced hepatocellular carcinoma in April 2021, and in May 2023, a New Drug Application (NDA) was submitted to the FDA for camrelizumab in combination with rivoceranib for the first-line treatment of unresectable hepatocellular carcinoma. Camrelizumab has not been frequently studied in the context of pMMR rectal cancer. A systematic review of clinical trials by Lote et al. [2022] utilizing immunotherapy in pMMR metastatic rectal cancer summarized results from over 35 trials with published data (15). Camrelizumab was not used in any of these trials. The few clinical trials investigating camrelizumab in the non-metastatic setting are all based out of China (16). Additional prospective studies with camrelizumab will need to use larger sample sizes, recruit diverse patient populations (e.g., stratifying by race) with variable tumor characteristics (e.g., stratifying by proximal versus distal lesions), and investigate immunologic biomarkers for their prognostic and predictive value. The decision to study camrelizumab in the neoadjuvant setting is supported by precedent in the NICHE trial (17) and other published data in melanoma (18) and glioblastoma (19) indicating the immune response is more robust in the neoadjuvant setting.

Additionally, notable is the alternative sequence of TNT utilized by Li et al. The NCCN recommends either CRT followed by chemotherapy, or chemotherapy followed by CRT, prior to restaging and the consideration of surgical resection (1). The optimal sequencing of chemotherapy and CRT in TNT is likely impacted by variable patient and tumor characteristics, but has been an area of active investigation. The benefit of administering chemotherapy prior to CRT is the opportunity for potential omission of radiation, and even surgery, for complete clinical responders. This is being evaluated in multiple trials. Omission of radiation was first investigated in the pilot phase 2 study NCT00462501 by Schrag et al. [2014] (20) and then in the phase 3 trial PROSPECT (NCT01515787), for patients with T2 node-positive staging, T3 node-negative staging, or T3 node-positive staging who were appropriate candidates for sphincter-sparing surgery. Patients were randomly assigned to either CRT followed by surgery then chemotherapy (control arm) or neoadjuvant chemotherapy followed by only selective use of CRT (if <20% response) followed by surgery and postoperative chemotherapy (investigational arm). Preoperative FOLFOX was noninferior to preoperative CRT with respect to DFS (10). In the FOLFOX group, only 53 patients (9.1%) received preoperative CRT and 8 (1.4%) received postoperative CRT. In the phase 2 OPRA study (NCT02008656), LARC patients were treated with induction chemotherapy followed by CRT or CRT followed by consolidation chemotherapy, and either TME or watch-and-wait based on tumor response. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. The TNT-like regimen utilized by Li et al. diverges from TNT in the aforementioned trials in that it straddles CRT with three cycles of “induction” with CAPOX and an additional two cycles of “consolidation” CAPOX. This is reminiscent of the prior old standard adjuvant “sandwich” regimen of chemotherapy followed by CRT followed by additional chemotherapy (total 6 months of treatment) after surgery, which in essence is now replaced by TNT. It is not immediately clear what advantage an approach like this might yield. Hypothetically, it might reduce the risk of neurotoxicity from oxaliplatin by separating treatment cycles. Additionally, delaying surgery after radiation with more chemotherapy might enhance the effects of radiation for tumor reduction with the longer interval between RT and surgery. Li et al. are able to reference and benchmark results to an earlier Peking University-based trial, PKUCH-R02, which aimed to explore the efficacy of similarly “intensive total neoadjuvant treatment” that uses induction and consolidation chemotherapy before and after CRT respectively (21). Li et al. suggest the increased CCR rate of 44% with the inclusion of PD-1 blockade with camrelizumab compared to PKUCH-R02’s 27.9% warrants further investigation of immunotherapy in pMMR LARC. Of course, cross-trial comparisons of response rates, which may be useful in hypothesis generation, cannot substitute dedicated phase 3 trial data.

