2025 West Oncology Conference: Updates in Metastatic Colorectal Cancer with Dr Heinz-Josef Lenz
Presented by:
Heinz-Josef Lenz, MD, FACP, USC Norris Comprehensive Cancer Center, Los Angeles, CA
Conference:
2025 West Oncology Conference
Introduction: A Molecular Revolution in Colorectal Cancer
At the 10th Annual West Oncology Conference held in 2025, Dr Heinz-Josef Lenz from USC Norris Comprehensive Cancer Center in Los Angeles, CA set the stage for a discussion of the ongoing molecular revolution in treatment for patients with metastatic colorectal cancer (CRC). While acknowledging the progress made in characterizing tumors, Dr Lenz emphasized that the field has only scratched the surface, particularly in utilizing “multi-omics” data. While current molecular characterization approaches largely focus on DNA mutations, he noted that the integration of RNA (transcriptomics), protein (proteomics), metabolic factors (metabolomics), and radiologic data (radionomics) could further refine precision oncology and cancer prevention strategies in CRC. “We are still not integrating RNA analysis into our standard of care, even though it may be more important than DNA mutations,” Lenz noted. “A true multi-omics approach will not only predict efficacy but allow for personalized prevention and therapeutic strategies.”
Targeting HER2 in mCRC: Key Advances
Human Epidermal Growth Factor Receptor 2 (HER2) amplification remains an important oncogenic driver in a subset of metastatic CRC (mCRC) patients, and Dr Lenz emphasized the importance of routine testing for HER2 to guide therapy selection. He reviewed recent advances in HER2-targeted therapies, noting the paradigm shift in moving these treatments from the refractory setting to first-line therapy.
Dr Lenz noted that HER2-directed therapies demonstrate high response rates, with studies showing objective response rates (ORRs) ranging from 30% to nearly 50% in refractory HER2-positive mCRC, highlighting the necessity of biomarker-driven treatment selection. He also noted the potential for newer antibody drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd) to further expand treatment options in mCRC, with data from DESTINY-CRC-02 confirming that T-DXd was effective even in KRAS-mutated tumors, distinguishing it from other options such as tucatinib/trastuzumab combinations, which have been shown to be primarily effective in KRAS wild-type patients. He also noted findings from the MOUNTAINEER study, showing the potential for deep and durable responses with the tucatinib/trastuzumab combination, reinforcing the viability of dual blockade strategies. Lastly, he noted a new player in this treatment setting, zanidatamab, a bispecific antibody targeting HER2 at two distinct binding sites, to enhance efficacy. In this regard, Dr Lenz noted a case of complete remission in a patient with metastatic biliary cancer after prior HER2-directed therapy failures, suggesting potential for similar success with this agent in mCRC.
Clinical Implications
Given the potential impact of targeted therapies, Dr Lenz suggested that HER2 testing be done at the time of diagnosis to optimize options for treatment sequencing. In addition, he suggested T-DXd as an option for both KRAS-mutant and wild-type patients, and that progression on one HER2-directed therapy does not necessarily preclude response to another, as has been seen in patients with both breast and gastric cancers.
MET Alterations: A New Target in mCRC
Dr Lenz then turned the focus to patients with MET alterations, another oncogenic pathway gaining attention in mCRC. He noted that MET amplifications are associated with poor prognosis and resistance to epidermal growth factor receptor (EGFR) inhibitors, underscoring MET as a compelling therapeutic target in mCRC. Notably, early-phase trials of MET-directed ADCs have demonstrated a 20% response rate in patients with highly refractory mCRC, with ongoing trials refining MET expression cutoffs to optimize patient selection. Dr Lenz further noted the potential of amivantamab, an EGFR-MET bispecific antibody now in registration trials, which has demonstrated a 40% response rate in MET-amplified patients who are naïve to prior EGFR inhibitors. Notably, amivantamab remains effective even after EGFR-targeted therapy failure.
Clinical Implications
Given these data, Dr Lenz suggested that MET testing should be considered in treatment-refractory CRC. In addition, he notes that newer bispecific antibodies could challenge the current EGFR monoclonal antibody paradigm, by providing enhanced efficacy and a broader applicability, specifically for patients with right-sided CRC.
BRAF V600E-Mutant mCRC: A Paradigm Shift
Dr Lenz noted that BRAF V600E mutations define a distinct subset of mCRC patients having a poor prognosis and a characteristic pattern of metastatic disease, specifically, prone to peritoneal disease, bone metastases, and brain involvement. In this regard, Dr Lenz reviewed findings from the BREAKWATER trial, which he suggests has established a new standard for care or these patients. He noted that first-line therapy with encorafenib, cetuximab, and chemotherapy resulted in a 60% ORR, a finding that is unprecedented in this aggressive CRC subtype. Moreover, he highlighted the median overall survival (OS) improvement, with a hazard ratio (HR) of 0.47 as being a comparatively rare achievement for patients with mCRC. Findings from BREAKWATER, Dr Lenz noted, led to accelerated FDA approval under Project FrontRunner for use in the first line setting.
