A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer.

INTRODUCTION: Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H), defined as TMB ≥ 10 mut/Mb, independent of deficient mismatch repair (dMMR) and microsatellite instability high (MSI-H) status. METHODS: De-identified records of patients with colorectal cancer (CRC) profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500×) were identified from the Tempus Database. RESULTS: Among 9136 CRC samples profiled, the frequency of POLE/POLD1 genomic alterations was 2.4% (n = 217). Copy number loss was the most common genomic alteration (64%, n = 138) of POLE/POLD1, followed by copy number amplifications (18%, n = 40) and short variant mutations (18%, n = 39). The POLE/POLD1 mutated group presented with a higher frequency of TMB-H phenotype relative to wild type (WT; 22% vs. 9%, P < .001), with a median TMB of 127 mut/Mb in the TMB-H POLE/POLD1 subset. The TMB showed a dramatic contrast between POLE/POLD1 short variant mutations as compared to the group with copy number alterations, with a TMB of 159 mut/Mb vs 15 mut/Mb, respectively. Thus, the short variant mutations represented the so-called ultra-hypermutated phenotype. The POLE/POLD1 mutated group, as compared to WT, exhibited a higher rate of coexisting mutations, including APC, ALK, ATM, BRCA2, and RET mutations. CONCLUSION: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors.

Improving survival in metastatic colorectal cancer through optimized patient selection.

The systemic treatment options for patients with metastatic colorectal cancer have recently expanded with the US Food and Drug Administration approval of fruquintinib being added to previously approved trifluridine/tipiracil with or without bevacizumab and regorafenib. These therapies are recommended for use based on the initial clinical trials that focused on their safety and efficacy in extending overall survival of patients with refractory metastatic disease, as well as later studies, including the ReDOS study that confirmed the dose-escalation strategy of regorafenib to be key in optimizing duration of therapy and preventing side effects. Although more research is needed on how to sequence third-line therapies, data from real-world studies showed that switching from regorafenib to trifluridine/tipiracil with or without bevacizumab allowed patients to have a chemotherapy-free break and led to improved survival, suggesting that there may be a benefit for using regorafenib first. Current treatment guidelines state that each therapy can be given before or after the others. Generally, sequencing considerations in the refractory setting include multiple variables such as tumor characteristics, toxicities, factors that are important to the patient, response to prior lines of therapy, and extent of disease.

Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer.

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months (95% CI, 5.7-7.4) and median overall survival was 15.9 months (95% CI, 11.8-18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3-4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance. SIGNIFICANCE: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897.

Treatment options for HER2-expressing colorectal cancer: updates and recent approvals.

Colorectal cancer is a leading cause of cancer-related mortality worldwide. Approximately 3-5% of colorectal tumors harbor human epidermal growth factor receptor (HER2) amplification which is associated with a higher incidence of intracranial metastasis and overall worse outcomes. In the setting of refractory metastatic RAS wild-type tumors, evidence supports the use of various HER2-blocking agents, including monoclonal antibodies, tyrosine kinase inhibitors, and novel antibody-drug conjugates. With a number of relatively active agents clinically available and even more in development, it is crucial for clinicians to familiarize themselves with the mechanisms of action, efficacy data, and safety profiles of these treatments. In this review, we aim to summarize key findings from past and ongoing trials with anti-HER2 agents in metastatic colorectal cancer.