Immune Modulation in Colorectal and Anal Cancers

Highlights from ASCO 2016 Annual Meeting

The results from studies on checkpoint inhibition for three emerging indications in colorectal and anal cancers were presented in the oral abstract session at ASCO 2016 Annual Meeting (3-7 June, Chicago, United States). The data are compelling, but do not yet change standard practice. PD-1 blockade alone or in combination with CTLA-4 inhibition in microsatellite unstable colon cancer, MEK inhibition plus PD-L1 in microsatellite stable colon cancer, and PD-1 blockade in anal squamous cell cancer warrant further investigation.

PD-1 blockade alone or with CTLA-4 blockade in MSI-H colon cancer

Although approximately 15% of early colorectal cancers (CRCs) display a high degree of microsatellite instability (MSI-H), indicating a deficient DNA mismatch repair system, MSI-H status is found in approximately 4% of metastatic CRC (mCRC). MSI-H CRC is known to have an exceptionally high mutation burden. In CRC, MSI-H is associated with increases in immune infiltration and expression of immune checkpoint regulators. Interim results from CheckMate-142, a phase II study that evaluates nivolumab or nivolumab plus ipilimumab in patients with mCRC, MSI-H and non-MSI-H were presented (1).

Increased presence of tumour-specific neoantigens in hypermutated tumours is associated with an increased quantity of tumour-infiltrating lymphocytes (TILs) and overexpression of immune checkpoint receptors and ligands, such as programmed death-1 (PD-1) and PD-1 ligand 1 (PD-L1). Checkpoint inhibitor blockade, including PD-1 blockade and CTLA-4 blockade, is expected to be particularly effective in MSI-H CRC.

The presented results indicate that nivolumab monotherapy demonstrated encouraging activity in patients with MSI-H status at this interim analysis; the combination of nivolumab plus ipilimumab also demonstrated promising preliminary activity. Responses to nivolumab monotherapy and the nivolumab plus ipilimumab combination were durable in patients with MSI-H.

Nivolumab and the combination of nivolumab plus ipilimumab demonstrated tolerable safety profiles in relation to clinical benefit that were consistent with observations in other solid tumours.  

Results are encouraging and support continued evaluation of nivolumab monotherapy and nivolumab plus ipilimumab in patients with MSI-H metastatic CRC and potentially other tumours with mismatch repair defects.

MEK inhibition plus PD-L1 in MSS colon cancer

MSI-H CRC, which is associated with deficiency in DNA mismatch repair and high mutation load demonstrates response to single agent therapy targeting PD-L1/PD-1 axis. This is consistent with the hypothesis that tumours with high mutation burden are more responsive to cancer immunotherapy. However, MSI-H CRC represents only approximately 4% of metastatic CRC. Treatments resulting in potent and durable responses remain an unmet need for patients with microsatellite stable (MSS) mCRC.

The MAP kinase pathway is one of the most frequently dysregulated pathways in cancer due to hyperactivation by growth factor receptors or activating mutations. Single agent MEK inhibition has shown little activity in mCRC. Response to PD-L1/PD-1 targeting agents in mismatch-repair proficient CRC (ie MSS) has been lower than seen in other indications.

In preclinical models, targeted inhibition of MEK leads to upregulation of MHC I on tumour cells, induces intratumoural T-cell infiltration and enhances anti-PDL1 activity. The researchers therefore conducted a phase Ib study combining cobimetinib (MEK inhibitor) and atezolizumab in patients with advanced solid tumours (2). Tumour-specific expansion cohorts, including KRAS-mutant CRC, and serial biopsy cohorts in solid tumours were opened.

Cobimetinib plus atezolizumab was well tolerated at the maximum administered doses in patients with chemorefractory KRAS mutant mCRC. The combination resulted in a higher clinical response rate in MSS patients than expected from either cobimetinib or atezolizumab alone. The overall response rate (ORR) of 17% and 6-month overall survival (OS) of 72% represent clinical improvements over a historical 1% of ORR and approximately 6-month median survival for standard of care in this setting.  

These results suggest that cobimetinib can sensitise tumours to atezolizumab by increasing MHC I expression on tumour cells and promoting intratumoural CD8 T cell accumulation.  

Based on these encouraging preliminary results, the expansion of this phase Ib study is ongoing in mCRC.

PD-1 blockade in anal squamous cell cancer

Over 27,000 new cases annually of anal cancer are diagnosed worldwide. The incidence of anal cancer continues to rise annually. There is no established standard of care for patients with refractory metastatic anal squamous cell cancer. To date, a prospective phase II clinical trial has not been completed for patients in metastatic setting.

Aproximately 80-95% of cases are linked to human papillomavirus (HPV). The role of HPV in the tumourigenesis of this cancer type provides rationale for the use of immune checkpoint blockade agents as a novel therapy for treatment of patients with a virally driven disease.

The researchers presented at ASCO 2016 the results from the first prospective phase II study to be completed in metastatic refractory anal squamous cell cancer (3). Single agent nivolumab was well tolerated and fulfilled the primary endpoint of response. No additional unexpected serious adverse events in HIV-positive patients were observed. Rapid enrolment was feasible. Continued clinical trial enrollment is crucial in the hopes of obtaining an FDA indication for the “rare” cancer of metastatic squamous cell carcinoma of the anal canal.

Additional updated cfDNA data will be presented at the ESMO World Congress on Gastrointestinal Cancer, (29 June – 2 July 2016, Barcelona, Spain). 

References 

  1. Overman MJ, Kopetz S, McDermott RS, et al. 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. J Clin Oncol 34, 2016 (suppl; abstr 3501)
  2. Bendell JC, Kim TW, Goh BC, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol 34, 2016 (suppl; abstr 3502)
  3. Morris VK, Ciombor KK, Salem MS, et al. NCI9673: A multi-institutional eETCTN phase II study of nivolumab in refractory metastatic squamous cell carcinoma of the anal canal (SCCA). J Clin Oncol 34, 2016 (suppl; abstr 3503)