Metastatic Colorectal Cancer Treatment by Biomarker
Before you choose a first-line regimen, you need 5 test results. Do you have all of them?
Non-negotiable tests before ANY systemic therapy
Required for all patients
- 1MMR/MSI status (dMMR/MSI-H: 3.5–6.5%)
- 2KRAS exons 2, 3, 4 + NRAS exons 2, 3, 4 (extended RAS)
- 3BRAF V600E (5–12%)
- 4Primary tumor sidedness (left vs. right)
- 5Resectability assessment
Additional biomarkers in RAS-WT patients
- HER2 amplification (IHC 3+ or 2+/FISH, 3–5% of RAS-WT)
- KRAS G12C mutation
- NTRK fusion
- RET fusion
- POLE/POLD1 mutations (2–4% all-stage, <1% mCRC)
- TMB-H
Tissue is gold standard. ctDNA if tissue unavailable (sensitivity 67%, specificity 96%, concordance 61–93%).
Jump to section
Section 1 — Workup
What tests must be completed before starting any systemic therapy in mCRC?
Colonoscopy & Tissue Acquisition
- Preoperative colonoscopy: localize tumor, obtain tissue (synchronous invasive CRC 3–5%, synchronous adenomas ~30%)
- If incomplete: CT colonography (preferred), MRI colonography, or barium enema (less preferred)
- If not feasible pre-op: completion colonoscopy post-resection
Imaging
- Initial staging: contrast CT chest/abdomen/pelvis
- Liver MRI: when CT findings equivocal, or liver mets appear potentially resectable (better sensitivity for small lesions, assessing number/size/vasculature relationship)
- FDG-PET useful for: rising CEA without visible metastatic disease, clarifying disease extent for metastasectomy planning, may avoid non-therapeutic laparotomy
Biomarkers & Labs
- Baseline CEA: obtain pre-treatment; persistent post-operative elevation suggests residual disease or metastasis (not for screening — low sensitivity/specificity for early-stage)
- DPD deficiency testing prior to 5-FU-based chemotherapy
- UGT1A1*28: affects irinotecan metabolism → dose adjustment may be needed (some NGS panels include this)
Family History & Lynch Screening
Collect 3-generation pedigree; at minimum 1st and 2nd degree relatives. Inquire about CRC, endometrial, ovarian, gastric, small bowel, renal pelvis/ureter — may identify Lynch syndrome.
Section 2 — Resectability Assessment
Are the metastases resectable? This single question changes the entire treatment goal.
Resectability Criteria
- Limited number and location of mets
- Adequate remnant organ function
- Good performance status
- Absence of prohibitive comorbidities
Survival Outcomes
- 5+ year survival possible in selected cases
- ~50% survival with metastasectomy
- Cure rare (~20–30%) even after complete resection
- Most patients have recurrence
Sites
- Most feasible for liver and lung mets
- Controlled/resectable primary tumor required
- Peritoneal limited to specialized centers
- Oligometastatic (≤5 lesions, ≤2 organs)
Timing of Surgery in Synchronous Metastatic Disease
No universal consensus — individualize based on symptoms, tumor burden, and institutional expertise.
Standard sequence
Primary resection first → systemic therapy → metastasectomy
Liver-first strategy
Reverse strategy: address liver mets before primary in select cases
Simultaneous resection
Primary and metastases resected in same operation (selected centers)
Perioperative Chemotherapy
When perioperative chemo may NOT be needed
- Good PS, resectable disease with favorable biology, high chance of R0 resection
- e.g. upfront surgery for initially resectable, low-risk liver-only met (≤4 lesions, all in one lobe, RAS/BRAF-WT)
- Avoids oxaliplatin/irinotecan hepatotoxicity; no OS benefit shown with perioperative chemo in this setting
Preferred perioperative regimens
- Oxaliplatin-based (FOLFOX or XELOX) — preferred
- FOLFOXIRI for young fit patients
- FOLFIRI if received adjuvant FOLFOX within past 12 months
- Left-sided RAS-WT: add cetuximab or panitumumab for conversion therapy
Pre-op chemo duration limits
Limit pre-op chemo to ≤4 cycles (~16 weeks); imaging every 6–8 weeks.
Extended chemo (>16 weeks): no improvement in pathologic response + increases chemo-related liver injury (oxaliplatin → sinusoidal injury; irinotecan → steatosis/steatohepatitis).
Delay resection ≥4 weeks post-chemo; ≥6 weeks if bevacizumab used.
