Krazati (adagrasib) / ZAI Lab, BMS - LARVOL DELTA

LC-MS/MS method development and validation for novel targeted anticancer therapies adagrasib, capmatinib, ensartinib, entrectinib, larotrectinib, lorlatinib, pralsetinib, selpercatinib and sotorasib. (PubMed, J Pharm Biomed Anal) - "After the validation, 74 plasma samples were measured in the application phase and all results but one fell within the validated ranges. This assay allows simultaneous quantification of nine novel targeted therapies and supports therapeutic drug monitoring."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Krazati: Data readout from P3 KRYSTAL-10 trial (NCT04793958) for 2L CRC in 2026 (Bristol-Myers Squibb) - Q2 2025 Results: Data readout from P2/3 KRYSTAL-7 trial (NCT04613596) for 1L NSCLC PD-L1≥50% in 2028

P2/3 data • P3 data • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Generation of actionable, cancer-specific neoantigens from KRAS(G12C) with adagrasib. (PubMed, Proc Natl Acad Sci U S A) - "Our previous study with sotorasib, an FDA-approved covalent inhibitor of KRAS(G12C), demonstrated that drug-treated cells produce such neoantigens and can be killed by T cell engagers directed against the drug-peptide/MHC complex. The antibodies in a bispecific T cell engager format killed adagrasib-resistant lung cancer cells upon adagrasib treatment. These results support the broad applicability of the HapImmune approach for creating actionable cancer-specific neoantigens and offer candidates for therapeutic development."

Journal • CNS Disorders • Cognitive Disorders • Lung Cancer • Oncology • Solid Tumor • KRAS

RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches. (PubMed, Medicina (Kaunas)) - "Recent advancements in targeted therapies, particularly the focus on novel agents such as KRAS G12C inhibitors, including sotorasib and adagrasib, have shown promising efficacy in overcoming resistance to conventional treatments. Furthermore, this review discusses future directions, emphasizing the need for research into non-RAS targets to address the complexities of resistance mechanisms and improve therapeutic outcomes. This review aims to provide a detailed overview of the current treatments and innovative approaches, supporting the development of personalized management strategies for patients with mCRC."

Journal • Review • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • KRAS • NRAS • RAS

KRYSTAL-4: Phase 3 Study of Adagrasib Plus Pembrolizumab and Chemotherapy Intreatment-Naïve, Advanced KRAG12C-Mutated NSCLC (IASLC-WCLC 2025) - "Abstract is embargoed at this time."

Metastases • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor

Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1 (clinicaltrials.gov) - P1/2 | N=822 | Recruiting | Sponsor: Mirati Therapeutics Inc. | Trial completion date: Jan 2026 ➔ Dec 2026 | Trial primary completion date: Jul 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

SOS1 inhibitor BMS-986509 and EGFR inhibitor combinations are synergistic with adagrasib in KRAS G12C mutant tumor organoid models (ESMO 2025) - No abstract available

Oncology • KRAS

Lipophilic statins enhance the antitumor efficacy of the KRAS inhibitor adagrasib in NSCLC cell lines (ESMO 2025) - No abstract available

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Severe Hypercalcemia In A Patient With Metastatic Colon Cancer: Role of Parathyroid Hormone and Vitamin D (ENDO 2025) - "She was on adagrasib and cetuximab after progression on FOLFIRINOX...Hypercalcemia resolved rapidly with IV fluids, calcitonin and zoledronic acid...In addition, vitamin D deficiency remains undertreated due to lack of screening, despite potential implications for malignancy-related calcium disorders. Future management should include continued endocrinologic and oncologic evaluation to clarify the hormonal interplay and optimize treatment."

