ASCO 2025: metastatic colorectal cancer—focus on precision oncology
- Open Access
- 03.11.2025
- short review
Erschienen in:
Summary
Introduction
According to current European Society for Medical Oncology (ESMO) living guidelines, fit patients should be offered a combination of chemotherapy and a biologic agent as first-line therapy. In RAS wild-type (wt) and BRAF wt metastatic colorectal cancer (mCRC), tumor sidedness is a relevant parameter for selecting optimal therapy. Doublet chemotherapy + anti-epidermal growth factor receptor (EGFR) is the standard of care (SOC) for left-sided tumors, whereas for right-sided colon cancer, the preferred option is doublet chemotherapy + bevacizumab or triplet chemotherapy for fit patients without comorbidities. For patients with RAS-mutated (mt) mCRS, doublet or triplet chemotherapy + bevacizumab is recommended as first-line treatment.
Options for chemorefractory patients are limited. Regorafenib and tipiracil/trifluridine demonstrated moderate progression-free survival (PFS) and overall survival (OS) benefits, partially at the price of considerable toxicity [1, 2]. Based on a phase 3 trial (FRESCO), fruquintinib was approved in 2024 for all comers after standard therapy [3].
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The presentations at ASCO confirm that comprehensive biomarker testing is mandatory for selecting optimal therapy.
Targeting BRAFV600E mutations
This prognostically unfavorable mutation occurs in 8–12% of patients with mCRC and is linked to chemoresistance with a median OS of 10–15 months [4, 5]. Early tumor control is mandatory because only half of the patients make it to the second-line treatment phase [6].
Encorafenib, a highly selective BRAF inhibitor, was first approved for second-line treatment in combination with cetuximab based on the results of the BEACON trial that showed a modest improvement in outcomes [7].
The BREAKWATER study evaluated upfront BRAFV600E inhibition with encorafenib/cetuximab (EC) plus mFOLFOX6. In the SOC arm, mFOLFOX6/CAPOX/FOLFIRINOX ± bevacizumab was administered, while in the third study arm, patients received EC.
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The objective response rate (ORR), as one of the primary endpoints, was met (EC/FOLFOX: 60.9%; SOC: 40%), and these data were presented at ASCO GI 2025 [8].
During ASCO 2025, results for the second dual primary endpoint of PFS, alongside a second interim analysis of OS and safety data, were presented. When compared with SOC, EC/FOLFOX demonstrated a significant and clinically meaningful PFS benefit (12.8 vs. 7.1 months; HR: 0.53 [95% CI: 0.407–0.677], p < 0.0001). Furthermore, OS was doubled, increasing from 15.1 months (SOC) to 30.3 months (HR: 0.49 [95% CI: 0.375–0.632], p < 0.0001; [9]).
The benefit in PFS and OS was significant in all prespecified subgroups, even in those with poor prognostic features such as liver metastases and involvement of more than three organs.
The safety profile is consistent with that known for each agent, and no substantial increase in dose reduction or discontinuation for EC/FOLFOX vs. SOC was noted.
A summary of the safety data shows higher rates of anemia, arthralgia, rash, and pyrexia in the experimental arm. The cumulative toxicities are most likely attributable to the much longer duration of treatment in the EC/FOLFOX arm (median 49.8 vs. 25.9 weeks in the SOC arm).
Notably, EC alone did better than SOC, yielding numerically higher ORR and median OS (19.5 vs. 15.1 months), with a more favorable safety profile.
Based on these excellent results, EC/FOLFOX is clearly the new first-line SOC. Furthermore, EC should be an option for patients not fit for or declining chemotherapy.
Some issues concerning BRAFV600E mt mCRC remain unclear. To date there are no data on the combination of EC + FOLFIRI; overlapping toxicities may pose tolerability issues. Additionally, optimal second-line treatment after progression on EC/FOLFOX remains an open question.
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Of special interest is the optimal therapeutic strategy for the small population of patients with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-h) and BRAFV600Emt. It is hoped that the ongoing phase 2 SEAMARK trial randomizing patients 1:1 to EC/pembrolizumab or pembrolizumab monotherapy will provide robust data [10].