Postoperative Management
- No prior chemo → adjuvant FOLFOX or XELOX; avoid irinotecan-containing regimens
- Neoadjuvant chemo given → complete full 6-month course inclusive of pre-op cycles; do not repeat FOLFOX if received within prior 12 months
Section 3 — Systemic Therapy Principles
Doublet or triplet? Bev or anti-EGFR? How fit is the patient for intensive therapy?
Treatment Goals
- Potentially resectable: maximal tumor shrinkage → curative surgery
- Unresectable: palliation (prolong survival, maintain QOL)
- Early initiation preferred; defer only for minimal burden, slow tempo, or patient preference
Chemotherapy Backbone
- 5-FU/capecitabine, oxaliplatin, irinotecan
- 1L efficacy: FOLFOX = FOLFIRI = XELOX
- SOX = FOLFOX = XELOX in Asian populations
- XELIRI not recommended in the US (higher toxicity, especially diarrhea)
Targeted Agents
Anti-EGFR
Cetuximab, panitumumab
RAS/BRAF-WT ONLY
Anti-VEGF
Bevacizumab, ramucirumab, aflibercept
All molecular subgroups
KRAS G12C inhibitors
Adagrasib, sotorasib (+ anti-EGFR)
KRAS G12C mutation
HER2-targeted
Trastuzumab+tucatinib, T-DXd, trastuzumab+pertuzumab/lapatinib
HER2-amplified
NTRK inhibitors
Larotrectinib, entrectinib, repotrectinib
NTRK fusion
Immunotherapy
Pembrolizumab, nivolumab ± ipilimumab
dMMR/MSI-H ONLY
Triplet vs Doublet Chemotherapy — When to escalate
Indications for FOLFOXIRI + bevacizumab
- • Good PS, high tumor burden, or initially unresectable liver mets needing conversion therapy
- • Duration: 3–4 months, then transition to non-oxaliplatin maintenance (5-FU + bev)
Meta-analysis evidence (TRIBE, TRIBE2, CHARTA, OLIVIA, STEAM): FOLFOXIRI+bev → better PFS, OS, and RR at expense of higher toxicity.
Triplet + anti-EGFR — NOT recommended
TRIPLETE trial: FOLFOXIRI+panitumumab vs FOLFOX+panitumumab → ORR not improved, more toxic, no added benefit.
Oxaliplatin & Irinotecan Management Strategies
Oxaliplatin
- • Stop at 3–4 months to avoid cumulative neuropathy
- • Continue 5-FU or capecitabine ± targeted as maintenance
- • OPTIMOX-1: "stop and go" supported
- • OPTIMOX-2: maintenance better than complete stop for PFS and OS
Irinotecan
- • Continue as long as response and tolerance persist
- • Intermittent schedules (2 months on/off) may be considered with comparable PFS and OS
- • No cumulative dose-limiting toxicity like oxaliplatin neuropathy
Complete treatment break
Valid after CR or PR — appropriate for small-volume disease, symptom-free patients, patient preference. Monitor every 2 months, restart at progression.
Section 4 — First-Line Therapy by Biomarker
Which biomarker subgroup is this patient? This is the core branching decision.
Molecular subgroups — select 1L pathway
dMMR/MSI-H
3.5–6.5%
BRAF V600E
5–12%
RAS/BRAF-WT Left
~25%
RAS/BRAF-WT Right
~15%
RAS-mutant
~50%
KRAS G12C
3–4%
HER2-amplified
3–5% RAS-WT
POLE/POLD1
<1%
4a. dMMR/MSI-H
3.5–6.5% of mCRCCheckMate 8HW — Nivolumab + Ipilimumab (preferred 1L)
ORR 71% vs 38% vs 35% (nivo+ipi vs nivo vs chemo)
PFS NR vs 40 months vs 6 months; superior OS vs chemotherapy
Preferred option for dMMR/MSI-H — combination recommended over monotherapy
CheckMate 8HW — Nivolumab monotherapy
ORR 58%, PFS 40 months
Lower PFS/ORR vs combo; use if toxicity concerns or ipilimumab contraindicated
KEYNOTE-177 — Pembrolizumab vs chemotherapy
OS 78 vs 37 months, PFS 17 vs 8 months, ORR 46% vs 33%
Durable responses and favorable toxicity over chemotherapy
ICI Duration Guidance
- • No universal standard; expert recommendation: minimum 12 months, maximum 2 years
- • CR confirmed on ≥2 scans → may stop at 1 year
- • PR/SD → continue up to 2 years if tolerated
- • Retrospective data: no OS difference between fixed 2 years vs >2 years
Resectable dMMR: Despite ICI efficacy, recommend chemotherapy upfront if resectable; immunotherapy still being explored in this setting.
