Assessing the Current Standard of Care Treatment for Colorectal Cancer

Smitha Krishnamurthi, MD Cleveland Clinic | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Circulating tumor DNA (ctDNA) is a meaningful predictive marker in early-stage colorectal cancer and may be used to guide adjuvant therapy decisions.

• Recent trials have suggested neoadjuvant or adjuvant immunotherapy may improve outcomes for patients with microsatellite instability-high (MSI-H) disease.

• In the metastatic setting, next-generation sequencing and biomarker testing are needed to select frontline and subsequent treatment options.

Standard of Care Colorectal Cancer Treatment

Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, invited Smitha Krishnamurthi, MD, a gastrointestinal medical oncologist at Cleveland Clinic, to discuss the current standard of care treatment for colorectal cancer from early stage to refractory metastatic disease. 

Treating Early-Stage Colorectal Cancer 

Upfront surgery is the standard of care treatment for stage I, II, and III colorectal cancer. Following surgery, patients may start or discontinue adjuvant chemotherapy based on biomarkers such as microsatellite instability and ctDNA status. Specifically, data from the DYNAMIC trial showed that ctDNA status can guide adjuvant treatment decisions in stage II colorectal cancer without compromising recurrence-free survival. 

In stage IIa colorectal cancer, adjuvant chemotherapy is strongly indicated for high-risk patients with positive ctDNA, and may also be considered for low-risk patients with low MSI. Otherwise, for MSI-H or ctDNA–negative stage IIa disease, surveillance or observation may be appropriate. For stage IIb to IIc populations, ctDNA status is less conclusive, and adjuvant chemotherapy might be considered even in ctDNA–negative patients, said Dr. Krishnamurthi. When using adjuvant chemotherapy, Dr. Krishnamurthi typically selects an oxaliplatin plus fluorouracil (5-FU) or capecitabine doublet.

Recently, the NICHE-2 and ATOMIC trials showed that the addition of immunotherapy may improve outcomes in MSI-H colorectal cancer. The phase 2 NICHE-2 trial evaluated neoadjuvant nivolumab plus ipilimumab, while the phase 3 ATOMIC trial evaluated adjuvant atezolizumab plus chemotherapy. Based on these trials, the ATOMIC regimen became a standard of care for resectable, MSI-H, stage III colorectal cancer, and neoadjuvant immunotherapy was added to National Comprehensive Cancer Network recommendations for patients with bulky disease. Broadly, however, more data are needed to optimize the timing and duration of immunotherapy in patients with early-stage colorectal cancer, said Dr. Krishnamurthi. 

First-Line Standard of Care Treatment for Metastatic Colorectal Cancer

Standard of care treatments for colorectal cancer in the first-line metastatic setting include immunotherapy, chemotherapy, and targeted agent combinations. As such, upfront biomarker and NGS testing are necessary for therapy selection. Treatment options also differ based on left-sided or right-sided disease. 

For right-sided or RAS–mutated disease, the standard of care is 5-FU or capecitabine–based chemotherapy plus bevacizumab, an anti-VEGF agent, based on the TRIBE study. Comparatively, for RAS–unmutated and left-sided disease, the PARADIGM trial showed that chemotherapy plus panitumumab, an anti-EGFR agent, outperformed the TRIBE regimen. More recently, the phase 3 BREAKWATER trial showed that mFOLFOX6 (modified leucovorin, 5-FU, and oxaliplatin) plus encorafenib and cetuximab significantly improved survival outcomes in patients with BRAF V600E mutations compared with standard chemotherapy alone or with bevacizumab.

For MSI-H metastatic colorectal cancer, the CheckMate 8HW trial showed ipilimumab plus nivolumab improved outcomes compared with single-agent immunotherapy. Toxicity is a potential limitation to using dual immunotherapy over single-agent therapy, but common adverse events are typically manageable, Dr. Krishnamurthi said. 

Treating Refractory Metastatic Colorectal Cancer

For second-line treatment of metastatic colorectal cancer after progression, BRAF V600E–mutated patients on the BREAKWATER regimen may be swapped to encorafenib plus an anti-EGFR agent. Patients in other subgroups can be swapped from frontline oxaliplatin–based chemotherapy to irinotecan–based chemotherapy, or vice versa. In Dr. Krishnamuthi’s practice, she often switches patients from FOLFOX plus bevacizumab to irinotecan plus bevacizumab, dropping the 5-FU component. 

In the third-line setting, available options include TAS-102 with or without bevacizumab, regorafenib, and fruquintinib, as well as adagrasib plus cetuximab for KRAS G12c–mutated disease and tucatinib or trastuzumab for RAS–unmutated, HER2–positive disease. In the absence of clinical trial options, Dr. Krishnamurthi typically uses TAS-102 plus bevacizumab or fruquintinib in the third-line. Step-wise dosing with regorafenib and fruquintinib, or staggered dosing with TAS-102, may improve tolerability for patients.

Next in the colorectal cancer series on Oncology Brothers, Drs. Rahul and Rohit Gosain go in-depth on the BREAKWATER trial and review how to manage toxicities associated with the standard of care treatments for colorectal cancer.