Kras inhibitors in clinical trials. Additionally, other mutant-specific inhibitors (e.

Kras inhibitors in clinical trials KRAS G12C inhibitors recently developed have limited use because only 3% of PDAC express this mutation, highlighting the urgent need for pan-RAS inhibitors to address the complex mutation landscape in PDAC while avoiding Jun 27, 2024 · The first patient has been dosed in the monotherapy portion of a Phase 1 clinical trial evaluating QTX3046, a KRAS G12D-selective inhibitor, and patient dosing has begun in the combination portion Sep 10, 2024 · The predominant driver in PDAC is mutated KRAS proto-oncogene, KRA, present in 90% of patients. The data indicate that HRX-0233 had little single-agent activity in H358 and SW837 cells but Nov 15, 2021 · Table 3 Combination therapy of KRAS (G12C) inhibitors in clinical trials. Cetuximab is a recombinant chimeric human/mouse IgG1 monoclonal antibody that inhibits EGFR and is approved for CRC and head and neck cancer. 2 By Phase 11. Nov 20, 2024 · KRAS is among the most frequently mutated oncogenes with multiple subtypes conferring a worse clinical prognosis. Sep 20, 2024 · Micro abstractCCTG IND. K RAS is a small guanosine triphospha-tase (GTPase) that cycles between an in-active[guanosinediphosphate(GDP)– Dec 18, 2024 · RAMP 203 is a Phase 1/2, multicenter, open label, dose evaluation/expansion study evaluating the efficacy and safety of avutometinib and sotorasib with or without defactinib in patients with KRAS G12C mutant non-small cell lung cancer (NSCLC) who have not been previously treated with a KRAS G12C inhibitor as well as in patients who have been The clinical trials on this list are studying kras g12d inhibitor tsn1611. New information and approaches for direct targeting of mutant Ras have fueled hope for the development of direct KRas inhibitors. Mar 5, 2023 · Kirsten rat sarcoma viral (KRAS) oncogene is the most commonly mutated isoform of RAS, accounting for 85% of RAS-driven human cancers. Dr. Despite challenges such as resistance mechanisms and tumor heterogeneity, the development of KRAS inhibitors represents a significant advance in CRC treatment and holds promise Jun 2, 2022 · SAN DIEGO, June 02, 2022 (GLOBE NEWSWIRE) -- Erasca, Inc. In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ra Promising early results from clinical trials with the two inhibitors AMG 510 and MRTX849, both targeting the KRAS G12C mutant allele covalently and specifically (12,13), have been reported. The study follows a multicenter, open-label, dose-escalation, and dose-expansion design. Additionally, other mutant-specific inhibitors (e. Combinatory approaches utilizing avutometinib or pembrolizumab to increase the Jul 15, 2024 · Verastem Oncology has announced the dosing of the first patient with GFH375/VS-7375, a potent and selective oral KRAS G12D (ON/OFF) inhibitor, as part of a Phase I/II clinical trial in China. 3 million new cancer cases worldwide in 2020. May 22, 2024 · These drugs seem to hold clinical promise as, only recently, a spinout of California-based BridgeBio launched with $200 million to solely focus on the development of KRAS inhibitors. Historically deemed undruggable due to its complex structure and essential role in tumorigenesis, KRAS Jul 16, 2024 · Though KRAS G12C is a prominent mutation seen in lung cancer, certain malignancies such as pancreatic cancer most commonly have the G12D mutation in the KRAS gene. This multi-center trial is currently recruiting patients with advanced KRAS -mutated cancers to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and preliminary efficacy of BI 1701963 alone and in combination with trametinib. Methods: In this 3 + 3 dose-escalation phase 1/2 trial, patients with previously treated advanced KRAS mutant NSCLC received selinexor (dosed orally weekly) plus docetaxel 75 mg/m 2 IV every three weeks (NCT03095612). Additional compounds under development as KRAS G12C inhibitors include the Eli Lilly drug LY3537982 which is actually their “second attempt” after the failure of their first drug LY3499446 (NCT04165031) form Dec 21, 2022 · Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. A phase 1 study for bbo-8520 is currently enrolling participants. Jul 11, 2024 · Mutations in the KRAS gene are the primary driver of pancreatic cancer. And even those that do tend to quickly KRAS G12D mutation is one of the most prevalent subtypes in RAS mutant cancers. The KRAS G12C-selective inhibitors . Unlike in NSCLC, early studies of KRAS inhibitors in CRC struggled to demonstrate single agent activity. 