Colorectal cancer was once considered unresponsive to immunotherapy. This view changed considerably when a subset of colorectal cancers with microsatellite instability (MSI), indicative of mismatch repair (MMR) deficiency, demonstrated significant clinical responses to the immune checkpoint inhibitor Keytruda (Le DT, 2015). Since then there has been an explosion in the number of trials assessing a variety of immunotherapies in metastatic colorectal cancer [for more information, see Cancer Immunotherapies – 2015]. The 2016 ASCO meeting has seen data presented from two clinical trials, both discussing the role of immune checkpoint inhibitors in Microsatellite Instability-High (MSI-H) and Microsatellite Stable (MSS) colorectal cancer.

MSI-H colorectal cancer tumors are shown to have an exceptionally high mutational burden which corresponds to an increased presence of tumor-specific neoantigens. This is associated with an increased number of tumor-infiltrating lymphocytes and overexpression of immune checkpoint receptors and ligands, e.g. PD-1 and PD-L1. To date there has been little/or no clinical reports of dual immune checkpoint blockade in colorectal cancer, representing an untapped area of research. Data from this year’s ASCO meeting has begun to address this issue.

 

Dual immune checkpoint inhibitor blockade is validated in MSI-H colorectal cancer

  • Interim data from the Phase I/II Checkmate-142 trial (NCT02060188) showed that Opdivo monotherapy and Opdivo plus Yervoy induced impressive ORRs of 25.5% and 33.3% respectively. mPFS for Opdivo monotherapy was 5.3 months and mOS 17.1 months (these data had not been reached in the Opdivo + Yervoy arm) (Overman MJ, 2016).
  • Consistent with safety and tolerability profiles in other cancer indications, the addition of Yervoy to Opdivo was associated with a greater degree of adverse events compared to Opdivo alone (the incidence of any grade 3/4 adverse events in ≥ 15% patients with MSI-H was 26.7% for the combination and 14.3% for Opdivo monotherapy) but was considered manageable.

 

Immune checkpoint inhibitor use may begin to address unmet need for MSS colorectal cancer

Currently only colorectal cancer patients with MSI-H have shown potent and durable responses with immune checkpoint inhibitors. However, this subpopulation only constitutes 4% of all metastatic colorectal cancer, highlighting a need for novel therapies for the remaining 96% of patients with MSI-low or MSS colorectal cancer. Further data presented at this year’s ASCO meeting focused on beginning to address this unmet need.

  • Data from a Phase Ib dose escalation and cohort expansion study (NCT01988896) assessing atezolizumab in combination with cobimetinib (a MEK inhibitor) demonstrated an ORR of 17% in all MSS colorectal cancer patients (n=23); data were slightly higher in tumors harboring a KRAS mutation (ORR: 20% (n=20)) (Bendell JC, 2016).
  • Cobimetinib plus atezolizumab was well tolerated with grade 3 toxicities occurring in 35% of patients.
  • In MSS tumors cobimetinib is hypothesized to sensitize cells to atezolizumab by increasing MHC class I expression on tumor cells, encouraging CD8 T cell accumulation.

Clinical development of immune checkpoint inhibitors in colorectal cancer has largely focused on the MSI-H subpopulation of colorectal cancer however; combinatory approaches with other targeted agents may provide novel treatment options for patients with MSS disease. Both the trials detailed above, although small, have demonstrated clinical efficacy that shows signs of being more favorable compared to therapies such as Stivarga or Lonsurf that are currently used in the third- or later line setting. This is supported by the recent initiation of a Phase III trial comparing the efficacy of atezolizumab plus cobimetinib and atezolizumab monotherapy to regorafenib in MSS metastatic colorectal cancer (NCT02788279).  It is too early to speculate on the trial outcomes of immune checkpoint inhibitors in colorectal cancer; however, the large number of ongoing trials with several of these agents (particularly in the MSI-H sub-population), and physician enthusiasm for this drug class is likely to further drive clinical development over the next few years.

Furthermore, insights from experts interviewed by Decision Resources Group for the upcoming Colorectal Cancer Disease Landscape and Forecast report reveal that they believe combinatory approaches with different immunotherapy agents or dual blockade with immunotherapies and targeted agents could be promising treatment options for MSI-H and MMS colorectal cancer. In addition, they highlight that clinical differences in currently available immune checkpoint inhibitors are minimal; emphasizing that being first-to-market will be an important feat in this indication.

Further insights into clinical development of immunotherapies in colorectal can be found in our 2015 report: Cancer Immunotherapies – 2015 and the upcoming Colorectal Cancer Disease Landscape and Forecast report.

Bibliography:

Bendell JC. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). Journal of Clinical Oncology. 2016; 34:suppl; abstract 3502.

Le DT, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. New England Journal of Medicine. 2015; 372:2509-2520.

Overman MJ. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. Journal of Clinical Oncology. 2016; 34:suppl; abstract 3501.

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