Positive Outcomes Confirmed for Frontline ICI Use in Metastatic CRC
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Frontline use of immune checkpoint inhibitors (ICIs) in patients with metastatic colorectal cancer (mCRC) whose tumors were microsatellite instability high (MSI-H) had significantly longer survival expectancy and lower likelihood of therapy discontinuation compared with patients treated with chemotherapy alone, according to findings published in JAMA Network Open.1 The findings also shed light on a subset of patients with microsatellite stable (MSS) tumors, who have historically shown limited response to ICIs in clinical trials.
Patients treated with ICIs in the first line had a longer overall survival (OS) than patients treated with chemotherapy alone (HR, 060; 95% CI, 0.44-0.82; P =.002), but not for those patients who received ICI therapy in the second or later line. When patients were stratified by mismatch repair (MMR) status, those with MSI-H tumors had a significantly longer OS associated with first line of ICI-based therapy compared with chemotherapy (HR, 0.37; 95%CI, 0.25-0.56; P <.001) whereas no association was found in the MSS cohort.
A total of 23,963 patients with mCRC were reviewed from a national health record database, and a total of 18,932 patients who received ICI-based therapy for mCRC were eligible. As this was a noninterventional study that used deidentified patient records, informed consent was not required per the scientific review committee. ICI-based therapy involved treatment with either nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), ipilimumab (Yervoy), tremelimumab (Imjudo), durvalumab (Imfinzi), or avelumab (Bavencio).
Primary outcomes were receipt of ICI-based therapy (yes/no) and OS, defined as the time from index date to date of death, last known follow-up, or end of study period (December 31, 2019), whichever occurred first. Time to deterioration (TTD) was the secondary outcome and it was defined as the time from the first to the last episode of treatment regimen, last known follow-up, or death, whichever occurred first.
The majority of patients were male (55.7%) and 65.2% were White, 10.6% were Black or African American, 8.8% were Hispanic, and 2.9% were Asian, with 21.4% of unknown race or ethnicity. The median age at time of metastatic diagnosis was 64.6 years (range, 55.0-73.3).
Patients with MSI-H tumors were more likely to receive ICIs than those with MSS tumors (OR, 22.7; 95% CI, 17.30-29.73; P <.001). Intriguingly, 12.3% (29 of 235) of MSS patients and 13.1% (16 of 122) of those with MSS/KRAS-mutated tumors exhibited durable responses to ICI therapy, a finding that warrants further investigation.
Regarding clinical factors, investigators reported that among patients with MSS tumors, ICI therapy was associated with longer OS in patients with high albumin levels vs low (HR, 0.28; 95% CI, 0.18-0.45; P <.001) and antibiotic use vs nonuse (HR, 0.43; 95% CI, 0.27-0.67; P <.001). For TTD, a significantly lower likelihood of immunotherapy discontinuation was observed for patients with MSI-H tumors vs MSS cohort (HR, 0.41; 95% CI, 0.30-0.55; P <.001).
The investigators noted that the results support the KEYNOTE-177 trial (NCT02563002), which evaluated the efficacy of frontline pembrolizumab vs chemotherapy for patients with MSI-H tumors.2
Strengths of the study include its large and heterogeneous patient population and its sizeable MSS cohort. Limitations include incomplete or missing data in the patient record database, including somatic/molecular features, tumor mutational burden, and germline test results.
