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

Biological Combinations

Another pragmatic approach is to exploit the inherent immunomodulatory properties of conventional CRC therapies in combination with immune-stimulatory agents. These combinations include chemotherapy, small molecule tyrosine kinase inhibitors, targeted mAbs, and radiotherapy (RT).


Numerous cytotoxic agents (ie, anthracyclines and oxaliplatin) have been shown to induce cell death through immunogenic mechanisms resulting in cellular fragmentation that is taken up by APCs and presented to T cells.[62] Intuitively, myeloablative chemotherapy would be assumed to work in an antagonistic fashion by suppressing the immune response; however, chemotherapy-induced bone marrow suppression decreases immune suppressive cells (ie, Tregs) to a greater extent as well as induces proliferation of homeostatic T-cell populations, providing a complementary potential partner for immune stimulation.[63]

In the proof-of-concept GOLFIG-1 trial of 46 mCRC patients (74% had ≥1 prior systemic treatment),[64] the combination of granulocyte macrophage colony stimulating factor and IL-2 following chemotherapy (gemcitabine, oxaliplatin, levofolinic acid, and 5-FU) was associated with manageable toxicity and promising antitumor activity with an ORR of 56.5% (95% CI = 42.1% to 69.8%) and DCR of 91.3% (95% CI = 79.6% to 96.4%). Of note, there was a pronounced survival benefit observed in the six patients who developed therapy-related self-limiting autoimmunity, associated with a mean time to progression of 24 months and OS of 32 months.[65] Validation of this approach was explored in a subsequent phase III RCT comparing GOLFigure to FOLFOX-4 in first-line mCRC;[66] however, the trial was unfortunately closed prematurely because of poor accrual despite allowing MSS patients.

The MODUL trial (NCT02291289) is a randomized multicenter, parallel-group trial investigating immunotherapy maintenance after first-line chemotherapy (FOLFOX + bevacizumab) in mCRC. Cohort two of this trial enrolled 445 patients with wild-type BRAF mCRC and treated them with fluoropyrimidine and bevacizumab with or without atezolizumab, with no difference in PFS (primary endpoint) seen with the addition of atezolizumab (P = .48).[67]

The use of chemoimmunotherapy in mCRC has shown early promise; however, with numerous limiting factors including small sample sizes and heterogeneity of previous systemic therapies, it is difficult at this time to make practice-changing conclusions. Additional studies with large sample sizes are required to elucidate and further characterize this effect.

Immunotherapy With Targeted mAbs

The combination of immunotherapy and targeted mAbs blocking growth factor receptors is one such strategy to enhance the host immune response.[68] Because these mAbs have the potential to induce antibody-dependent cell-mediated cytotoxicity (ADCC), there is preclinical justification to combine these with immunotherapies to enhance or potentiate that response, particularly with agents already proven to be active in mCRC (ie, anti-EGF receptor mAbs cetuximab and panitumumab). In a recently presented phase Ib/II trial of cetuximab plus pembrolizumab in nine RAS wild-type mCRC patients, toxicity was manageable and six patients (67%) maintained stable disease for at least 16 weeks.[69] An ongoing phase II study of 33 additional patients will use dual primary endpoints (ORR and 6-month PFS) to further assess the efficacy of this approach (NCT02713373).

Stimulation of NK cells represents an alternative ideal target for such a molecular approach because they are mediators of ADCC when tumor cells are bound by antitumor mAbs. This hypothesis-generating immunomodulatory approach in mCRC is currently under early investigation in a phase Ib study of cetuximab in combination with urelumab (CD137 agonist), which is designed to bind and activate both NK cells and cytotoxic T cells (NCT02110082). If validated, these and other approaches to leverage ADCC may have an impact with agents already widely in use.