6 Phase II/III 8. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, today announced a trial to investigate the ERK1/2 inhibitor ERAS-007 in combination with a KRAS G12C Jun 2, 2022 · SAN DIEGO, June 02, 2022 (GLOBE NEWSWIRE) -- Erasca, Inc. Full size table. Early clinical trials testing drugs targeting a specific change in KRAS, like adagrasib (Krazati) and sotorasib (Lumakras), alone in pancreatic cancer showed promising results. 2A shows long-term cell proliferation assays of H358 and SW837 cells in the presence of either drug alone or the combination of sotorasib and HRX-0233. In addition to the marketed drugs, sotorasib and adagrasib, there are currently 10 clinical drugs for covalent RAS inhibitors involving 24 clinical Apr 15, 2024 · KRAS mutations contribute substantially to the overall colorectal cancer burden and have long been a focus of drug development efforts. Tricomplex inhibitors that selectively target active KRASG12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985). Apr 4, 2024 · Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced it has initiated a Phase 3 clinical trial evaluating MK-1084, an investigational oral selective KRAS G12C inhibitor, in combination with KEYTRUDA for the first-line treatment of certain patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor KRAS G12C mutations and express PD-L1 “The KRAS protein cycles between an inactive and active state, and cancer-causing KRAS mutations can drive KRAS into the active state,” Spira said, adding that increased signaling of wild-type RAS can also be a driver of tumors. Jun 7, 2023 · Dublin, June 07, 2023 (GLOBE NEWSWIRE) -- The "Global KRAS Inhibitors Market, Drug Price, Sales, & Clinical Trials Insight 2029" report has been added to ResearchAndMarkets. Jul 23, 2024 · These results are particularly encouraging given the historically poor outcomes in pancreatic cancer and the limited efficacy of other KRAS G12C inhibitors in this indication. a Phase 1b/2 clinical trial evaluating Feb 27, 2024 · Apart from Revolution only one other company, 280Bio, has a pan-KRAS inhibitor in the clinic; 280Bio is the US subsidiary of China’s Shanghai Yingli, and presented a poster at last year’s AACR showing that the molecule YL-17231 overcame resistance in KRAS-mutant tumours resistant to G12C inhibition. We first focused on synergy with sotorasib, as this KRAS inhibitor is in routine clinical use. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants Aug 30, 2022 · Innovative techniques used in the TOPAZ trial for Parkinson's disease have ensured that enrolment targets were met, patient participation was boosted, and project costs were reduced. While both trials are investigating these agents as single agents, preclinical data 4 days ago · Additionally, the Phase 1 clinical trial evaluating QTX3034, an oral G12D-preferring multi-KRAS inhibitor, as a monotherapy and in combination with cetuximab, continues to enroll patients, and Apr 22, 2024 · The US Food and Drug Administration (FDA) has granted approval for GenFleet Therapeutics’ Phase III clinical trial of GFH925, a KRAS G12C inhibitor, for the treatment of patients with refractory metastatic colorectal cancer (CRC). McCormick, will likely enter clinical trials in the next year or so. Prior treatment Apr 1, 2022 · AbstractKRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Sep 1, 2024 · Second, KRAS inhibitors demonstrate encouraging single-agent clinical activity in chemo-refractory solid tumors. G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. Oct 31, 2022 · Last year, FDA approved the first KRAS inhibitor, sotorasib, to treat people with non-small cell lung cancer that has this specific KRAS mutation. Unfortunately, results from NCT01951690 clinical trial demonstrated the modest antitumor efficacy of FAK inhibitor defactinib (ORR: 2 % mPFS: 45 days) (Gerber et al. The company also initiated the combination phase of its ongoing Phase 1 trial evaluating QTX3046, a G12D-selective KRAS inhibitor, with cetuximab, an EGFR inhibitor. The 2013 discovery of covalent small molecule inhibitors selective for mutant cysteine at residue 12 of KRAS provided proof of concept for the development of direct RAS Mar 11, 2021 · Buoyed by the