LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation

Weiss, Jared; Yaeger, Rona; Johnson, Melissa L.; Spira, Alexander I.; Klempner, Samuel J.; Barve, Minal; Christensen, James G.; Chi, Andrew; Der-Torossian, Hirak; Velastegui, Karen; Kheoh, Thian; Ou, S-H.I.

doi:10.1016/j.annonc.2021.08.2093

Cited by 66 publications

(44 citation statements)

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“…The importance of Bcl-xL as a mediator of acute resistance to KRAS G12C inhibitors was demonstrated in vivo, where combined treatment of KRAS G12C MT CRC xenografts with the BCL-2/Bcl-xL and KRAS G12C inhibitors, Navitoclax and AZ'8037, resulted in supra-additive reductions in tumour growth or regression. During this manuscript's preparation, initial results of the phase Ib study of cetuximab with Adagrasib were released, showing a response rate of 43% in KRAS G12C MT CRC patients (48). Although initial results of this small study are encouraging, it also suggests that a major part of this population will not respond to this combination, indicating the need for alternative treatment combinations.…”

Section: Discussionmentioning

confidence: 99%

Bcl-xL is a key mediator of apoptosis following KRAS^G12C inhibition in KRAS^G12C mutant colorectal cancer

Khawaja

Briggs

Latimer

et al. 2022

Preprint

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PurposeNovel covalent inhibitors of KRASG12C have shown limited response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed.Experimental designSmall molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were employed. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo. AZ’1569-resistant CRC cells were generated and characterised.ResultsResponse to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as single-agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as a top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ’1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12CMT xenografts. Finally, AZ’1569-resistant cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to several targeted agents. Importantly, KRAS amplification and AZ’1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification.ConclusionsCombinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRASG12CMT CRC patients.

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Section: Discussionmentioning

confidence: 99%

Bcl-xL is a key mediator of apoptosis following KRAS^G12C inhibition in KRAS^G12C mutant colorectal cancer

Khawaja

Briggs

Latimer

et al. 2022

Preprint

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“…In 45 colorectal cancer patients evaluable for analysis with adagrasib monotherapy, 22% had a confirmed response while the disease control rate was 87% and PFS was 5.6 months. The combination therapy with cetuximab led to 43% response rate and 100% disease control rate in 28 patients 173 , 174 Thus, both studies showed promising activity in pretreated patients. Further G12 C inhibitors JNJ-74699157, GDC-6036, and JDQ433 are currently being tested in similar trials with colorectal cancer patients (NCT04006301, NCT04449874, and NCT04699188).…”

Section: Targeting the Mapk Pathwaymentioning

confidence: 95%

Precision medicine for metastatic colorectal cancer in clinical practice

2022

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Globally, metastatic colorectal cancer is one of the leading causes for cancer-related death. Treatment limited to conventional chemotherapeutics extended life for only a few months. However, advances in surgical approaches and medical treatment regimens have greatly increased survival, even leading to long-term remission in selected patients. Advances in multiomics analysis of tumors have built a foundation for molecular-targeted therapies. Furthermore, immunotherapies are on the edge of revolutionizing oncological practice. This review summarizes recent advances in the growing toolbox of personalized treatment for patients with metastatic colorectal cancer. We provide an overview of current multimodal therapy and explain novel immunotherapy and targeted therapy approaches in detail. We emphasize clinically relevant therapies, such as inhibitors of MAPK signaling, and give recommendations for clinical practice. Finally, we describe the potential predictive impact of molecular subtypes and provide an outlook on novel concepts, such as functional precision medicine.

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“…Early trial data provide clinical support for this observation: the response rate for sotorasib was 7-10% in CRC 7 and, in the rst report of sotorasib plus the EGFR antibody panitumumab, the response rate was 27% 8 . For adagrasib monotherapy, it was ~20% and, for adagrasib with the EGFR antibody cetuximab, it increased to ~40% 9 . Based on these data, these KRAS G12C and EGFR antibody combination treatments are being evaluated in registrational, phase 3 trials.…”

Section: Full Textmentioning

confidence: 99%

Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers

Misale

Yaeger

Mezzadra

et al. 2022

Preprint

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KRAS G12C inhibitors, such as sotorasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Clinical efficacy is achieved in NSCLC as a single agent and in CRC in combination with anti-EGFR monoclonal antibodies, however, secondary resistance impairs the effects of KRAS G12C blockade. In this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS-EGFR inhibition. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signalling by drug can be detected at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumour marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification became addicted to these agents and undergoes oncogene-induced senescence upon drug withdrawal. Accordingly, the KRAS G12C signal in circulating DNA from relapsed patients harbouring G12C amplification rapidly recedes upon treatment holiday. These data indicate that KRAS G12C amplification is a recurrent resistance mechanism to KRAS-EGFR co-inhibition and suggest a potential therapeutic vulnerability, whereby therapies that target this senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition.

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LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation

Cited by 66 publications

References 0 publications

Bcl-xL is a key mediator of apoptosis following KRAS^G12C inhibition in KRAS^G12C mutant colorectal cancer

Bcl-xL is a key mediator of apoptosis following KRAS^G12C inhibition in KRAS^G12C mutant colorectal cancer

Precision medicine for metastatic colorectal cancer in clinical practice

Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers

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LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation

Cited by 66 publications

References 0 publications

Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer

Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer

Precision medicine for metastatic colorectal cancer in clinical practice

Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers

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Bcl-xL is a key mediator of apoptosis following KRAS^G12C inhibition in KRAS^G12C mutant colorectal cancer

Bcl-xL is a key mediator of apoptosis following KRAS^G12C inhibition in KRAS^G12C mutant colorectal cancer