Immunotherapy With VEGF Inhibition

The role of anti-angiogenic agents to enhance immunomodulation of the TME has been supported by early-phase trials in metastatic melanoma[70] and renal cell carcinoma.[71,72] Preclinical data suggest this could also be a therapeutic strategy in mCRC.[73] VEGF inhibition has been shown to suppress activation of tumor-associated macrophages, enhance interactions between APCs and dendritic cells, as well as augment vasculature endothelium to enhance lymphocyte chemotaxis and T-cell tumor infiltration (Figure 1).[74]

The first phase Ib study evaluating this approach for MSI-H:dMMR mCRC was presented at ASCO 2017, reporting outcomes of 10 pretreated patients (70% had ≥2 prior chemotherapies) who received a combination of atezolizumab and bevacizumab.[75] At 11 months, the median OS had not been reached, ORR was 30% (95% CI = 6.7% to 65.3%), median duration of response was 7.8 months (95% CI = 5.5 to 7.8 months), and DCR was 90% (30% PR).

However, the previously mentioned MODUL trial demonstrated no benefit with the addition of atezolizumab combined with 5-FU and bevacizumab after initial oxaliplatin-based therapy in BRAF wild-type mCRC. The randomized phase-2 BACCI trial is further exploring the efficacy of this biologic combination, adding atezolizumab to capecitabine and bevacizumab in refractory mCRC (NCT02873195).

Also, as mentioned previously, the NRG-GI004/S1610 ("COMMIT") trial (NCT02997228) will investigate the role of bevacizumab added to chemoimmunotherapy (mFOLFOX6 and atezolizumab) in the first-line management of MSI-H:dMMR mCRC. In addition to the primary survival endpoint (PFS), therapeutic arms will undergo comparative analysis using multiple simultaneous stratification variables, including BRAF mutation status, history of prior adjuvant therapy for CRC, and site of metastatic disease. The results will help to further define the optimal way to incorporate immunotherapy in MSI-H:dMMR mCRC, particularly in the initial treatment planning for this patient population.

Because not every patient with MSI-H:dMMR mCRC derives durable benefit from immunotherapy, several studies are in development or are ongoing that test reexposure of the patient to anti–PD-(L)1 therapy in conjunction with novel immune-oncology targets (eg, T-cell activators). As an example, the Glucocorticoid-induced TNF receptor family-related protein-agonist (INCAGN01876) is being tested in several combinations and sequences in immunotherapy-naive patients with relapsed MSI-H:dMMR mCRC (NCT03126110). This is but one of several studies looking to overcome the immunoediting associated with checkpoint inhibitor resistance in this patient population. Clinical signals in these early studies will leverage correlative biomarker assessments to identify a population of patients in whom to validate the results in expansion cohorts.

Immunotherapy With RT

In keeping with a multidisciplinary approach to CRC management, there is a growing body of evidence suggesting the combination of immunotherapy and RT enhances our ability to harness the abscopal effect. The abscopal effect is characterized by delivering RT to a solitary site of cancer with resultant immune activation against tumor cells at more distant (nonirradiated) sites, extending the antitumor treatment effects of RT both to local and metastatic disease (Figure 1). There is anecdotal evidence in melanoma of combining ipilimumab with localized RT, resulting in dramatic tumor regression of unirradiated metastatic sites.[76] Our current understanding of this phenomenon is based on preclinical work highlighting the concept of immunogenic cell death with subsequent release of damage-associated molecular patterns,[77,78] which include cancer-associated neoantigens, inflammatory cytokines, upregulation of immunogenic cell surface markers on tumor cells and stroma, and increased antigen presentation by APCs (Figure 1).[79–81]

The clinical utility of this proposed synergistic treatment modality was recently presented by Segal and colleagues in a nonrandomized phase II study (NCT02437071) of pembrolizumab plus RT for patients with MSS:pMMR mCRC (n = 22).[82] Palliative RT was delivered to a metastasis followed by the first dose of pembrolizumab (200 mg every 3 weeks), with objective response in a nonradiated lesion as the primary endpoint. Despite the combination being very well tolerated, only one patient achieved a partial response (ORR = 4.5%), suggesting the single-agent immunotherapy with RT used in this trial is not enough to induce a systemic anticancer effect. As a logical next step, NSABP FC-9 is currently enrolling patients with MSS:pMMR refractory mCRC (NCT02701400). This phase II single-arm study tests dual checkpoint inhibitor with durvalumab (PD-L1) plus tremelimumab (CTLA-4) following palliative hypofractionated RT. Similarly, a phase II trial of durvalumab plus tremelimumab with either standard RT or local ablation in mCRC is underway (NCT03122509). Results from both studies are eagerly awaited.