No abstract

Background Metastatic colorectal cancers (MCRCs) with microsatellite stability (MSS) are resistant to immunotherapy with programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 inhibitors. However, the addition of regorafenib to nivolumab was recently associated with a high response rate and a protracted progression‐free survival in a small cohort of MSS Japanese patients with metastatic colorectal cancer. Materials and Methods We evaluated the outcome of patients with MSS metastatic colorectal cancer who were treated on a compassionate basis with PD‐1 inhibitors in combination with regorafenib in a single U.S. center. Results A total of 18 patients were treated with a combination of regorafenib and PD‐1 inhibitors. No treatment‐related grade 3 or above toxicities were noted. Thirteen patients (69%) had progressive disease, and five patients (31%) experienced stable disease as best response. Four out of five stable diseases occurred in patients without liver metastases, whereas only 1 of 14 patients with history of liver metastases had a short disease stabilization. A rise in circulating tumor DNA (ctDNA) at the 4‐week time pointuniversally predicted tumor progression at 2 months, whereas a decline was associated with radiographic disease stabilization. Conclusions Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy‐resistant metastatic colorectal cancer. Selection for patients without history of liver metastases may identify a cohort of patients with MSS colorectal cancer with a higher likelihood of benefit from this combination. ctDNA may represent a powerful tool for predicting early therapeutic efficacy of immunotherapy in the MSS colorectal cancer population. Implications for Practice This study showed that the combination of regorafenib and nivolumab was associated with a modest clinical activity in patients with advanced microsatellite stability (MSS) metastatic colorectal cancer. This combination should be avoided in clinical practice, especially in patients with MSS colorectal cancer with liver metastases. Further investigation of regorafenib plus PD‐1 inhibitors should be considered in MSS colorectal cancer without liver metastases.

Key Points Question Is immunotherapy targeting programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) associated with the presence of liver metastasis at the time of therapy and outcomes among patients with treatment-resistant microsatellite stable (MSS) metastatic colorectal cancer? Findings This cohort study included 95 patients with MSS metastatic colorectal cancer. Patients without liver metastases had a significantly superior objective response rate (19.5% vs 0) and median progression-free survival (4.0 vs 1.5 months) compared with patients with liver metastases; multivariate analysis revealed that the presence of liver metastases was an independent prognostic factor associated with poor outcome of PD-1/PD-L1 therapy. Meaning This cohort study suggests that PD-1/PD-L1 inhibitors should be reinvestigated in prospective trials in patients with MSS metastatic colorectal cancer without liver involvement.

The treatment of metastatic colorectal cancer has evolved over the last two decades with the FDA approval of several cytotoxic, biological, and targeted agents. In this paper, we review the impact of sidedness, RAS, BRAF, HER‐2, and other immune biomarkers on metastatic colorectal cancer treatment selection and sequencing in both the palliative and curative intent settings.

Background Direct comparisons between Guardant360 (G360) circulating tumor DNA (ctDNA) and FoundationOne (F1) tumor biopsy genomic profiling in metastatic colorectal cancer (mCRC) are limited. We aim to assess the concordance across overlapping genes tested in both F1 and G360 in patients with mCRC. Materials and Methods We retrospectively analyzed 75 patients with mCRC who underwent G360 and F1 testing. We evaluated the concordance among gene mutations tested by both G360 and F1 among three categories of patients: untreated, treated without, and treated with EGFR inhibitors, while considering the clonal and/or subclonal nature of each genomic alteration. Results There was a high rate of concordance in APC, TP53, KRAS, NRAS, and BRAF mutations in the treatment‐naive and non–anti‐EGFR‐treated cohorts. There was increased discordance in the anti‐EGFR treated patients in three drivers of anti‐EGFR resistance: KRAS, NRAS, and EGFR somatic mutations. Based on percentage of ctDNA, discordant somatic mutations were mostly subclonal instead of clonal and may have limited clinical significance. Most discordant amplifications noted on G360 showed the magnitude below the top decile, occurred in all three cohorts of patients, and were of unknown clinical significance. Serial ctDNA in anti‐EGFR treated patients showed the emergence of multiple new alterations that affected the EGFR pathway: EGFR and RAS mutations and MET, RAS, and BRAF amplifications. Conclusion G360 Next‐Generation Sequencing platform may be used as an alternative to F1 to detect targetable somatic alterations in non–anti‐EGFR treated mCRC, but larger prospective studies are needed to further validate our findings. Implications for Practice Genomic analysis of tissue biopsy is currently the optimal method for identifying DNA genomic alterations to help physicians target specific genes but has many disadvantages that may be mitigated by a circulating free tumor DNA (ctDNA) assay. This study showed a high concordance rate in certain gene mutations in patients who were treatment naive and treated with non–anti‐EGFR therapy prior to ctDNA testing. This suggests that ctDNA genomic analysis may potentially be used as an alternative to tumor biopsy to identify appropriate patients for treatment selection in mCRC, but larger prospective studies are needed to further validate concordance among tissue and ctDNA tumor profiling.