ESMO 2021 Congress: CRC highlights

Colorectal (CRC) cancer screening and diagnosis during the COVID-19 pandemic in Quebec, Canada

CRC is the third most common cancer in Quebec, with projected cases in 2020 consisting of 3900 in males, and 3100 in females. During the first wave of the COVID-19 pandemic which extended from March to July 2020, Quebec experienced 59 845 infections and 5829 COVID-19 -related deaths. Quebec, like all other provinces, was forced to scale back health care services including CRC screening and treatment modalities such as colonoscopy and surgery.

In January 2021, the Ministry of Health of Quebec released data related to fecal immunochemical test (FIT), colonoscopy and CRC surgery. An analysis was conducted by Dr. Mustapha Tehfe and his team of researchers and presented at the 2021 ESMO Congress to compare the 4-month period of April to July of 2020 to the same months in 2019 to study the impact of the pandemic on CRC screening and diagnosis.

Prior to the second wave in the period between August-October 2020, health care services resumed but due to the delays and back-log, FIT was still occurring 5% less than the previous year, colonoscopy 11.4% less, and CRC surgery 28% less. These data underline how the pandemic led to unprecedented delays to cancer screening, diagnosis and treatment. Though the overall impact on mortality is not yet known, it is likely to be significant. Catching up with the delays will be a major challenge and will likely require adding substantial resources to the health care system.

KRAS G12C inhibition shows potential for the improved management of advanced CRC

Patients with KRAS-mutated colorectal cancer (CRC) have a significant need for new treatment options. KRAS is part of the RAS gene family is among the most studied cancer-related genes. All human cells contain the KRAS gene which serves as an important regulator of signalling pathways that are responsible for cell proliferation, differentiation, and survival. If a mutation occurs in a KRAS gene, it may cause the cell to multiply out of control, leading to cancer.

Of the three different RAS genes – NRAS, KRAS, HRAS – KRAS is the most frequently mutated gene, occurring in 17-25% of all cancers and 30-40% of CRCs[1]. Since KRAS mutations are so common in CRC and patients with this mutation tend to experience poorer survival outcomes compared to the KRAS wild-type (the natural, unmutated form of the gene) patient population, developing KRAS-specific treatments is an area of high unmet need. To date, the development of therapies for CRC that directly target KRAS has been largely unsuccessful.

Among KRAS mutations, there exists subsets of mutations. One that is being actively studied is the KRAS G12C mutation, which represents 3-4% of CRCs.

G12C is a single point mutation in the KRAS gene, with a glycine-to-cysteine amino acid substitution at codon 12. This substitution favours the “on” or activated state of KRAS, leading to amplified signalling pathways and oncogenesis.

The KRYSTAL-1 phase I/II trial is currently evaluating the use of a targeted therapy drug, adagrasib, as both a single agent and in combination with the targeted therapy cetuximab for patients with heavily pre-treated KRAS G12C-mutated CRC. Adagrasib is a targeted agent that inhibits KRAS G12C activity by irreversibly binding to the KRAS gene and locking it in its inactive state. When a patient has the KRAS G12C mutation, it is a negative predictor for cetuximab efficacy. Therefore, the researchers hypothesized that by combining a KRAS G12C inhibitor with cetuximab, overall treatment efficacy would be improved.

In the study, patients with pre-treated KRAS-G12C-mutant CRC were randomly assigned to received either adagrasib alone or adagrasib plus cetuximab. 46 patients who had received an average of 3 previous lines of therapy received adagrasib monotherapy (single agent). Their response rate was 22% and disease control rate was 87%. Among the 23 patients who received adagrasib plus cetuximab, response rate was 39% and disease control rate of 100%.

According to lead researcher Dr. Jared Weiss, the overall response data was still too immature to determine a meaningful analysis for the duration of response (how robust are these outcomes among patients?) and progression-free survival (do these treatments extend the amount of time a patient lives with the disease, but it does not worsen?).

Adagrasib was well-tolerated with a manageable safety profile as both a single agent and in combination with cetuximab. The combination therapy is currently being evaluated as a second line therapy, in a phase III trial among patients with KRAS G12C-mutated CRC.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4316144/#:~:text=Of%20the%20three%20human%20ras,survival%20and%20increased%20tumor%20aggressiveness.