Krazati (adagrasib)

P1, N=150, Recruiting, Mirati Therapeutics Inc. | Not yet recruiting --> Recruiting

Pharmacological KRAS inhibition is a promising new approach to the treatment of many kinds of cancer.

Recent breakthroughs include the development of KRAS G12C inhibitors (sotorasib and adagrasib) and promising agents targeting G12D mutations. Advances in KRAS-targeted therapies offer hope for improved outcomes, but resistance mechanisms and organ-specific differences limit efficacy. Continued efforts in personalized treatment strategies and translational research are critical for overcoming these challenges and improving patient survival.

P1, N=11, Completed, Mirati Therapeutics Inc. | Active, not recruiting --> Completed

Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRASG12Ci detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations.

P1, N=150, Not yet recruiting, Mirati Therapeutics Inc.

P3, N=453, Active, not recruiting, Mirati Therapeutics Inc. | Trial completion date: Dec 2024 --> Jul 2026

This research affirms KRAS-G12C inhibitors as promising treatments, especially for certain patient subgroups, and underscores KEAP1 mutations as key biomarkers for resistance. The findings highlight the urgent need for alternative therapeutic approaches in KEAP1-mutant patients and emphasize the role of molecular profiling in tailored treatment strategies.

Recently, these and other newly developed inhibitors have been investigated as monotherapies and in combination for metastatic KRASG12C-mutant CRC. This review examines the development of these inhibitors and highlights data supporting the inclusion of sotorasib and adagrasib, in combination with either panitumumab or cetuximab, in the NCCN Guidelines for CRC for the treatment of refractory metastatic disease.

P2, N=186, Recruiting, Alliance for Clinical Trials in Oncology | Trial completion date: Jun 2026 --> Jun 2028 | Trial primary completion date: Oct 2025 --> Oct 2026

KEAP1, STK11 and NRF2 status define KRASG12C-mutant NSCLC patients with markedly distinct outcomes to adagrasib. These results further support the use of genomic features - mutational and non-mutational - for treatment selection of KRASG12C-mutant NSCLC patients.

P3, N=461, Active, not recruiting, Mirati Therapeutics Inc. | Trial primary completion date: Feb 2025 --> Jan 2026

P1, N=437, Not yet recruiting, Bristol-Myers Squibb

The discovery in 2013 by Shokat and colleagues of a druggable pocket in KRAS paved the way to FDA approval of the first covalently binding KRASG12C inhibitors, sotorasib and adagrasib, in 2021 and 2022, respectively. However, rather than marking the end of a successful assault on the Mount Everest of cancer research, this landmark only revealed new challenges in RAS drug discovery. In this review, we highlight the progress on defining resistance mechanisms and developing combination treatment strategies to improve patient responses to KRAS therapies.

P2, N=186, Recruiting, Alliance for Clinical Trials in Oncology | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

KRASG12C inhibitors sotorasib and adagrasib have been approved for the treatment of KRASG12C-mutant non-small cell lung cancer (NSCLC)...Through unbiased high-throughput screening of 1,395 kinase inhibitors, we identified adavosertib, a WEE1 inhibitor, as a promising combination partner of sotorasib...Importantly, WEE1 inhibition re-sensitized resistant cells to sotorasib treatment. The current findings demonstrate that combined inhibition of KRASG12C and WEE1 not only exhibits synergistic antitumor efficacy but also overcomes resistance to KRASG12C inhibitors, thus representing a novel therapeutic strategy for KRASG12C-mutant NSCLC.

Results from the phase 3 KRYSTAL-12 trial were recently presented, showing benefit with adagrasib compared to docetaxel, with participants in the adagrasib group demonstrating a PFS of 5.5 months compared to 3.8 months in the docetaxel group. However, these results fall short of the 6-month PFS benchmark that had seemed achievable from what had been seen in phase 1 and 2 trials, mirroring similarly disappointing results from the CodeBreaK 200 trial wherein sotorasib, the first-in-class KRAS G12C inhibitor, also failed to meet the 6-month benchmark also thought to be possible when examining earlier trials. These results raise the question of adagrasib's true value in the second-line treatment setting and compel us to explore more potent novel therapies, combination therapies, and more as we seek to break the 6-month PFS barrier in the treatment of KRAS G12C mutant NSCLC.

KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS mutant alleles in cancer patients. The pan-KRAS inhibitors BI-2493 and BI-2865 show potent anti-tumor activity in vitro and in vivo in KRAS wild-type amplified cell lines from this and other tumor types. In conclusion, this is the first study to demonstrate that direct pharmacological inhibition of KRAS shows anti-tumor activity in preclinical models of cancer with KRAS wild-type amplification, suggesting a novel therapeutic concept for patients with cancers bearing this KRAS alteration.

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.