Krazati (adagrasib)

P2, N=200, Recruiting, Mirati Therapeutics Inc. | Trial completion date: Sep 2025 --> Mar 2025

P1, N=7, Terminated, Mirati Therapeutics Inc. | Completed --> Terminated; The decision was made to terminate this study to further enrollment, as of 08 March 2022. The decision was made primarily due to a change in development strategy.

SRC inhibitors (DGY-06-116, dasatinib, and bosutinib) also exhibit synergistic effects with MRTX849 in eliminating various tumor cell lines carrying KRAS-G12C mutations. Thus, SRC inhibitors amplify the therapeutic utility of G12Ci.

Although once thought to be "undruggable", KRAS p.G12C inhibitors such as sotorasib and adagrasib have been developed. This paper focuses on adagrasib, the second KRAS p.G12C inhibitor to obtain regulatory approval by the FDA and describes the details on its study design, development and current place in therapy.

The PBPK model well-described the single and multiple-dose adagrasib PK data as well as DDI data with itraconazole, rifampin, midazolam, warfarin, dextromethorphan, and digoxin, with model predictions within 1.5-fold of the observed clinical data. is predicted to be a strong inhibitor of CYP3A4, a moderate inhibitor of CYP2C9 and CYP2D6, and an inhibitor of P-glycoprotein (P-gp). These results successfully supported regulatory interactions with the United States Food and Drug Administration regarding dosing recommendations for when adagrasib is used concomitantly with other medications, supporting a range of label claims in lieu of clinical trials.

P2, N=42, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Active, not recruiting

Although most adverse effects are reversible, vigilance is warranted particularly for nephrotoxicity and hepatotoxicity during the administration of KRAS G12C inhibitors.

Our study highlights the critical need for blocking both intrinsic and extrinsic mechanisms of resistance for the prolonged response and shows that such treatment is ineffective in KRASG12Ci-AcR tumors.

The development of KRAS-targeted drugs like sotorasib and adagrasib has generated significant excitement in the clinical arena, offering new therapeutic options. However, the efficacy of immune checkpoint inhibitors in this context still requires comprehensive evaluation. The response to anti-Programmed Cell Death Protein 1/Programmed Cell Death Protein 1 Ligand (anti-PD-1/PD-L1) drugs in NSCLC may be significantly influenced by co-occurring mutations, underscoring the need for a personalized approach to treatment based on the specific genetic profile of each tumor.

Noteworthy, CodeBreaK100 and KRYSTAL-1 clinical trials have recently demonstrated that sotorasib and adagrasib, two novel selective KRASG12C inhibitors, have clinical activity with acceptable adverse-event profile for the treatment of advanced NSCLC patients with KRASG12C mutation. In this paper, we describe the role of KRAS mutations in NSCLC focusing on the clinical and molecular characteristics which potentially identify specific subtypes of NSCLC patients based on different KRAS mutations. We also provide an overview of the main clinical trials testing novel selective KRASG12C inhibitors as well as novel potential therapeutic strategies for NSCLC patients with non-G12C KRAS mutations.

The subtle differences observed, particularly in PFS, could inform clinical decision-making, emphasizing the need for personalized treatment strategies. Future research should focus on long-term effects and identifying patient subgroups that may benefit more from one drug over the other.

The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance...We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells...Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.

Symptoms resolved after treatment with prednisone and therapy interruption of adagrasib followed by a permanent dose reduction. After the dose reduction, there was an ongoing effective tumor response at follow-up, and serum concentrations of adagrasib remained within the therapeutic index. Through this case report, we aim to bring attention to the possibility of this side effect, as we believe it is important to be aware of it for future patients undergoing treatment with adagrasib.

P1/2, N=85, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2024 --> Dec 2024

Recently, an emergency approval from the US-FDA has been issued for KRASG12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. Moreover, because KRASG12D and KRASG12V are more common than KRASG12C, focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors.

No abstract available

The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45-0.76; P<0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRAS G12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRAS G12C enigma code in NSCLC.

Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRASG12C mutated NSCLC. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future.

ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRAS G12C inhibitors. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

The recent approval of KRASG12C inhibitors, adagrasib and sotorasib, has validated KRAS as a direct therapeutic target and demonstrated the feasibility of selectively targeting specific RAS mutants. Despite these challenges, new approaches have generated optimism about targeting specific RAS mutations in an allele-dependent manner for cancer therapy, supporting by compelling biochemical and structural evidence, which inspires further exploration of RAS allele-specific vulnerabilities. This review will discuss recent advances and challenges in the development of therapies targeting RAS signaling, highlight emerging therapeutic strategies, and emphasize the importance of allele-specific approaches for leukemia treatment.

KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

P3, N=320, Recruiting, Hoffmann-La Roche | Trial completion date: Jul 2028 --> Sep 2029

Our findings would provide valued evidence for healthcare professionals to recognize AEs associated with KRAS (G12C) inhibitors and differences between sotorasib and adagrasib, and guide their clinical practice.

Although the advent of sotorasib and adagrasib, has lifted the "undruggable" stigma of KRAS, the resistance to KRAS inhibitors quickly becomes a major issue. Meanwhile, we established that GTF2I is dephosphorylated at S784 via ERK by KRAS inhibitors, which hinders its nuclear translocation and mediates ALDH1A1's upregulation in response to KRAS inhibitors. In summary, the results offer valuable insights into targeting ALDH1A1 to enhance the effectiveness of KRAS-targeted therapy through ferroptosis in cancer treatment.

Previously considered undruggable, sotorasib and adagrasib are the first available OFF-state KRASG12C inhibitors, but treatment resistance is frequent. We highlight the lack of data on non-genomic resistance and the need for comprehensive clinical studies exploring histological, genomic, and non-genomic changes at resistance. This knowledge could help foster new treatment initiatives in this challenging context.

P1/2, N=31, Recruiting, M.D. Anderson Cancer Center | Suspended --> Recruiting

Unlike adagrasib, sotorasib is less dependent on H95 for its binding, making it a RAS isoform-agnostic compound, having a similar functionality also with NRAS and HRAS G12C mutants. Our results emphasize the accessibility of SII-P beyond oncogenic G12C and aid in understanding the molecular mechanism behind the clinically observed drug resistance, associated especially with secondary mutations on KRAS H95 and Y96.

In adagrasib, only 2 SAEs were detected, with renal failure showing significant signals in four algorithms. This study offers a comprehensive evaluation of the major safety signals associated with sotorasib and adagrasib, providing valuable information for clinicians regarding drug selection and safety considerations, thereby facilitating the design of future prospective safety studies.

P1/2, N=31, Suspended, M.D. Anderson Cancer Center | Initiation date: Nov 2024 --> Aug 2024 | Not yet recruiting --> Suspended

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRASG12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC)...Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRASG12C-driven lung cancer cell proliferation in vitro and superior tumor control in vivo. Additionally, in genetically engineered mouse models of KRASG12C-driven NSCLC, inhibition of either KRASG12C or ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRASG12C in lung cancer.

Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRASG12C-mutated previously treated advanced non-small cell lung cancer. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRASG12C-selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRASG12C(ON) inhibitor RMC-6291 alone or in combination with KRASG12C(OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading.

Structure-activity relationship (SAR) studies have been instrumental in optimizing the binding affinity, selectivity, and pharmacokinetic properties of these inhibitors, leading to the development of promising therapeutic agents like Sotorasib and Adagrasib. This review provides an overview of the KRAS pathway, KRAS binding sites, strategies for direct and indirect inhibition using small molecules, and SAR based on the co-crystal structures of inhibitors with KRAS mutants which is expected to offer new hope for patients with KRAS-driven cancers through the development of new KRAS-targeted drugs.

P1, N=86, Active, not recruiting, Mirati Therapeutics Inc. | Phase classification: P1/2 --> P1

P3, N=320, Recruiting, Hoffmann-La Roche | Not yet recruiting --> Recruiting

Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.

FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation...Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors...Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population.

P1, N=52, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Aug 2028 --> Aug 2030

Additionally, immunological approaches utilizing T-cell receptor (TCR)-engineered T cell therapy or vaccines, and Hapimmune antibodies are ongoing. This review delineates the recent advancements in KRAS inhibitor development in the post-sotorasib/adagrasib era, with a focus on NSCLC.

Among 1122 BRAF-wild-type colorectal carcinomas, compared with KRAS-wild-type tumors, multivariable-adjusted colorectal cancer-specific mortality hazard ratios (95% confidence interval) were 1.82 (1.05-3.17) in KRAS c.34G>T (p.G12C)-mutated tumors (p = 0.035) and 1.57 (1.22-2.02) in other KRAS-mutated tumors (p = 0.0004). Our study provides novel evidence for clinical and tumor characteristics of KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma.

KRASG12C inhibitors have good ORR, DCR, PFS rate, OS rate, tolerable trAEs, and early response with long duration in advanced solid tumors; however, most of the pooled results were heterogeneous. Sotorasib has shown better safety results.

P3, N=320, Not yet recruiting, Hoffmann-La Roche

While KRAS has long been considered undruggable, the FDA recently approved two direct acting KRAS inhibitors, Sotorasib and Adagrasib, that covalently bind and inactivate KRASG12C. This review provides an update on clinical trials involving CRC patients treated with KRASG12C inhibitors as a monotherapy or combined with other drugs. Mechanisms that contribute to resistance to KRASG12C inhibitors and the development of novel RAS inhibitors with potential to escape such mechanisms of resistance are also discussed.