Analyst notes: Are PD-1/PD-L1 checkpoint inhibitors soon to carve their niche in colorectal cancer?

PD-1/PD-L1 (programmed cell death-1/ligand-1) checkpoint inhibitors have been highly successful in malignant melanoma and non-small-cell lung cancer (NSCLC), where they have fast become the standards of care in later lines of therapy. Although colorectal cancer (CRC) has a high global incidence, development of checkpoint inhibitors has lagged behind in this space. There is an abundance of targeted treatments already available for the treatment of metastatic CRC (mCRC), and PD-1/PD-L1 inhibitors are being positioned in patients with tumours that have high microsatellite instability (MSI-H), and are DNA mismatch repair (MMR)-deficient (approximately 15 percent to 20 percent of non-hereditary CRC and in hereditary CRC associated with Lynch syndrome). Both Merck & Co.'s PD-1 inhibitor Keytruda (pembrolizumab) and Roche's PD-L1 inhibitor Tecentriq (atezolizumab) are currently being evaluated in Phase III studies in advanced CRC patients.

Insights, Analysis & Opinion

Key opinion leaders (KOLs) interviewed by FirstWord for the forthcoming report Colorectal Cancer: KOL Insight were highly optimistic about the future use of Keytruda and Tecentriq in mCRC, noting their similar efficacy profiles and prior successful approvals in other cancer indications. They note that the efficacy benefit for Keytruda was restricted to MSI-H CRC patients in a recent Phase II study, and a number of experts suggested that these therapies could represent a new treatment option for this tough-to-treat population and potentially become the standard of care.

"They are only going to work in microsatellite unstable or Lynch syndrome-type patients. I think that is where they are going to have the most success based on the literature that has already come out. That is a small portion of CRC patients, but I think there will be success in that group.” - US Key Opinion Leader

As it stands, the specialists were uncertain whether the checkpoint inhibitors would be best utilised as monotherapies or as part of a combination approach. The pivotal KEYNOTE-177 trial will compare Keytruda monotherapy with Avastin (bevacizumab) or Erbitux (cetuximab), in combination with chemotherapy, in MSI-H mCRC. Most of the KOLs felt that the study will meet its primary endpoint of progression-free survival (PFS) and were supportive of the decision to target this niche patient population. However, others were hesitant suggesting that the data so far were not a guarantee of its success in the Phase III trial. Overall, the KOLs felt very strongly about Keytruda in CRC, with many suggesting that with additional data from the ongoing trials, it could easily become a first-line treatment of choice. Reflecting on the Phase Ib trial results with Tecentriq and Exelixis/Roche's MEK inhibitor cobimetinib, presented earlier this year, the KOLs were somewhat apprehensive about the low observed response rate of 17 percent, but suggested that these data could be further teased out in the larger Phase III trial by further examination of patient subgroups. Overall, KOLs remain hopeful about the pivotal COTEZO study investigating the combination of cobimetinib and Tecentriq. With a lack of effective treatments in the MSI-H population, experts believe that checkpoint inhibitors may hold the potential to become the new first-line standard of care in this subgroup characterised by high unmet need.

For companies operating in the colorectal cancer market in Europe and the US, Colorectal Cancer: KOL Insight is a must read. The report provides actionable insights and commentary on some of the most critical issues in the colorectal cancer market, and provides perspectives on pipeline therapies and how their potential in a rapidly increasing market. The report also discusses how treatment paradigms could change in CRC. For more information, please click here.

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