DMMR/MSI-H in mCRC
In 2021, the Keynote-177 trial established pembrolizumab as upfront therapy in MSI‑h mCRC, showing a doubling of PFS (16.5 vs. 8.2 months) compared to SOC. At the 5‑year follow-up, results remain consistent, demonstrating that median OS is more than twice as long in patients treated with pembrolizumab (77.5 vs. 36.7 months), despite an effective crossover rate of 62% [11, 12].
The CheckMate 8HW trial evaluated whether dual immunotherapy (IO) with nivolumab/ipilimumab (Nivo/Ipi × 4 followed by nivolumab monotherapy) yields even better results compared to SOC and to nivolumab. The dual primary endpoints of PFS for Nivo/Ipi vs. SOC as first-line treatment (54.1 vs. 5.9 months; HR: 0.21 [95% CI: 0.14–0.32], p < 0.0001) and for Nivo/Ipi vs. Nivo across all lines (NR vs. 39 months; HR: 0.62 [95% CI: 0.48–0.81], p = 0.0003) were met [13].
At ASCO 2025, expanded analyses including PFS2 and safety updates were presented, further supporting Nivo/Ipi as the preferred upfront therapy in MSI‑h mCRC [14].
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The relevance of early exposure to dual IO was confirmed by PFS2, defined as the time from randomization to progression after the first subsequent therapy. Despite a high rate of subsequent IO in the SOC arm (roughly 70%), PFS2 favored Nivo/Ipi (NR vs. 30.3 months; HR: 0.28 [95% CI: 0.18–0.14]). This effect was shown for the comparison with nivolumab monotherapy, too. Progression-free survial 2 was not reached in either arm; the 3‑year PFS on subsequent therapy was 80% with dual IO vs. 66% with nivolumab. The clear plateauing of survival curves suggests there is a potential for cure with dual IO.
Notably, an early decline in Kaplan–Meier curves is shown, which is more pronounced with nivolumab than with Nivo/Ipi, possibly due to early resistance. This may suggest there is a small subgroup of patients benefitting even more from dual IO plus chemotherapy.
Taken together, the results of the CheckMate 8HW trial emphasize the relevance of an optimal upfront strategy, as delayed use of IO cannot recapture a missed benefit.
Toxicity updates showed no new safety signals. In particular, skin and endocrine adverse events were observed more often with dual IO. The predicable timing of side effects enables proactive monitoring, and treatment algorithms are broadly available with recommendations for early initiation of corticosteroids. Therefore, the benefits of dual immune-checkpoint blockade, including possible cure, outweigh potential risks.
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Targeting RAS mutations
The KRASG12C mutation occurs in roughly 3–4% of mCRC and is linked to poorer response to standard chemotherapy and a worse overall prognosis compared to non-G12C mutations [15]. KRASG12C inhibitors are emerging as a promising therapeutic strategy. Sotorasib and adagrasib have shown some efficacy in chemorefractory patients, especially when combined with anti-EGFR inhibitors [16‐18].
During ASCO 2025, a cohort of the phase 1b CodeBreaK101 trial, where FOLFIRI was added to sotorasib and panitumumab in pretreated patients, was presented [19]. All patients had previously received fluorouracil and oxaliplatin; 73% had earlier exposure to irinotecan and most of them progressed on irinotecan. Mature OS and PFS data as well as a safety update were reported for 40 evaluable patients. Adverse events were consistent with the safety profile of the drugs used. A large number of grade 3 (or higher) side effects in more than 50% of patients was observed, mainly dermatitis acneiform, dry skin, stomatitis, and neutropenia. The disease control rate (DCR) was 97%, ORR was 57%, median PFS was 8.2 months, and median OS was 15.6 months. Outcome was markedly better in patients with only one prior therapy for advanced disease, with an ORR of 69.2% and OS of 22 months, suggesting that earlier use would be more favorable. Even in patients with progression on prior irinotecan, some benefit was demonstrated, with an ORR of 55% and OS of 14.6 months.