4b. BRAF V600E
5–12% of mCRCBREAKWATER — Encorafenib + cetuximab + FOLFOX (preferred 1L BRAF V600E)
OS 30 vs 15 months; PFS 13 vs 7 months; ORR 60% vs 37% vs SOC
Standard of care when targeted therapy available
If targeted therapy unavailable: FOLFOXIRI+bev (triplet-suitable patients) or FOLFOX+bev
Critical: BRAF V600E + dMMR co-mutation
BRAF V600E often co-occurs with sporadic dMMR (MLH1 methylation). If dMMR co-mutation present, immunotherapy is preferred over targeted therapy.
Dabrafenib+trametinib in mCRC
Though FDA tumor-agnostic approval exists, the approval trial excluded mCRC. NOT recommended in patients who progress on encorafenib+cetuximab.
4c. RAS/BRAF-WT — Left-sided Primary
Anti-EGFR preferred- Anti-EGFR (cetuximab or panitumumab) + doublet chemotherapy = standard of care
- Primary tumor sidedness is both prognostic and predictive
- Anti-EGFR should only be used in extended RAS-WT tumors (KRAS + NRAS exons 2, 3, 4)
- Triplet + anti-EGFR NOT routinely recommended (TRIPLETE trial: no benefit, more toxic)
4d. RAS/BRAF-WT — Right-sided Primary
Bevacizumab preferred- Bevacizumab-based therapy preferred (doublet or triplet)
- Anti-EGFR has no role in right-sided 1L and may be harmful if used without specific cytoreduction intent
- Triplet (FOLFOXIRI+bev) for high tumor burden or conversion intent
4e. RAS-mutant (KRAS or NRAS)
~50% of mCRC- Doublet or triplet chemo ± bevacizumab
- Avoid anti-EGFR (cetuximab, panitumumab) — no benefit, potential harm
- Triplet only in selected fit patients (high tumor burden, conversion intent)
- Right-sided and/or RAS-mutant for conversion: FOLFOXIRI+bev preferred
4f. KRAS G12C mutation
3–4% of mCRCKRYSTAL-1 — Adagrasib + cetuximab (Phase 1/2)
ORR 34%, PFS 7 months, OS 16 months
Landmark response rates in a historically difficult-to-treat subgroup
CodeBreak 300 — Sotorasib + panitumumab (Phase 3)
ORR 26% vs 0%, PFS 6 vs 2 months vs lonsurf/regorafenib
Line of therapy considerations
More often used in 2L/3L after prior oxaliplatin AND irinotecan exposure. Formal 3L+ indication requires prior 5-FU/capecitabine, oxaliplatin, AND irinotecan treatment.
4g. HER2-amplified
3–5% of RAS-WT- HER2 amplification: IHC 3+ or 2+/FISH confirmation required
- 1L: Trastuzumab + tucatinib + FOLFOX (MOUNTAINEER-03 ongoing — no efficacy results published yet)
- For established options in later lines, see Section 8 (3L+)
4h. POLE/POLD1 mutation
<1% of mCRCKey features
- • Rare <1% of mCRC but highly immunogenic
- • Associated with ultramutated phenotype (TMB >100 mut/Mb)
- • POLE mutations more common in pMMR/MSS tumors
- • POLD1 mutations more common in dMMR/MSI-H
TMB >50 mut/Mb → ICI strategy
Treat like dMMR/MSI-H: nivo+ipi preferred; monotherapy options: pembrolizumab, nivolumab. Retrospective data suggests superior outcomes vs dMMR/MSI-H on ICI.
TMB <50 mut/Mb → pMMR/MSS strategy
Follow standard pMMR/MSS strategy: chemo ± targeted. TMB level (not MSI/MMR status alone) guides ICI use.
Note: No RCTs available; management relies on retrospective studies, expert consensus, and real-world outcomes.
Section 5 — Maintenance Therapy
Oxaliplatin is done at 3–4 months — what do you maintain with?