Clinical Implications
In view of these data, Dr Lenz suggested that combination therapy is best used upfront, as delaying targeted treatment reduces efficacy. In addition, he noted that patients with BRAF V600E mutations should be treated aggressively, as evidence suggests that chemotherapy alone is no longer sufficient for this patient subgroup.
Immunotherapy in mCRC: Expanding the Benefit Beyond MSI-H
In the final portion of his presentation, Dr Lenz highlighted new data from CheckMate 8HW, a study comparing immunotherapy with nivolumab (NIVO) monotherapy versus nivolumab plus ipilimumab (IPI) in patients with microsatellite instability-high (MSI-H) mCRC. He noted that the NIVO + IPI combination showed superior efficacy, with a 71% response rate versus 58% with nivolumab alone, and complete response rates of 30% versus 28%. In addition, progression-free survival (PFS) was also superior, with a hazard ratio [HR] of 0.62. Dr Lenz noted that overall toxicity for the combination was manageable, with only a modest increase in Grade 3 and 4 immune-related adverse events compared to the monotherapy. As such he encouraged oncologists to use the combination regimen whenever possible, as it provides overall deeper responses with minimal added toxicity.
By comparison, for patients with microsatellite stable (MSS) mCRC, Dr Lenz noted that immune checkpoint inhibitors (ICIs) have historically failed in clinical trials although he highlighted some novel strategies, such as Fc-enhanced anti-CTLA-4 therapy (botensilimab + balstilimab) which achieved a 17% ORR in MSS mCRC, including patients with liver metastases. In addition, he noted combination strategies with epigenetic therapies (HDAC inhibitors) which have produced ORRs of up to 44% in patients with refractory MSS mCRC. Dr Lenz also cited bispecific antibody and T cell engager therapies (e.g., REGN7075, cibisatamab) which can enhance remodeling of the tumor cell microenvironment and potentially improve immune responses in patients with MSS disease.
Clinical Implications
In view of these data, Dr Lenz suggests that MSI-H patients should receive NIVO plus IPI over single-agent nivolumab when possible. He further suggests that emerging immunotherapy strategies for MSS mCRC warrant investigation and clinical trial participation, and that epigenetic and immune-targeted combinations are beginning to show meaningful response rates in the clinically relevant subgroup of MSS mCRC patients.
The Future: Moving Beyond Tumor-Centric Approaches
Moving beyond the tumor centric approach of the “tissue is the issue” Dr Lenz concluded with a glimpse into the next frontier of mCRC targeted treatment, that of targeting the tumor microenvironment (TME). He noted that CD8+ T cell recruitment, and immune activation are key to unlocking efficacy for patients with MSS mCRC. He also cited the potential for circadian rhythm modulation (targeting CLOCK genes) and inhibition of metabolic pathways which are emerging as next generation therapeutic avenues, for example, mouse models have shown dramatic survival benefits when combining CTLA-4 blockade immunotherapy with metabolic pathway inhibitors, suggesting a potentially translatable strategy for human trials.
Dr Lenz’s Key Takeaways in mCRC
HER2-targeted therapies are now standard in mCRC, and multiple agents are available.
MET amplification is an emerging target, with bispecific antibodies showing high efficacy.
BRAF V600E-mutant mCRC now has a validated first-line regimen with encorafenib + cetuximab + chemotherapy.
Nivolumab plus ipilimumab should be the default regimen for MSI-H mCRC.
MSS mCRC remains a challenge, but novel approaches—including Fc-enhanced CTLA-4 therapy and epigenetic modulation—are showing promise.
A deeper focus on the tumor microenvironment will define the next generation of therapies.
Dr Lenz concluded with a German proverb: “The one who knows more may decide better...” He further suggested that the way forward in mCRC was clear—oncologists must embrace molecular testing and precision strategies in order to maximize patient outcomes in mCRC.
Speaker Disclosure Information: Dr Lenz reported the following disclosures for this presentation: Advisory Boards:Merck, Bayer, Boehringer Ingelheim, Abbvie, Fulgent, Bicara, GSK, 3T Bioscience, Adagene, Affini-T, Beigene, Protagonist, BMS, Janssen, Merus; Stock Options: BreakBio, Fulgent, 3T Bioscience; Funding: SWOG, NCI, NIH.
You can see the full presentation by Dr Heinz-Josef Lenz at the 2025 West Oncology Conference on our YouTube channel here.