Immunotherapy for Colorectal Cancer

A Review of Current and Novel Therapeutic Approaches

Aaron J. Franke; William Paul Skelton IV; Jason S. Starr; Hiral Parekh; James J. Lee; Michael J. Overman; Carmen Allegra; Thomas J. George


J Natl Cancer Inst. 2019;111(11):1131-1141. 

In This Article

Treatment With Immune Checkpoint Inhibitors

A growing body of translational and clinical research has identified multiple molecular regulators of lymphocyte activation and suppression that can be therapeutically targeted (Figure 1). The most notable checkpoints in mCRC under active clinical investigation include those that inhibit T-cell activation (ie, CTLA-4, PD-1, and PD-L1), those that promote T-cell activation (ie, LAG-3, OX40, and glucocorticoid-induced TNF receptor family-related protein), and those involved in T-cell metabolism (ie, indoleamine 2, 3-dioxygenase) (Figure 1).[49] Blockage of the suppressive checkpoints (ie, PD-1, PD-L1, CTLA-4) have thus far demonstrated clinical benefit only in patients with MSI-H:dMMR mCRC.

Figure 1.

Select targets of immunotherapy therapeutics currently under investigation in colorectal cancer clinical trials. AKT = protein kinase B kinase (AKT8 virus oncogene cellular homolog); APC = antigen-presenting cell; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; EGFR = epidermal growth factor receptor; ERK = extracellular signal-regulated kinase; GITR = glucocorticoid-induced TNF receptor family-related protein; IDO = indoleamine 2, 3-dioxygenase; LAG3 = lymphocyte-activation gene 3; MEK = mitogen-activated protein extracellular signal-regulated kinase; MHC = major histocompatibility complex; NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells; PD-1 = programmed cell death 1; PD-L1 = PD-1 ligand; PI3K = phosphoinositide 3-kinase; RAF = rapidly accelerated fibrosarcoma; RAS = rat sarcoma; TLR = Toll-like receptor; VEGF = vascular endothelial growth factor.


Despite the FDA approval for a variety of cancers based on improvements in disease control rate (DCR) and OS, including the landmark tumor-agnostic approval of pembrolizumab for all MSI-H:dMMR solid tumors, most studies of checkpoint inhibitors in unselected mCRC populations have shown limited efficacy of this therapeutic option.[50] In the seminal phase I study of nivolumab in 39 patients with advanced-stage solid tumors, including 14 mCRC patients, one mCRC patient (7%) achieved a durable complete response at 6 months, which remained ongoing at 3 years (51). Importantly, the one responder in the trial was found to have MSI-H:dMMR mCRC as well as high expression of PD-L1 on TILs. In a similar phase I study of nivolumab across multiple cancers (n = 296), no objective responses (0 of 19, 0%) were seen in an unselected mCRC population.[50]

The utility of checkpoint inhibitors for MSI-H:dMMR mCRC was further highlighted in the aforementioned KEYNOTE-016 trial of pembrolizumab (10 mg/kg every 14 days) in patients with refractory mCRC (≥2 prior systemic therapies).[8] An updated data analysis for an expanded cohort of 54 mCRC patients (28 of 54 MSI-H:dMMR, 52.0%) was presented at the 2016 Annual American Society of Clinical Oncology meeting.[52] At a median follow-up of 8.7 months, ORR and DCR were 50% (95% CI = 31% to 69%) and 89% (25 of 28) for MSI-H:dMMR mCRC compared with 0% (95% CI = 0% to 14%) and 16% (4 of 25) for MSS:pMMR mCRC, respectively.

Further clinical benefit of targeting PD-1 was illustrated in CheckMate 142, a nonrandomized phase II trial of nivolumab with or without ipilimumab in heavily pretreated patients with MSI-H:dMMR mCRC (NCT02060188). In the previously reported interim analysis of 74 patients in the nivolumab monotherapy arm, investigator-assessed ORR was 31.1% (95% CI = 20.8% to 42.9%), with a complete response in 3%, DCR 12 or more weeks in 69% (95% CI = 57% to 79%), and 1-year OS of 73% (95% CI = 62% to 82%).[46] In an updated analysis of all treated patients (median follow-up 21 months), Overman et al. reported a similar ORR (34%, 95% CI = 23.2% to 45.7%), with 24% (18 of 74) having a PR as their best response. Of note, the rate of complete response increased from 3% (2 of 74) at 13 months to 9% (7 of 74). The DCR remained durable: 47% at 13 months and 46% at 21 months.[9] The benefits of PD-1 monotherapy were seen across all subgroups regardless of tumor or TIL PD-L1 expression, mutational status (BRAF, KRAS), or the presence of germline dMMR.

