Cathy Eng, MD, FACP, FASCO, shared insights on biomarker testing and sequencing strategies for patients with colorectal cancer (CRC), emphasizing the importance of NGS and ctDNA in treatment decisions. The discussion included clinically relevant data from the phase 3 CheckMate-8HW and MOUNTAINEER-03 trials, highlighting advancements in immunotherapy and targeted therapies.
The Role of NGS in Metastatic CRC
According to Dr. Eng, NGS is critical for all patients with metastatic disease. "The most important take home point for any patient with metastatic disease is that you definitely need molecular sequencing completed," she stated. NGS helps identify potential molecular markers that may impact treatment and the sequence of therapy, guiding decisions about clinical trial eligibility and providing prognostic information.
Immunotherapy Advancements
Dr. Eng highlighted recent data on the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrating superiority over chemotherapy for newly diagnosed, mismatch repair-deficient patients with CRC. This regimen has shown an improvement in progression-free survival compared to systemic chemotherapy. Additionally, she noted updated results with dostarlimab-gxly (Jemperli) in the neoadjuvant setting of locally advanced CRC and rectal cancer, showing a 100% clinical response, which is being validated in an ongoing phase 2 study (NCT04165772).
Data presented at the 2024 ESMO Congress investigated the combination of nivolumab and ipilimumab for T3/T4 or node-positive patients with early-stage colorectal cancer in the CheckMate-8HW trial. The role of LAG3 in combination regimens for patients with early-stage colon carcinoma was also assessed, reporting an impressive clinical pathologic complete response and overall major pathologic response.
Targeted Therapies and HER2
Updates from the phase 2 MOUNTAINEER trial were discussed, reminding attendees that the phase 3 MOUNTAINEER-03 trial is open for patients with HER2-positive, newly diagnosed metastatic CRC. Fam-trastuzumab deruxtecan-nxki (Enhertu), an antibody-drug conjugate (ADC), has been tested in patients previously treated with HER2 therapy. T-DXd received tumor-agnostic approval in April 2024. However, interstitial lung disease remains a concern.
Sequencing Strategies in Refractory Settings
When sequencing treatments in refractory settings, Dr. Eng considers regorafenib (Stivarga), trifluridine and tipiracil (Lonsurf) plus bevacizumab (Avastin), and fruquintinib (Fruzaqla), which was FDA approved in November 2023. She emphasizes discussing potential adverse effects with patients, as each agent has different AEs. Ultimately, patients with good performance status and normal laboratory tests may receive most of these drugs.
T-DXd in HER2-Positive Tumors
Dr. Eng has found T-DXd most beneficial for patients who previously received HER2-targeted therapy, such as tucatinib (Tukysa) and trastuzumab (Herceptin). She also plans to use T-DXd for a patient with a HER2 mutation, which is uncommon in CRC, to provide additional benefit.
The Utility of ctDNA Testing
ctDNA testing is of great interest in multiple malignancies, particularly in CRC. Several ongoing trials include ctDNA as part of their correlative work. While the FDA may not yet consider it a primary endpoint, ctDNA can benefit patients. For example, in patients who had a liver resection or a metastatic resection, ongoing trials in stage III CRC are evaluating its utility. ctDNA detection is more easily achieved in patients with liver metastasis compared to lung or peritoneal metastasis.
The GALAXY study from a Japanese group provided interesting information on the prognostic value of ctDNA. Their recent paper examined the role of ctDNA following liver resection and whether adjuvant therapy is warranted. Dr. Eng considers ctDNA as one of the tools when evaluating patients and considering next options, especially for those who do not participate in clinical trials.
