Midhun Malla, MD of University of Alabama at Birmingham.

, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was rejoined by Midhun Malla, MD, of the University of Alabama at Birmingham, to discuss therapeutic options for patients with metastatic colorectal cancer (mCRC), particularly in the third-line setting and beyond.

In the final part of this 3-part episode miniseries, Drs Park and Malla explored the challenges faced by community oncologists, especially in rural or underserved areas, in accessing clinical trials, which remain a preferred disease management approach due to their role in advancing novel therapies. However, in the absence of trial availability or when patients are ineligible, they emphasized the importance of evidence-based, FDA-approved agents for later lines of therapy.

Three primary agents were discussed for patients who have progressed on first-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) and second-line FOLFIRI (folinic acid, fluorouracil, and irinotecan) regimens: trifluridine/tipiracil (TAS-102; Lonsurf) plus bevacizumab (Avastin); fruquintinib (Fruzaqla); and regorafenib (Stivarga). These agents offer viable treatment pathways in biomarker-unselected patient populations. However, direct comparisons between these agents are lacking, as most were tested against placebo controls. The choice among them is often individualized based on patient performance status, prior exposure to biologics, and toxicity profiles.

TAS-102 plus bevacizumab has generated promising results, though real-world data may show diminished efficacy due to frequent prior exposure to 5-fluorouracil and bevacizumab in US patients. Fruquintinib offers a VEGF-targeted approach with a more favorable hematologic toxicity profile, whereas regorafenib is associated with notable adverse effects, including hypertension, gastrointestinal toxicity, and mucositis. Park and Malla emphasized the importance of treatment sequencing, toxicity management, and individualized patient-centered care, including consideration of dose modifications to preserve quality of life in later-line settings.

In addition to later-line options, the conversation also touched on emerging frontline therapies. Notable investigational agents include zanidatimab-hrii (Ziihera) and KRAS G12C–directed therapies. Additionally, a novel integrin-targeted cytotoxin is currently under evaluation at the University of Alabama at Birmingham in patients with treatment-naive mCRC. This agent induces apoptosis via caspase-8 activation and has demonstrated encouraging preclinical activity. Overall, the discussion highlighted a nuanced, biomarker-informed, and patient-tailored approach to mCRC management, emphasizing both the value of clinical trials and the importance of optimizing currently available therapies.

Podcasts

Drs Park and Malla discuss therapeutic options for patients with metastatic colorectal cancer, particularly in the third-line setting and beyond.

Biomarker-Directed Therapies Improve Outlooks for the mCRC Treatment Arsenal: With Chandler Park, MD; and Midhun Malla, MD

, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was rejoined by Midhun Malla, MD, a gastrointestinal oncologist at Allegheny Health Network in Pittsburgh, Pennsylvania, to discuss treatment personalization in metastatic colorectal cancer (mCRC), with a focus on 

 V600E–mutant tumors, HER2-altered disease, and the clinical implications of tumor sidedness.

In part 2 of this conversation, Drs Park and Malla began by addressing treatment sequencing for patients with 

 V600E–mutant CRC, particularly those who progress after adjuvant FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin)–based therapy. Dr Malla noted the lack of prospective data supporting rechallenge in this setting and advocated for shifting to a FOLFIRI (leucovorin, fluorouracil, and irinotecan)–based backbone, aligning with emerging real-world practices and evolving combination data involving encorafenib (Braftovi) and cetuximab (Erbitux). He referenced encouraging safety and tolerability findings from presentations at recent international meetings.

The conversation then turned to patients with microsatellite instability–high (MSI-H)/

 V600E–mutant tumors. Dr Malla discussed data from the phase 2 CheckMate 142 (NCT02060188) and phase 3 CheckMate 8HW (NCT04008030) trials, highlighting the consistent benefit of immunotherapy in this molecularly defined population, regardless of 

 mutation status. He emphasized that MSI-H biology appears to outweigh the typically poor prognostic impact of 

 mutations, supporting the use of checkpoint blockade in the frontline setting.

For left-sided, HER2-positive mCRC, Malla provided insight into second-line therapy selection following progression on FOLFOX and EGFR inhibition. He outlined the clinical rationale for selecting fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with concurrent 

 mutations and HER2 alterations, as well as reserving trastuzumab (Herceptin) plus tucatinib (Tukysa) for those with HER2 overexpression and 

 wild-type disease. He also highlighted key differences between the phase 2 DESTINY-CRC02 (NCT04744831) and MOUNTAINEER (NCT03043313) trials that inform treatment stratification in this setting.

Throughout the discussion, Malla emphasized the importance of early molecular profiling within the context of individualized treatment selection, as well as the evolving paradigm of targeted therapy for patients with advanced CRC.

Chandler Park, MD and Midhun Malla, MD discuss treatment personalization in mCRC, with a focus on BRAF V600E–mutant tumors and HER2-altered disease.

BRAF-Mutant and HER2+ mCRC Management Strategies Are Becoming Increasingly Tailored: With Chandler Park, MD, and Midhun Malla, MD

, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was joined by Midhun Malla, MD, a gastrointestinal oncologist and associate professor of medicine—hematology & oncology at the University of Alabama at Birmingham School of Medicine, to discuss evolving approaches to colorectal cancer (CRC) management, with a focus on circulating tumor DNA (ctDNA), adjuvant therapy decision-making, and molecular profiling in metastatic disease.

Drs Park and Malla began by talking through the clinical utility of ctDNA in patients with stage II and III colon cancer. Dr Malla referenced the DYNAMIC (ACTRN12615000381583) and observational BESPOKE CRC (NCT04264702) trials, noting that ctDNA serves as a prognostic biomarker for recurrence and is increasingly used to guide post-surgical surveillance.

They also addressed clinical nuances in managing stage II T4 tumors, which Dr Malla identified as being at high risk for peritoneal spread—an anatomical site less likely to shed detectable ctDNA. For such patients, he supports offering adjuvant chemotherapy irrespective of ctDNA results. When the discussion turned to stage III disease, Dr Malla drew on evidence from the IDEA collaboration to recommend 3 months of capecitabine and oxaliplatin for low-risk patients, including those who are elderly but have preserved performance status.

In the metastatic setting, Drs Park and Malla highlighted the expanding role of next-generation sequencing and liquid biopsy. Dr Malla advocated for dual tissue-based and plasma-based testing to capture tumor heterogeneity and accelerate actionable insights. He emphasized the importance of rapid molecular profiling in guiding first-line therapy decisions, particularly in patients with

Park and Malla discuss evolving approaches to colorectal cancer (CRC) management, with a focus on ctDNA, adjuvant therapy decision-making, and molecular profiling in metastatic disease.

Midhun Malla, MD

Articles

Biomarker-Directed Therapies Improve Outlooks for the mCRC Treatment Arsenal: With Chandler Park, MD; and Midhun Malla, MD

BRAF-Mutant and HER2+ mCRC Management Strategies Are Becoming Increasingly Tailored: With Chandler Park, MD, and Midhun Malla, MD

Evolving Molecular Profiling and Liquid Biopsy Practices Guide First-Line CRC Therapy Decisions: With Chandler Park, MD; and Midhun Malla, MD