Scenario
After oxaliplatin + bevacizumab
Strategy
De-escalate to fluoropyrimidine + bevacizumab
Scenario
After oxaliplatin + anti-EGFR
Strategy
De-escalate to fluoropyrimidine + anti-EGFR
Scenario
After FOLFIRI or XELIRI
Strategy
Continue full regimen (no cumulative toxicity concerns)
Scenario
Disease progression on maintenance
Strategy
Reintroduce initial therapy if previously effective
Section 6 — Conversion to Resectability
The mets responded — is resection now possible? How do you reassess?
Imaging frequency
Every 6–8 weeks during induction chemotherapy
Surgery timing
As soon as metastases become clearly resectable — do not over-treat
Chemo limit
≤16 weeks; extended chemo does not improve pathologic response
Resection after poor response to 1L
- • Do NOT deny metastasectomy/ablation solely because of poor response to chemotherapy
- • Patients still benefit from 2L followed by resection
- • Intra-arterial chemotherapy as rescue tool for liver-dominant disease
Oligometastatic Disease (OMD)
Definition: ≤5 metastatic lesions, limited sites (liver, lung, peritoneum); synchronous or metachronous.
- • Start systemic therapy in all patients to test tumor biology and downstage (ESMO recommendation)
- • Responded disease → proceed with local treatment
- • Oligoprogressive disease → local treatment to progressive lesions, continue same systemic therapy
Local Therapy Options
| Modality | Indication | Key Criteria |
|---|---|---|
| Surgery | Curative-intent resectable OMD | ≤5 lesions, ≤2 organs, R0 feasible, good PS |
| Thermal ablation (RFA/MWA) | Small deep liver mets, surgery unfit | ≤3cm, ≤3–5 lesions, ≥1cm from major bile ducts |
| SBRT | Not suitable for surgery/ablation | ≤5 lesions, ≤5cm, well-defined target |
| HAIC / TARE/SIRT Y-90 | Chemorefractory liver-only or oligoprogression | Preserved liver function, patent vessels, no extrahepatic shunting |
| TACE | Chemorefractory liver-only, not Y-90/HAIC candidate | Preserved liver function, patent portal vein |
Isolated peritoneal metastases
Offer complete cytoreduction surgery where feasible. HIPEC considered experimental — should only be used in clinical trials; no consensus or OS benefit shown outside studies.
Section 7 — Second-Line Therapy by Biomarker
What changed at progression? Which biomarker drives second-line choice?
Second-line therapy is determined by prior exposure and molecular profile. Key principle: switch chemotherapy backbone (oxaliplatin → irinotecan or vice versa) and reassess targeted agent eligibility.
RAS-WT and anti-EGFR naïve at 2L
Left-sided
Anti-EGFR (cetuximab/panitumumab) ± chemotherapy
Right-sided
Anti-angiogenic + chemotherapy preferred
BRAF V600E — 2L (BEACON trial)
BEACON — Encorafenib + cetuximab ± binimetinib (≥1 prior line)
Triplet vs doublet vs SOC: OS 9 vs 9 vs 5.4 months; ORR 26% vs 20% vs 2%
FDA approved doublet (encorafenib + cetuximab) only
Triplet considered in highly symptomatic/bulky disease — no OS advantage over doublet, higher toxicity
Note: Dabrafenib+trametinib has tumor-agnostic FDA approval but was excluded from mCRC in the approval trial — not recommended after encorafenib+cetuximab failure.
dMMR/MSI-H and IO naïve at 2L
CheckMate 142 — Nivolumab + ipilimumab
ORR 65%, 4yr PFS 53%, 4yr OS 71%
CheckMate 142 — Nivolumab monotherapy
ORR 31%, 4yr PFS 36%, 4yr OS 49%
KEYNOTE-164 — Pembrolizumab
1+ prior line: ORR 35%, PFS 4 months, OS 47 months
2+ prior lines: ORR 33%, PFS 2 months, OS 31 months
GARNET — Dostarlimab
ORR 44%, PFS 8 months, OS not reached
KRAS G12C — 2L/3L (after prior oxaliplatin AND irinotecan)
KRYSTAL-1 — Adagrasib + cetuximab
ORR 34%, PFS 7 months, OS 16 months
CodeBreak 300 — Sotorasib + panitumumab (Phase 3)
ORR 26% vs 0%, PFS 6 vs 2 months vs lonsurf/regorafenib
RET fusions — Pan-tumor, any line
Libretto-001 — Selpercatinib (mCRC subgroup)
ORR 20%, DOR 9 months
Other RET inhibitors (pralsetinib) under investigation
NTRK fusions — Pan-tumor, any line
Larotrectinib — mCRC subgroup
ORR 50%, DOR 4 months
Entrectinib — mCRC subgroup
ORR 20%, DOR 18 months; better CNS penetration
Repotrectinib — at TRK resistance
Active against TRK resistance mutations; ORR 33%, DOR 18 months
TMB-H (≥10 mut/Mb) — Pan-tumor
KEYNOTE-158 — Pembrolizumab (pan-tumor)
ORR 29% — NOTE: no mCRC patients included; approval extrapolated to CRC
TMB-H + pMMR/MSS without POLE/POLD1: Do NOT routinely offer immunotherapy. Consider only if no other systemic options exist, with informed patient consent.