data, Lilly plans to start a phase 1 clinical trial of the KRAS inhibitor later this year. Oct 4, 2024 · In KRAS G12D, meanwhile, disappointment abounds, with ESMO data on Astellas’s degrader ASP3082 adding to underwhelming results with HengRui’s inhibitor HRS-4642 a year earlier. Global KRAS Inhibitors Clinical Pipeline By May 1, 2024 · A phase I/II clinical trial of MRTX1133 for KRAS G12D-mutated solid malignancy is ongoing (NCT05737706). This marks the first Phase III trial of KRAS G12C inhibitor monotherapy targeting CRC patients globally. In cell culture, NRAS-mutant melanoma cells have greater sensitivity to pan-RAF inhibition than KRAS-mutant cells and have comparable sensitivity to BRAF V600E cells 130. Both inhibition and degradation repressed the established markers of MAPK signaling pERK (fig. However, no results of KRAS G12D inhibitors from any clinical trials have been reported yet. Feb 26, 2024 · The KRAS inhibitor market is expected to grow significantly in the coming years, driven by the increasing incidence of cancer and the growing demand for personalized cancer treatments; ongoing research and clinical trials have identified potential treatment strategies. Although these advancements inspire optimism, we stand on the cusp of a thrilling chapter in KRAS-targeted treatments, with many mysteries yet to be unraveled. HRS-4642 is a highly selective KRAS G12D inhibitor. Toshihiko Doi (National Cancer Center Hospital East) presented his talk entitled "RAS Inhibitors: From the Standpoint of Early Clinical Development", in which he raised the issue of delayed development of KRAS inhibitors in Japan. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour May 25, 2020 · In preclinical studies this has been shown to lead to cytostasis in cancer cells addicted to KRAS signaling. SOS1::KRAS inhibitors exhibit activity against a broad spectrum of KRAS alleles, including the major G12D/V/C and G13D oncoproteins, while sparing the interaction of KRAS with SOS2. Jun 23, 2021 · In early-phase clinical trials, two potent, selective, and irreversible small-molecule KRAS G12C inhibitors have shown promising results in non–small-cell lung cancer (NSCLC) and more modest Oct 12, 2024 · Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with significant public health concerns. 5,6 Intermsofeffectorenzymes,RASdirectlycontrols,orcontrib- Jun 15, 2022 · The pan-KRAS SOS1 inhibitor BI 1701963 is the first direct KRAS signaling modifier, which entered phase I clinical trials both as a monotherapy as well as in combination with KRAS G12C inhibitors, MEK inhibitors and irinotecan. Primary objectives are to determine the maximum tolerated dose (MTD) and recommended Phase II dose of BI Jan 1, 2025 · As a result, clinical trials testing FAK inhibitor for the treatment of NSCLC were developed. Sotorasib Citation 55 and adagrasib Citation 56 have already shown some promising results in early phase clinical trials, which is encouraging for developing CNS-targeted therapies. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. KRAS functioning as a signaling hub participates in multiple cellular signaling pathways and regulates a variety of critical processes such as cell proliferation, di … Aug 24, 2023 · KRAS inhibitors that are selective for KRAS mutations including G12D, G12S and G12R have been identified 4,5,6, and several G12D-selective inhibitors are currently in clinical trials. After a lengthy preclinical road, KRAS inhibition via the G12C allele has finally become a therapeutic reality. These compounds may overcome resistance to GDP-bound inhibitors which can acquire secondary resistance mutations . gov identifier: NCT05737706) and RMC-9805 (ClinicalTrials. 1 summarizes the targets and agents for the RAS pathway. The SOS1i::KRAS inhibitor BI 1701963 is the first direct RAS signaling modifier to enter phase I clinical trials both as a monotherapy as well as in combination. S4E) in KRAS-dependent cell lines. Clinical trials look at new ways Mar 11, 2024 · In melanoma, MEK inhibitors are now routinely added to BRAF inhibitors, providing a significant, although modest, delay in the onset of development of drug resistance. This finding has led to multiple clinical trials to combine KRAS G12C inhibitors with RTK-targeted therapies predominantly for KRAS G12C-mutated CRC. Additionally, novel therapeutic approaches targeting other KRAS subvariants are also