Clinical • Metastases • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Endocrine Cancer • Endocrine Disorders • Metabolic Disorders • Oncology • Renal Disease • Secondary Hyperparathyroidism • Solid Tumor

Phase Ib Trial of the KRASG12C Inhibitor Adagrasib (MRTX849) in KRAS G12C Mutant Metastatic Pancreatic Cancer Patients (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: M.D. Anderson Cancer Center | N=14 ➔ 0 | Trial completion date: Nov 2027 ➔ Jul 2025 | Active, not recruiting ➔ Withdrawn | Trial primary completion date: Nov 2027 ➔ Jul 2025

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Specific inhibitor to KRASG12C induces tumor-specific immunity and synergizes with oncolytic virus for enhanced cancer immunotherapy. (PubMed, J Immunother Cancer) - "Small molecule inhibitors of KRASG12C are novel inducers of tumor-specific immunity, and a unique triple combination regimen is highly efficacious through elicited potent antitumor immunity for KRASG12C cancers."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • CTLA4 • GZMB • HAVCR2 • IFNG • KRAS

Profiling opnurasib (JDQ-443) for the treatment of non-small cell lung cancer (NSCLC). (PubMed, Expert Opin Pharmacother) - "Oral small molecule inhibitors, including sotorasib and adagrasib, have demonstrated moderate efficacy in targeting KRAS G12C in NSCLC. In the face of an expanding market, development of JDQ-443 has been halted despite promising safety and efficacy outcomes and ongoing innovative trials, highlighting critical challenges in the drug development process. The existing body of work characterizing JDQ-443 remains extremely informative."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Bioequivalence Study Between Adagrasib Reference Tablets and High Drug Load Tablets (clinicaltrials.gov) - P1 | N=160 | Completed | Sponsor: Mirati Therapeutics Inc. | Recruiting ➔ Completed

Trial completion

ADEPPT: Adagrasib in Patients With KRASG12C-mutant NSCLC Who Are Elderly or Have Poor Performance Status (clinicaltrials.gov) - P2 | N=68 | Active, not recruiting | Sponsor: ETOP IBCSG Partners Foundation | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Adagrasib in the treatment of colorectal cancer. (PubMed, Future Oncol) - "When combined with cetuximab, an anti-EGFR monoclonal antibody, efficacy was further improved with an ORR of 34% and median OS of 15.9 months, leading to the accelerated approval of the combination by the Food and Drug Administration (FDA) in USA in 2024, but it is not yet approved in the European Union. Adagrasib is a well-tolerated drug as monotherapy and in combination with cetuximab and represents a novel treatment for KRASG12C-mutated mCRC."

Journal • Review • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Population-adjusted unanchored indirect comparisons of cancer therapies with borrowing of pan-tumor information. (PubMed, Stat Methods Med Res) - "The method is illustrated with a case study of adagrasib versus sotorasib in previously treated KRASG12C-mutated advanced/metastatic tumors: non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The analysis illustrated that a reasonably conservative assumption about the degree of similarity can result in more meaningful and interpretable findings. The proposed model allows for population adjustment and information sharing across tumor types when performing an unanchored indirect comparison of interventions for which it is believed a pan-tumor effect holds."

Journal • Pan tumor • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Adagrasib for previously treated KRAS G12C mutation-positive advanced non-small-cell lung cancer (terminated appraisal) (NICE) - "NICE is unable to make a recommendation on adagrasib (Krazati) for previously treated KRAS G12C mutation-positive advanced non-small-cell lung cancer in adults. This is because Bristol Myers Squibb will consider restarting this evaluation when the final overall survival analysis can be included in the economic model."

NICE • Non Small Cell Lung Cancer

The complex journey of targeting RAS in oncology. (PubMed, BMC Cancer) - "This breakthrough has led to the development of targeted therapeutics, such as sotorasib and adagrasib, for KRAS G12C-mutated non-small cell lung cancer (NSCLC)...New inhibitors, such as LY3537982 or GDC-6036, are promising, but achieving effective and selective RAS inhibition remains a significant challenge...Challenges such as off-target effects and delivery issues remain significant barriers in the introduction of effective therapies based on RAS inhibitors. This overview highlights the evolving nature of targeting RAS in cancer therapy."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • TP53