Other 2L Options (by prior exposure)
- Switch chemotherapy backbone: oxaliplatin → irinotecan (or vice versa)
- Add anti-angiogenic: bevacizumab, aflibercept (VELOUR trial), ramucirumab (RAISE trial)
- Bevacizumab continuation beyond PD or reintroduction (ML18147/TML, BEBYP trials)
Section 8 — Third-Line and Beyond
What are the options after two lines of therapy?
RAS-WT + BRAF-WT
SUNLIGHT — Lonsurf + bevacizumab (PREFERRED)
vs lonsurf alone: PFS 6 vs 2 months, OS 11 vs 8 months
Now preferred over lonsurf monotherapy in eligible patients
RESOURCE — Lonsurf monotherapy
vs placebo: OS 7 vs 5 months
CORRECT — Regorafenib vs placebo
PFS 1.9 vs 1.7 months, OS 6.4 vs 5 months
CONCUR (Asia) — Regorafenib
PFS 3.2 vs 1.7 months, OS 8.8 vs 6.3 months
ReDOS — Regorafenib dose-escalation strategy
Weekly dose escalation (80→120→160mg) improved tolerability and OS 9.8 vs 6 months
Start at 80mg, escalate weekly — preferred dosing strategy
FRESCO (China) + FRESCO-2 (international) — Fruquintinib
FRESCO: PFS 3.7 vs 1.8 months, OS 9.3 vs 6.6 months
FRESCO-2: PFS 3.7 vs 1.8 months, OS 7.4 vs 4.8 months
VELO — EGFR rechallenge: panitumumab + lonsurf
vs lonsurf alone: PFS 4 vs 2.5 months, OS 13 vs 12 months
Appropriate after multiple intervening lines (RAS-WT clones re-emerge)
Also consider: single-agent anti-EGFR (if not previously used), irinotecan + cetuximab (if not previously used)
RAS-WT + BRAF-WT + HER2-amplified
MOUNTAINEER — Trastuzumab + tucatinib (≥2 prior lines)
ORR 38%, PFS 8 months, OS 24 months
DESTINY-CRC01 — T-DXd (Enhertu)
ORR 45%, PFS 7 months, OS 16 months
Reserved for later lines after trastuzumab+chemo failure
DESTINY-CRC02 — T-DXd dose comparison
5.4mg/kg vs 6.4mg/kg: similar ORR/PFS, lower ILD risk at 5.4mg/kg → use 5.4mg/kg
Off-label options: Trastuzumab+lapatinib (HERACLES), trastuzumab+pertuzumab (MyPathway, TAPUR)
RAS-mutant
- Lonsurf + bevacizumab (preferred), lonsurf monotherapy, regorafenib, fruquintinib
- KRAS G12C: adagrasib + cetuximab, sotorasib + panitumumab
RAS-mutant + HER2-amplified (rare co-occurrence)
Co-occurrence is rare.
Do NOT use HER2-targeted therapy in RAS-mutant tumors outside clinical trials — no demonstrated benefit.
SOC: chemo doublets/triplets ± bevacizumab.
BRAF V600E
- Encorafenib + cetuximab (BEACON) — if not used in 1L
- Lonsurf + bevacizumab, lonsurf monotherapy, regorafenib, fruquintinib
Section 9 — Special Populations
Elderly, frail, peritoneal-only, oligometastatic — how do you adapt?
