Exploration of Targeted Anti-tumor Therapy

Table 2. Intrinsic (basal) targeted therapy biomarkers of efficacy in metastatic colorectal cancer.

References	Schedule of therapy	BOR%	HR (95% CI)	mPFS (95% CI)	12 months PFR%
Shitara et al. [67] +	FOLFOX-PAN vs. FOLFOX-BEV	83.3 vs. 66.5*	0.76 (0.61–0.95)**	-	NE
Stintzing et al. [80] +	FOLFIRI-CET vs. FOLFIRI-BEV	88 vs. 71* 76 vs. 55**	1.04 (0.73–1.43)*** 0.67 (0.45–0.99)***	-	NE
Lenz et al. [81] +	FOLFOX/FOLFIRI-CET vs. FOLFOX-FOLFIRI-BEV	NE	0.91(0.62–1.23)*** 0.8% (0.68–1.21)***	-	NE
Elez et al. [71] ++	FOLFOX-ENCO-CET vs. FOLFOX +/– BEV	65.1 vs. 37.4	0.53 (0.41–0.68)	-
Middleton et al. [82] ++	DABRAFENIB-TRAMETINIB-PAN	38 vs. 7&&	4.33&& (p = 0.0012)	-	20 vs. < 5
Kopetz et al. [69] ++	IRI-VEMURAFENIB-CET vs. IRI-CET	17 vs. 4	0.3 vs. 0.6&&&	-	NE
Kopetz et al. [79] ++	ENCO-BINIMETINIB-CET vs. ENCO-CET vs. IRI-CET	26.8 vs. 19.5 vs. 1.8	1.85 (1.20–2.84)&&&& 0.56 (0.37–0.84)&&&&&	-	NE
Desai et al. [83] +++	DIVARASIB-CET	62.5	-	8.1 (5.5–12.3)$	< 15
Yaeger et al. [72] +++	ADAGRASIB-CET	34	-	6.9 (5.7–7.4)$	< 20
Fakih et al. [73] +++	SOTO (960)-PAN vs. SOTO (240)-PAN vs. SOC	26.4 vs. 5.7 vs. 0	0.49 (0.3–0.8) and 0.58 (0.36–0.93)$$		30 vs. 15 vs. 15
Siena et al. [75] ++++	TRASTUZUMAB DER	45.3	-	6.9 (4.1–NE)$	NE
Raghav et al. [76] ++++	TRASTUZUMAB DER (5.4) TRASTUZUMAB DER (6.4)	37.8 27.5	-	5.8 (4.6–7)$ 5.5 (4.2–7)$	< 10 < 10
Strickler et al. [77] ++++	TRASTUZUMAB + TUCATINIB	42.9	-	8.2 (4.2–10.3)$	34

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+: RAS WT population; ++: BRAF mutant population; +++: KRAS G12C population; ++++: HER2-positive population. *: BOR comparing FOLFOX-PAN vs. FOLFOX-BEV in ctDNA left-sided double WT patients; **: HR for overall survival comparing FOLFOX-PAN vs. FOLFOX-BEV in left-sided double WT patients; ***: BOR in CMS2 comparing CET vs. BEV; ****: BOR in CMS4 comparing CET vs. BEV; *****: PFS HR between PAN/CET and BEV in CMS2 and CMS4 subtypes. &&: BOR comparing BM1 vs. BM2; &&&: HR for PFS benefit in BM1 vs. BM2 with doublets vs. SOC (HR extracted from [69]); &&&&: benefit in OS with double therapy in cytolytic-low (BM2); &&&&&: benefit in OS with triplet therapy in cytolytic-high (BM1). $: Median PFS and 95% CI; $$: HR for PFS comparing SOTO (960 mg) + PAN vs. SOTO (240 mg) + PAN vs. SC. BOR: best overall response; HR: hazard ratio; mPFS: median progression-free survival; CI: confidence interval; PFR: progression-free rate; PAN: panitumumab; BEV: bevacizumab; CET: cetuximab; IRI: irinotecan; ENCO: encorafenib; DER: deruxtecan; SOC: standard of care; SOTO: sotorasib; CMS: consensus molecular subtypes; ctDNA: circulating tumor DNA; BM: BRAF V600E-mutant; NE: not evaluated. Outcomes were expressed as HRs with 95% CIs or as median PFS with 95% CIs. Symbols (*, **, ***, ****, *****, &&, &&&, &&&&, &&&&&, $, $$) denote specific comparisons and do not indicate statistical significance. The only reported p-value is from Middleton et al. [82] (HR 4.33; p = 0.0012).

Declarations

Acknowledgments

Professional medical writing assistance was provided by Kevin Clayton.

Author contributions

MR: Writing—original draft, Writing—review & editing. MM: Supervision, Writing—original draft, Writing—review & editing. S Madurga: Supervision, Writing—review & editing. FEGV: Writing—original draft, Writing—review & editing. MAR: Writing—original draft, Writing—review & editing. S Marín: Supervision, Writing—review & editing. MC: Conceptualization, Supervision, Writing—review & editing. JM: Conceptualization, Supervision, Writing—original draft, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

Joan Maurel, who is the Editorial Board Member of Exploration of Targeted Anti-tumor Therapy, had no involvement in the decision-making or the review process of this manuscript. The other authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Both figures were created de novo by the authors using BioRender.com and do not reproduce or adapt material from previously published sources.

Funding

Authors acknowledge the support of MICIU/AEI/10.13039/501100011033/-European Commission FEDER funds [PID2023--150539OB-I00]; CIBER-EHD [EHD20PI03 and CB17/04/00023]; AC24/00028; AGAUR [2021-SGR-00350], and ICREA Foundation (ICREA Academia award). ARISTOS has received funding from the European Union’s Horizon Europe research and innovation programme under the Marie Sklodowska-Curie grant agreement No 101081334. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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