Immune checkpoint inhibitors in colorectal cancer: Who’s checking-in first?
Colorectal cancer was once thought to be unresponsive to immunotherapy, yet now it is poised to become one of the next oncology indications to be infiltrated by immune checkpoint inhibitors. To date immune checkpoint inhibitors have demonstrated the greatest efficacy in microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) tumours. mCRC dMMR or MSI-H tumors exhibit an exceptionally high neoantigen load and a greater level of immune cell infiltration, which is proposed to make such tumours amenable to immune checkpoint blockade (Overman MJ, 2017). However, such genetic abnormalities occur infrequently in mCRC, occurring in only 4% of patients (Le DT, 2015; Goldstein J, 2014). Nevertheless, the high incidence of colorectal cancer makes the patient population commercially lucrative.
On April 4 2017, Bristol-Myers Squibb announced that the FDA had accepted a sBLA application (based on the Phase II Checkmate-142 [clinicaltrials.gov: NCT02060188] trial) to extend the use of Opdivo to patients with MSI-H or dMMR mCRC after prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy. Updated data for Opdivo from the Checkmate-142 trial (n = 74) was presented at the 2017 Gastrointestinal Cancers Symposium, showing an ORR of 27% (according to the independent radiology review committee) and 31% (according to the investigator). OS rates at 6 and 12 months were 83.4% and 73.8%, respectively; the mOS was not reached (Overman, MJ, 2017). Notably, no further data was provided regarding the combination of Opdivo and Yervoy, which is also being assessed in this trial and previously reported higher response rates but greater toxicity than Opdivo alone in this trial. The lack of news on Opdivo plus Yervoy from Checkmate-142, and the fact that only Opdivo monotherapy has been filed from this trial indicates that this combination may not make it to market for this population; we await more data to understand the full picture. Nevertheless, the FDA action date for the sBLA for Opdivo is August 2 2017 which will intensify the race to be crowned the first-line immune checkpoint inhibitor in colorectal cancer.
In November 2015, the FDA awarded BTD for Keytruda in MSI-H mCRC and more recently for unresectable or metastatic MSI-H non-colorectal cancer. Keytruda has demonstrated impressive efficacy in this population, with an ORR of 50% in patients with dMMR tumours (N = 28), corresponding to an OS rate of 66% at 24 months (mOS not reached) (Le DT, 2016). In November 2016, the FDA granted priority review for ’s sBLA application for previously treated patients with advanced MSI-H cancer. The broad population of this sBLA makes it unclear which indications will be covered by the filing; however, we assume previously treated MSI-H mCRC will be included. It has not been plain sailing for Merck & Co. however, as the original action date for the sBLA (March 8 2017) was extended following the submission of additional data to the FDA which was considered a major amendment to the filing. The action date has now been extended to June 9 2017. Furthermore, the primary completion date for the Phase II registrational trial in MSI-H mCRC (KEYNOTE-016; clinicaltrials.gov NCT02460198) has been pushed back by almost a year; another considerable setback. However, Merck & Co. remains the only company to have an ongoing Phase III trial (KEYNOTE-177; clinicaltrials.gov NCT02563002) assessing an immune checkpoint inhibitor as a monotherapy in the first-line setting for MSI-H or dMMR mCRC, which if positive would likely make Keytruda the standard of care in this subpopulation.
The clinical development for Tecentriq is distinctly different to that of the aforementioned immune checkpoint inhibitors, as Roche has initiated a Phase III trial to assess Tecentriq in combination with the companies MEK inhibitor, Cotellic, as a third or later-line therapy for microsatellite stable mCRC. Preliminary data for the combination has shown an encouraging ORR of 17% (N=23) in heavily pre-treated patients, which compares more favourably to the standard-of-care therapies in this setting (Stivarga or Lonsurf), which elicit an ORR of 0-2% (Bendell JC, 2016). In Tecentriq’s development, Roche have carved a niche target population in mCRC where no other immune checkpoint inhibitors are currently being assessed. Notably, the National Cancer institute are also poised to conduct two Phase III trials of Tecentriq in colorectal cancer: one assessing chemotherapy plus Avastin with or without Tecentriq in first-line MSI-H or dMMR mCRC (clinicaltrials.gov NCT02997228), and a second evaluating Tecentriq in combination with FOLFOX versus FOLFOX alone in stage III colon cancer with MSI-H or dMMR (clinicaltrials.gov NCT02912559). Of interest, the incidence of MSI-H and dMMR is approximately 12% in stage III disease, therefore if this Phase III trial is positive it may provide Roche a significant commercial opportunity that its competitors have yet to exploit (Tejpar S, 2009).
The race to be the first immune checkpoint inhibitor to enter the colorectal cancer market has intensified in the last year. Despite some setbacks, Merck & Co. is still on track to be the first immune checkpoint inhibitor to enter the colorectal cancer market, however Bristol-Myers Squibb will be hot on Merck & Co.’s heels as there is only a two-month difference in the FDA action dates for both companies sBLA applications. Although Tecentriq will not be the first immune checkpoint to the colorectal market, it is positioned in distinctly different patient populations to Keytruda and Opdivo which could result in significant commercial reward. Ultimately Keytruda will likely win in the foreseeable future as the first agent to market, but could Tecentriq overshadow Keytruda in the future? Only time will tell.
Bendell JC. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). Journal of Clinical Oncology. 2016; 34:suppl; abstract 3502.
Goldstein J. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Annals of Oncology. 2014; 25(5):1032-1038.
Le DT, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. New England Journal of Medicine. 2015; 372:2509-2520.
Le DT, et al. Programmed death-1 blockade in mismatch repair deficient colorectal cancer. Journal of Clinical Oncology. 2016;34:suppl; abstract 103.
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.
Overman MJ. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: Update from Checkmate 142. Journal of Clinical Oncology. 2017;35 suppl 4S;abstract 519.
Tejpar . Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial). 2009;27: suppl 15s;abstract 4001.