Elderly / Frail Patients
- Use G8, CARG, ECOG, CCI to assess fitness before starting therapy
- Dose-reduce oxaliplatin first when de-escalating
- Consider fluoropyrimidine monotherapy if doublet not tolerated
- Capecitabine preferred over infusional 5-FU (no port, fewer hospital visits)
- Avoid triplet (FOLFOXIRI) in frail patients
Poor Performance Status (ECOG 3–4)
- Best supportive care should always be discussed
- If PS is clearly performance-status related to disease (not comorbidity), a short trial of less intensive therapy may be justified
- Reassess PS after 4–8 weeks; discontinue if no improvement
- Avoid aggressive chemotherapy in truly frail patients
Peritoneal-only Disease
- Complete cytoreduction surgery + HIPEC (investigational only — clinical trial setting)
- Systemic therapy for disease control outside surgical candidates
- Survival significantly worse than liver/lung-only mCRC
- HIPEC should ONLY be offered within clinical trials — no OS benefit shown outside studies
Oligometastatic Disease
- Covered in detail in Section 6 (Conversion to Resectability)
- Key principle: systemic therapy first to test tumor biology, then local treatment if response
- Oligoprogressive disease: local treatment to progressive lesions, continue same systemic therapy
Synchronous Liver Metastases
- Simultaneous vs staged resection — no universal standard
- Individualize based on tumor burden, symptoms, and institutional expertise
- Liver-first strategy for liver-dominant, borderline-symptomatic primary
- Consider perioperative chemotherapy to assess tumor biology before committing to surgery
Section 10 — Clinical FAQs
Does sidedness matter if the patient has RAS mutation?
In RAS-mutant disease, sidedness does NOT change treatment — anti-EGFR is contraindicated regardless of tumor location. Sidedness matters primarily in RAS/BRAF-WT disease for the anti-EGFR vs bevacizumab decision.
When should I use FOLFOXIRI vs FOLFOX in 1L?
FOLFOXIRI + bevacizumab is indicated for good PS (ECOG 0–1), high tumor burden, or conversion intent for initially unresectable liver mets. Duration 3–4 months then transition to maintenance with 5-FU + bev. Triplet + anti-EGFR is not recommended (TRIPLETE trial: no added benefit, more toxic).
How long do you continue immunotherapy in dMMR mCRC?
No universal standard. Expert recommendation: minimum 12 months, maximum 2 years. CR confirmed on ≥2 scans → may stop at 1 year. Retrospective data shows no OS difference between fixed 2 years vs longer duration. PR/SD → continue up to 2 years if tolerated.
What is the EGFR rechallenge concept?
After progression on anti-EGFR therapy, RAS-WT clones may re-emerge and restore anti-EGFR sensitivity. The VELO trial demonstrated panitumumab + lonsurf vs lonsurf alone → PFS 4 vs 2.5 months. Most appropriate after multiple intervening lines where EGFR-resistant clones have been diluted.
Can I use bevacizumab beyond progression?
Yes. ML18147/TML and BEBYP trials both support bevacizumab continuation beyond first progression in combination with a new chemotherapy backbone. Reintroduction of bev after a treatment break is also valid.
What is the role of ctDNA in mCRC?
Tissue biopsy remains the gold standard for molecular profiling. ctDNA (liquid biopsy) is useful when tissue is unavailable or insufficient (sensitivity 67%, specificity 96%). The discordance rate between primary and recurrent tumor genotyping is ~20% — retesting at progression (especially for RAS status) is clinically relevant.
When is HIPEC indicated for peritoneal mets?
HIPEC remains experimental in mCRC and should only be offered within clinical trials. No OS benefit has been demonstrated outside of study settings. Complete cytoreduction to no visible residual disease is the primary goal of any peritoneal surgery.
What if a patient has both BRAF V600E and dMMR?
dMMR frequently co-occurs with BRAF V600E mutation (through sporadic MLH1 promoter methylation, not Lynch syndrome). In this setting, immunotherapy is preferred over BRAF-targeted therapy. Use ICI in 1L rather than encorafenib + cetuximab + FOLFOX.
Clinical Calculators for Metastatic CRC
All tools referenced in this guideline — access directly from here
Fong Clinical Risk Score
Liver Mets
Peritoneal Carcinomatosis Index
PCI
ECOG Performance Status
Functional assessment
Khorana VTE Risk Score
Thrombosis risk
G8 Geriatric Screening
Elderly assessment
CARG Toxicity Score
Chemo toxicity prediction
Charlson Comorbidity Index
Comorbidity burden
Modified Glasgow Score
Inflammatory prognosis
Medical Disclaimer
These guidelines are intended for qualified healthcare professionals as a clinical reference tool. Always apply individual clinical judgment and consider patient-specific factors. Content reflects NCCN CRC 4.2025 and ESMO Living Guideline v1.3 (Jul 2025). This is not a substitute for formal medical education, professional training, or individualized clinical decision-making.