Adquired resistance mechanisms to KRAS G12C inhibitors in lung cancer (EACR 2025) - "The first effective covalent G12C inhibitors (i) sotorasib and adagrasib bound to mutant cysteine, trapping KRAS in its inactive GDP-bound state...We tested new drug combinations to revert off-target resistant mechanisms with a SHP2 inhibitor (TNO155) and a MEK inhibitor (trametinib), with and without sotorasib, and analyzed the efficacy by cell viability and colony formation assays... On target KRAS mutations as mutant allele amplification and secondary KRAS nonG12C mutations are the most prevalent acquired resistance mechanisms. Upstream and downstream inhibitors as SHP2i and MEKi could be synergic in combination with sotorasib in partially resistant CLs."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Dissecting KRAS G12C inhibitor resistance at the transcriptomic level (EACR 2025) - "Our findings pinpoint that cells dynamically rewire their transcriptome upon sotorasib and adagrasib administration through the dysregulation of splicing factors. Adaptive resistance to these KRAS G12C inhibitors converges on MAPK signaling disruption and isoform remodeling in cell plasticity and adhesion pathways. This regulatory shift is conserved across mouse and human cells, with the strongest effects observed under adagrasib treatment."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

The role of drug efflux and uptake transporters in the plasma and tissue disposition of KRASG12D inhibitor MRTX1133 (EACR 2025) - P1 | "To date, there are no FDA-approved KRAS inhibitors other than Sotorasib and Adagrasib, which target uniquely the KRASG12C mutation. This study highlights the relevance of ABCB1/ABCG2 in the transporter-mediated restriction of brain penetration and reduction of kidney and liver accumulation of MRTX1133. We hypothesize that co-administration of the dual ABCB1/ABCG2 inhibitor elacridar could promote brain penetration and increase kidney and liver exposure for MRTX1133. The insights gained may contribute to enhancing the safety and efficacy of MRTX1133 in the clinic."

Biliary Cancer • Cholangiocarcinoma • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ABCB1 • ABCG2 • KRAS • SLCO1C1

Study of long non-coding RNAs in resistance to KRAS G12C inhibitors in lung cancers (EACR 2025) - "The development of covalent inhibitors targeting this variant, such as adagrasib, is a recent clinical breakthrough... Our study highlights the importance of lncRNAs in resistance mechanisms to KRAS G12C inhibitors in NSCLC. It suggests that non-genetic mechanisms involving lncRNAs contribute to the development of resistance. Further functional research into these lncRNAs could provide new therapeutic targets and strategies."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

MYC targeting by Omomyc boosts efficacy and overcomes resistance to KRAS inhibitors (EACR 2025) - "The FDA recently approved two direct KRAS-G12C inhibitors (KRASi), Sotorasib and Adagrasib, for NSCLC, while G12D-specific and pan-RAS inhibitors are still under clinical development. These findings support dual MYC and KRAS inhibition in KRAS-mutant cancer, offering a potential strategy to overcome resistance to KRAS inhibitors."

Clinical • Late-breaking abstract • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ANXA5 • KRAS

Matching-Adjusted Indirect Comparison of Sotorasib Versus Adagrasib in Previously Treated Advanced/Metastatic Non-Small Cell Lung Cancer Harboring KRAS G12C Mutation. (PubMed, Adv Ther) - "In this MAIC, sotorasib and adagrasib showed comparable efficacy in previously treated advanced KRAS G12C-mutated NSCLC. Among patients with baseline brain metastases, PFS point estimates favored sotorasib. Sotorasib also demonstrated a favorable overall safety profile. These findings may help inform payer decisions and clinical practice in the treatment of KRAS G12C-mutated NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Analysis of Pan-Specific Inhibitors of Oncogenic Mutant Forms of KRAS GTPase. (PubMed, Curr Med Chem) - "The clinical application of covalent KRAS inhibitors (sotorasib, adagrasib) is limited to the treatment of only certain KRASG12C-mediated types of cancer. The consideration of 28 patents included descriptions of the structures of the presented molecules, identification of the most active and selective examples of compounds, as well as results from structure-activity relationship (SAR) analyses for each sample. As a result of this work, some structural features of the most active examples of pan-KRAS inhibitors were identified."

Journal • Oncology • KRAS