Based on the data reported in these studies, the FDA extended the approval both for pembrolizumab and nivolumab, with or without ipilimumab, for MSI-H:dMMR mCRC refractory to fluoropyrimidine (5-FU), oxaliplatin, and irinotecan-based treatment.[34] The National Comprehensive Cancer Network lists PD-1 antibodies (ie, nivolumab and pembrolizumab, with or without ipilimumab) as suggested second-line therapy for MSI-H:dMMR mCRC.[53]

A crucial study to assess the role of anti-PD-1 in the front-line setting is the phase III international KEYNOTE-177 RCT (NCT02563002), in which investigators will evaluate pembrolizumab vs investigator's choice of chemotherapy for mCRC in the first-line setting. This trial has completed accrual and the results are highly anticipated.


Although there have been no clinical studies directly comparing PD-1 and PD-L1 inhibitors to date, indirect comparative analyses suggest similar outcomes in terms of tumor response and toxicity profile. In a phase I dose-escalation study of the anti-PD-L1 mAb atezolizumab (MPDL3280A), one of four unselected mCRC patients achieved a durable partial response.[54] In contrast, in a phase I study of anti–PD-L1 mAb (BMS-936559) in 207 patients with advanced solid tumors, no clinical response was observed among 18 unselected mCRC.[55]

The most logical next step in improving outcomes with immunotherapy in MSI-H:dMMR mCRC is in the treatment-naive patient population. The highly anticipated NRG-GI004/S1610 COMMIT trial (NCT02997228) is an ongoing phase III study whereby patients with newly diagnosed mCRC are randomly assigned between mFOLFOX with bevacizumab (control arm) with or without atezolizumab or atezolizumab monotherapy. The incorporation of immunotherapy with standard first-line cytotoxic agents or in comparison with it alone will represent a potential landmark change in treatment paradigms for patients with MSI-H:dMMR mCRC.

However, moving immunotherapy earlier in the stage of disease may offer the opportunity to improve both DFS and OS. The ALLIANCE 021502 (ATOMIC) trial (NCT02912559) is an ongoing phase III randomized controlled trial (RCT) allocating patients with stage III MSI-H:dMMR CRC to either standard adjuvant chemotherapy alone (6 months mFOLFOX6) or combined with atezolizumab, with continuation of anti–PD-L1 therapy for an additional 6 months (total 12 months of immunotherapy). It is hoped the results of this trial will elucidate whether immunotherapy can effectively eradicate minimal residual disease in a high-risk patient population.


Ipilimumab, an anti-CTLA-4 mAb, was the first checkpoint inhibitor to attain FDA approval based on its ability to achieve durable responses and prolong survival in unresectable and/or metastatic melanoma.[56,57] The role of dual checkpoint inhibition (PD-1/CTLA-4) in mCRC was investigated in the CheckMate 142 trial (NCT02060188), which is the largest study of combination immunotherapy in this population to date. In the first interim analysis presented at American Society of Clinical Oncology (ASCO 2016, Overman et al. reported modest activity in MSI-H:dMMR mCRC both with single-agent (nivolumab) and combination immunotherapy (four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks, followed by nivolumab alone 3 mg/kg every 2 weeks), with an ORR of 27% and 15%, respectively.[58] The updated findings for the combination arm presented at the 2018 Gastrointestinal Cancer Symposium suggested MSI-H:dMMR patients may achieve greater clinical benefit with dual checkpoint blockade, although the two study arms were not prospectively designed for direct comparison.[10] After a median follow-up of 13.4 months (range, 9–25), the ORR was 54.6% (95% CI = 45.2% to 63.8%), DCR 12 or more weeks of 80% (95% CI = 71.5% to 86.6%), 12-month PFS and OS of 71% (95% CI = 61.4% to 78.7%) and 85% (95% CI = 77.0% to 90.2%), respectively. Interestingly, the reported ORR in a subset of 16 patients (13%) who discontinued treatment because of immune-mediated toxicity was 63%, comparable to the overall population. The indirect comparison of outcomes in this trial suggests combination immunotherapy provides high response rates, durable disease control, encouraging survival, and clinically meaningful improvements in key patient-reported quality-of-life measures, albeit with more toxicity than seen in the monotherapy nivolumab arm. Based on these encouraging results, the FDA in July 2018 granted accelerated approval to the immunotherapy combination for the treatment of MSI-H mCRC following progression on standard chemotherapy.[34]

Although single-agent nivolumab appears to have activity in MSI-H:dMMR mCRC, it is important to note that a single-arm phase II study of anti–CTLA-4 monotherapy (tremelimumab) in 47 heavily pretreated mCRC patients failed to demonstrate clinical benefit when used alone.[59] Thus, for now, CTLA-4 therapy in mCRC is reserved for use in combination with anti–PD-1 therapy for patients with MSI-H:dMMR. The results of these ongoing pivotal studies will define the role and benefit of chemoimmunotherapy in advanced MSI-H:dMMR CRC. However, many questions will remain including the appropriate duration of immunotherapy treatment, sequencing of immunotherapy agents, interchangeable class effects of the checkpoint inhibitors, and the utility of alternative immunotherapy drugs in the salvage setting in patients who have previously been exposed to checkpoint inhibitors.