Based on the results of the CodeBreaK 101 trial, this combination is now explored in the first-line setting compared to SOC (FOLFIRI ± bevacizumab) in the global phase 3 study CodeBreaK 301.
Previous experience suggests that limited long-term benefit with first-generation KRASG12C inhibitors is a relevant issue. Potential reasons may be rapidly acquired resistance and toxicity leading to dose reduction and/or interruptions [20].
Early results for several new second-generation KRASG12C inhibitors were presented at ASCO 2025. The KANDLELIT-001 study tested MK-1084, a selective oral KRASG12C-GDP covalent inhibitor in solid tumors [21]. Patients with pretreated advanced CRC received oral MK-1084 daily as monotherapy or in combination with cetuximab (Cet) Q2W ± mFOLFOX6. Based on a promising ORR and the favorable toxicity profile of MKR 1084 (mainly restricted to AST/ALT elevation, nausea, and diarrhea), further exploration is planned. KANDLELIT-012 is a randomized first-line phase 3 trial that will randomize patients with KRASG12C mutation and pMMR/microsatellite-stable (MSS) tumors 1:1 to MK-1084 + Cet + mFOLFOX6 vs. mFOLFOX6 ± bevacizumab.
In the dose-optimizing LOXO-RAS-20001 phase 1/2 trial, olomorasib—another selective oral KRASG12C inhibitor—was tested in combination with Cet in 93 heavily pretreated mCRC patients [22]. All patients had received fluorouracil, oxaliplatin, irinotecan, and bevacizumab. Roughly 90% of patients achieved disease control; ORR was 43%, PFS was 7.4 months, with a median follow-up of 17.9 months. Further development of this regimen is also planned.
Taken together, the data presented for KRASG12C inhibition are very promising but not practice changing yet. To date, optimal partners for combinations have not been established. Potentially, KRASG12C inhibition as monotherapy is also an effective strategy. Combination with chemotherapy may not be necessary and it may even be harmful when leading to interruptions or to discontinuation of the KRASG12C inhibitor, with a relevant risk for early or primary resistance.
MSS/pMMR mCRC and immune therapy
Immunotherapy as a component of therapy in MSS mCRC remains an interesting issue. At this year’s ASCO, some preliminary data were presented on this topic.
A phase 2 trial explored vilastobart (XTX101), a tumor-activated, Fc-enhanced anti-CTLA‑4 monoclonal antibody, in combination with atezolizumab in patients with MSS mCRC. Overall, 40 patients were evaluated, 70% of whom had received three or more prior lines of therapy. Vilastobart has a distinct safety profile; fatigue, infusion-related reactions, and ALT/AST increase were reported alongside typical IO-associated toxicities such as diarrhea and colitis. Some efficacy was reported, with a preliminary ORR of 27% [23].
An update of a phase 1/2 dose escalation and expansion trial exploring ADG126, an anti-CTLA‑4 masking antibody + pembrolizumab, based on 54 patients was presented. The ORR was dose dependent, ranging from 23% to 33%, with an acceptable toxicity profile. The authors conclude that further development in broader populations is warranted [24].
Taken together, these data again provide positive signals for IO in MSS mCRC, but so far without clinical impact.
Take-home message
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Upfront comprehensive molecular testing in metastatic colorectal cancer (mCRC) is mandatory to guide optimal treatment decisions. Early use of the most active drugs is key to effective management of mCRC.
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Expanded analyses of the Checkmate 8HW trial confirmed nivolumab/ipilimumab as the preferred treatment option in first-line treatment of MSI‑h mCRC.
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Encorafenib/cetuximab plus FOLFOX showed a doubling of overall survival compared with chemotherapy ± antibody and is the new standard of care (SOC) for patients with BRAFV600E-mutated mCRC.
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KRASG12C inhibition was evaluated in pretreated patients with promising results. To date, however, these early trials do not have an impact on clinical practice.
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The ongoing global randomized phase 3 trial CodeBreaK 301 will potentially establish targeting the KRASG12C mutation as SOC in first-line treatment.
Conflict of interest
R. Schaberl-Moser declares that he/she has no competing interests.
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