83MO AMG 510, a novel small molecule inhibitor of KRAS(G12C), for patients (pts) with advanced gastrointestinal (GI) cancers: Results from the CodeBreaK100 phase I trial

Strickler, John H.; Fakih, Marwan; Price, Timothy; Desai, Jayesh; Durm, G.; Krauss, JC; Kuboki, Y.; Kim, T.W.; Sacher, Adrian G.; Henary, H.; Kim, J.; Hong, D.S.

doi:10.1016/j.annonc.2020.10.103

Cited by 4 publications

(5 citation statements)

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“…At the time of the conduct of the SLR, 2 publications had reported the ORR in patients with KRAS G12C-positive mCRC and other gastrointestinal cancers and treated with sotorasib. 63 , 65 A phase I trial of sotorasib in 42 patients with CRC reported an overall ORR of 7.1% (95% CI: 1.5, 19.5) across all doses tested. 63 An ORR of 12.0% was reported for patients with CRC and other GI cancers treated with 960 mg/day of oral sotorasib.…”

Section: Resultsmentioning

confidence: 99%

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Prevalence of KRAS G12C Mutation and Co-mutations and Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic Literature Review

et al. 2023

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Purpose A systematic literature review was conducted to estimate the global prevalence of Kirsten rat sarcoma virus gene (KRAS) mutations, with an emphasis on the clinically significant KRAS G12C mutation, and to estimate the prognostic significance of these mutations in patients with colorectal cancer (CRC). Design Relevant English-language publications in the Embase, MEDLINE, and the Cochrane Library databases (from 2009 to 2021) and congress presentations (from 2016 to 2021) were reviewed. Eligible studies were those that reported the prevalence and clinical outcomes of the KRAS G12C mutation in patients with CRC. Results A total of 137 studies (interventional [n = 8], post hoc analyses of randomized clinical trials [n = 6], observational [n = 122], and longitudinal [n =1]) were reviewed. Sixty-eight studies reported the prevalence of KRAS mutations (KRASm) in 42 810 patients with CRC. The median global prevalence of KRASm was 38% (range, 13.3%-58.9%) and that of the KRAS G12C mutation (KRAS G12C) 3.1% (range, 0.7%-14%). Available evidence suggests that KRASm are possibly more common in tumors that develop on the right side of the colon. Limited evidence suggests a lower objective response rate and inferior disease-free/relapse-free survival in patients with KRAS G12C compared with patients with KRASwt or other KRASm. Conclusion Our analysis reveals that KRAS G12C is prevalent in 3% of patients with CRC. Available evidence suggests a poor prognosis for patients with KRAS G12C. Right-sided tumors were more likely to harbor KRASm; however, their role in determining clinical outcomes needs to be investigated further.

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Section: Resultsmentioning

confidence: 99%

“… 63 An ORR of 12.0% was reported for patients with CRC and other GI cancers treated with 960 mg/day of oral sotorasib. 65 However, this study lacked a comparator arm, precluding a comparison of outcomes.…”

Section: Resultsmentioning

confidence: 99%

Prevalence of KRAS G12C Mutation and Co-mutations and Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic Literature Review

et al. 2023

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“…Our results suggest that KRAS mutations may not be oncogenic driver alterations in chemotherapy resistant PDAC. This is supported by the lower rate of antitumor activity of KRAS G12C covalent inhibitors in KRAS G12C mutant PDAC compared with KRAS G12C mutant non-small cell lung cancer (48,49). There may also be other intracellular signalling pathways beyond FAK that interact with MEK and drive tumor growth in PDAC.…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma

Aung¹,

McWhirter²,

Welch³

et al. 2022

J Gastrointest Oncol

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Background: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently coactivated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor.Methods: Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P 0 =0.15, P 1 =0.40; alpha =0.05, power 0.86).The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling.Results: Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5-1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7-not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression. Conclusions:The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.

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“…In the phase I CodeBreaK100 trial, KRAS G12C inhibitor sotorasib showed an ORR of 7.1% in various GI cancers ( n = 59) including one oesophageal cancer [ 99 ]. Another KRAS G12C inhibitor adagrasib was investigated in the KRYSTAL-1 multicohort phase I/II study and showed an ORR of 35% in the non-pancreatic GI cancers group.…”

Section: Tumour Agnostic Targetsmentioning

confidence: 99%

Targeted Therapies and Developing Precision Medicine in Gastric Cancer

Pihlak

Fong

Starling

2023

Cancers

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Gastric cancer is an aggressive disease with survival remaining poor in the advanced setting. More than a decade after the first targeted treatment was approved, still only HER2, MSI and PDL-1 status have reached everyday practice in terms of guiding treatment options for these patients. However, various new targets and novel treatments have recently been investigated and have shown promise in improving survival outcomes. In this review, we will summarise previous and currently ongoing studies on predictive biomarkers, possible new targeted treatments, potential reasons for conflicting trial results and hope for the future of precision medicine in gastric cancer.

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83MO AMG 510, a novel small molecule inhibitor of KRAS(G12C), for patients (pts) with advanced gastrointestinal (GI) cancers: Results from the CodeBreaK100 phase I trial

Cited by 4 publications

References 0 publications

Prevalence of KRAS G12C Mutation and Co-mutations and Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic Literature Review

Prevalence of KRAS G12C Mutation and Co-mutations and Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic Literature Review

A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma

Targeted Therapies and Developing Precision Medicine in Gastric Cancer

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