The search for predictive biomarkers

Currently, mismatch repair deficiency/microsatellite instability are the only well-recognized biomarkers to guide the use of immunotherapy in colorectal cancer. There may be a proportion of patients with pMMR who might benefit from immunotherapy, emphasizing the need to identify more precise biomarkers. Among other studied intrinsic tumor biomarkers, programmed death ligand 1 (PD-L1) expression on tumor cells has failed to perform as a predictive biomarker for response to immunotherapy (22). In contrast to non-small cell lung cancer, PD-L1 is evaluated in other cancer types through the combined positive score (CPS), which qualifies the PD-L1 expression on both the tumor cells and the immune cells in the tumor microenvironment (23). In the gastric carcinoma KEYNOTE-012 trial, tumor response to ICI was more significantly predicted by a PD-L1 scoring system that included immune cells (24). This is being evaluated as a potential biomarker in rectal cancer. Alternatively, tumor-infiltrating lymphocytes (TILs) also showed potential as a tumor microenvironment biomarker predictive of response to treatment. In an analysis study of the KEYNOTE-177 trial, colon cancer response to immunotherapy was associated with presence of TILs, but not TMB (25). Other assays currently being investigated include ImmunoScore—which enumerates CD3⁺ and CD8⁺ T-lymphocyte populations in the tumor core and invasive margin region—and circulating tumor DNA (ctDNA) levels, evaluated by liquid biopsy (26).

In an exploratory genomic landscape analysis by Li et al., tumor mutation burden (TMB), tumor neoantigen burden (TNB), human leukocyte antigen loss of heterozygosity, and pretreatment ctDNA level were not significantly associated with clinical benefit. Mutation in the LRP1B gene, however, was more prevalent in patients that exhibited ≥50% tumor shrinkage (P=0.04) and complete clinical responders (P=0.03) (6). LRP1B was the tenth most frequently mutated gene identified in this cohort, with a mutation rate of 33%. In other studies, across multiple different cancer times, it has been associated with favorable outcomes with the use of ICIs (27). Clinical trials with the inclusion of translational studies of immunologic parameters are needed to identify if indeed there are select pMMR patients who potentially would benefit from immunotherapeutic combinations. As of yet, however, there remains compelling data to suggest a practice-changing role for immunotherapy in this setting.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-79/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-79/coif). A.B.B. received funds to institution from Infinity Pharmaceuticals, Merck Sharp & Dohme, Taiho Pharmaceutical, Bristol-Myers Squibb—DMC, Celgene, Rafael Pharmaceuticals, MedImmune, Xencor, Astellas Pharma—DMC, Amgen, Syncore—DMC, Tyme Inc.—DMC, ITM Solucin GmbH, PANC003—Rafael, Pharmaceuticals, Inc., RM-110—Elevar Therapeutics, Inc., STP-ST-01—ST Pharm Co., Ltd., Mirati Therapeutics, Abbvie, Inc., Janssen, Pfizer, ITM Samsung Bioepsis, National Cancer Insitute Lead Academic Participating Site (LAPS), The Nathan Cummings Foundation, ECOG-ACRIN, travel expenses for NCCN panel and board meetings and in part to ACCC meetings as past president; and was on the Data Safety Monitoring Board or Advisory Board of BMS, Astellas, Apexigen, PrecisCA, Array (Pfizer), Novartis DMC, Amgen, Terumo, Mirati, GSK, Bayer, Aveo DMC, Gusto, Boehringer Ingelheim, Abbvie, Artemida, White Swan, Harborside Press, Patient Resources, LLC, Axis Medical Education, Envision Communications, Trialcard Incorp, Tempus Labs, Inc, Aptitude Health, Therabionic, Aptitude Health, Clarivate Analytics US LLC, Tukysa, Natera, Janssen, AIM Immuno Tech, Nuvation Bio, Xencor, Boston Scientific; played leadership or fiduciary roles in ECOG-ACRIN, Board of Directors NCCN and NCCN Foundation, Patient Advocate Foundation (PAF), National Patient Advocate Foundation (NPAF), Scientific Advisor Fight Colorectal Cancer, Fight Colorectal Cancer Advocacy Group. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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