Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial

Kuboki, Yasutoshi; Fakih, Marwan; Strickler, John; Yaeger, Rona; Masuishi, Toshiki; Kim, Edward J.; Bestvina, Christine M.; Kopetz, Scott; Falchook, Gerald S.; Langer, Corey; Krauss, John; Puri, Sonam; Cardona, Panli; Chan, Emily; Varrieur, Tracy; Mukundan, Lata; Anderson, Abraham; Tran, Qui; Hong, David S.

doi:10.1038/s41591-023-02717-6

Cited by 17 publications

(5 citation statements)

References 32 publications

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“…Recent reports indicate an association of baseline amplification in EGFR, MET , and/or ERBB2 in baseline circulating tumor DNA (ctDNA) with inferior progression-free survival (PFS) in BRAF V600E colorectal cancer ( 34 ) and of baseline BRAF amplification with shorter PFS in KRAS G12C colorectal cancer ( 35 ). In 48 patients where we were able to call baseline gene amplification status in tissue, we found that, among the 15 patients with at least one amplified gene, the median TOT was 5.5 months (IQR: 4.3–7.4) compared with 8.3 months (IQR: 5.6–11.9) for 33 patients whose tumor did not harbor an amplified gene ( P = 0.027; Fig.…”

Section: Resultsmentioning

confidence: 99%

Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer

Harrold,

Keane,

Walch

et al. 2024

Clinical Cancer Research

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Purpose: Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance. Experimental Design: We assembled a series of 52 patients with paired pre-treatment and progression samples who received therapy targeting EGFR (n=17), BRAF V600E (n=17), KRAS G12C (n=15), or amplified HER2 (n=3) to identify molecular and clinical factors associated with time on treatment (TOT). Results: All patients stopped treatment for progression and TOT did not vary by oncogenic driver (p=0.5). Baseline disease burden (≥3 versus <3 sites, p=0.02), the presence of hepatic metastases (p=0.02), and gene amplification on baseline tissue (p=0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy number changes (p=0.008) and high number (≥5) of acquired alterations (p=0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases. Conclusions: Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.

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Section: Resultsmentioning

confidence: 99%

Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer

Harrold,

Keane,

Walch

et al. 2024

Clinical Cancer Research

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“…The importance of identifying pathogenic variants in the KRAS gene is related to the application of the monoclonal antibodies cetuximab and panitumumab for patients with metastatic CRC and RAS/RAF wild-type tumors. However, targeted therapies based on KRAS variants have also been achieved in early-phase trials in advanced or metastatic CRC patients, with adagrasib [48] and sotorasib [49] being the first FDA-approved inhibitors that selectively target cells harboring the KRAS p.Gly12Cys variant. Although this is a low-frequency variant found in 3-8% of CRC patients [50][51][52], the benefits for carrier patients will be considerable.…”

Section: Discussionmentioning

confidence: 99%

KRAS Exon 2 Mutations in Patients with Sporadic Colorectal Cancer: Prevalence Variations in Mexican and Latin American Populations

Venegas-Rodríguez,

Hernández-Sandoval,

Gutiérrez-Angulo

et al. 2024

Cancers

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We searched for the prevalence of actionable somatic mutations in exon 2 of the KRAS gene in western Mexican patients with CRC. Tumor tissue DNA samples from 150 patients with sporadic CRC recruited at the Civil Hospital of Guadalajara were analyzed. Mutations in exon 2 of the KRAS gene were identified using Sanger sequencing, and the data were analyzed considering clinical–pathological characteristics. Variants in codon 12 (rs121913529 G>A, G>C, and G>T) and codon 13 (rs112445441 G>A) were detected in 26 patients (with a prevalence of 17%). No significant associations were found between these variants and clinical–pathological characteristics (p > 0.05). Furthermore, a comprehensive search was carried out in PubMed/NCBI and Google for the prevalence of KRAS exon 2 mutations in Latin American populations. The 17 studies included 12,604 CRC patients, with an overall prevalence of 30% (95% CI = 0.26–0.35), although the prevalence ranged from 13 to 43% across the different data sources. Determining the variation and frequency of KRAS alleles in CRC patients will enhance their potential to receive targeted treatments and contribute to the understanding of the genomic profile of CRC.

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“…No TRAE leading to treatment discontinuation was observed. In the dose expansion cohort (N = 40), the ORR was 30% with mPFS and mOS of 5.7 and 15.2 months, respectively ( 30 ). Other 46 patients were treated with a combination of panitumumab, sotorasib, and FOLFIRI.…”

Section: Currently Available Data On Combining Kras G12c Inhibitors A...mentioning

confidence: 99%

KRAS G12C inhibitor combination therapies: current evidence and challenge

Miyashita,

Kato,

Hong

2024

Front. Oncol.

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Although KRAS G12C inhibitors have proven that KRAS is a “druggable” target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors. The combinations of KRAS G12C inhibitors with immunotherapies and chemotherapies have also been investigated, and the preliminary results were reported. More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.

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Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial

Cited by 17 publications

References 32 publications

Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer

Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer

KRAS Exon 2 Mutations in Patients with Sporadic Colorectal Cancer: Prevalence Variations in Mexican and Latin American Populations

KRAS G12C inhibitor combination therapies: current evidence and challenge

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