being explored in clinical trials with encouraging early data. BPI-421286, GH35, BEBT-607, and JAB-21000, are all the KRAS inhibitors used in IND-enabling studies . The combination therapy led to durable tumor elimination Aug 30, 2024 · The first clinical trials investigating these agents in patients with previously treated advanced non-small Canon, J. 2 Preclinical 8. The platform will inform future late-phase studies and explore effects of novel therapies on the tumor immune . Investigation into these tissue-specific Feb 1, 2024 · Several other KRAS G12C inhibitors (hereafter KRAS G12Ci) have also entered clinical development more recently, ushering in a new era of targeted KRAS inhibition [19]. Jan 19, 2022 · We then examine the clinical relevance of KRAS, especially the KRAS G12C mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. used to target additional KRAS mutants and other undruggable cancer drivers. Other new entrants include a Werner helicase inhibitor from Ideaya and GSK, an EphA2 peptide drug conjugate from ConjuStar, and a CD73 x Lag3 bispecific from Akeso. To Jan 19, 2021 · In <5 years, the availability of novel therapeutics has transformed the landscape of KRAS treatments, and a target that was once considered “undruggable” now has several therapeutic inhibitors undergoing clinical trials. gov identifier: NCT06040541), both of which are currently enrolling patients with KRAS G12D-mutated CRC. In the lab, the compound was effective against many cancer cell lines and in mouse models of lung cancer and colorectal cancer. A drug based on the molecule may be effective in patients who don't respond to the KRAS^G12C inhibitors currently in clinical trials. KRAS multi-inhibitor clinical trial 3 days ago · Quanta Therapeutics announced advancements in its KRAS-directed drug candidates, including FDA IND clearance for QTX3544, a G12V-preferring multi-KRAS inhibitor, allowing for a Phase 1 clinical trial. Fig. 1 By Country 11. 5 Phase II 8. Finally, we review the preclinical evidence that supported the initial development of the direct KRAS G12C inhibitors and summarize the ongoing clinical trials of all direct KRAS G12C Dec 4, 2023 · We also discuss emerging promising KRAS-targeted therapeutic strategies, with a focus on mutation-specific and direct pan-KRAS inhibitors and indirect KRAS inhibitors through targeting the RAS Sep 6, 2023 · Covalent KRAS inhibitors in clinical trials. Apr 16, 2024 · Direct RAS inhibitors. In these 2 clinical trials (N-48), all the patients had advanced pancreatic cancer with Kras G12C May 29, 2024 · This clinical trial is now enrolling patients with advanced solid tumors harboring a KRAS G12D mutation. Preliminary data from a small clinical trial show that AMG 510 appears to be safe and has activity against different cancers with KRAS G12C mutations. Apr 3, 2019 · Drugmaker Amgen revealed the structure of AMG 510—the first covalent inhibitor of a mutant form of the cancer-target KRas to make it into human clinical trials. Global KRAS Inhibitors Clinical Trials Indicators 11. GMC-6236 is part of the emerging innovation being seen in the KRAS space. 0%), and fatigue (25. KRas is the most frequently mutated oncogene in human cancer, and even 40 years after the initial discovery of Ras oncogenes in 1982, no approved drug directly targets Ras in Ras-driven cancer. Now Roche is getting in on the act with GDC-7035 in a phase 1 study in KRAS G12D-mutated solid tumours. Not all tumors with a KRAS G12C mutation respond to these drugs, however. Other specific KRAS (G12C) inhibitors from other companies are also under investigation in clinical Although components of this triple-drug combination involving MEK inhibitors have been found to present notable adverse effects in clinical trials, we find that substitution of MEK inhibitor with the recently developed mutant-specific KRAS-G12C inhibitor ARS-1620 allows strong inhibition of KRAS-G12C mutant tumors with reduced toxicity and Nov 9, 2024 · Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. 17 While more potent ERK pathway inhibition is Jun 20, 2024 · Global KRAS Inhibitor Clinical Trials Insight by Country, Company, Indication & Phase 8. S4A). Lilly’s, however, does not, at least according to clinicaltrials. Table 2. 242A Substudy enrolls a maximum of 27 patients and evaluates major pathological response rate after neoadjuvant JDQ443 (opnurasib), a selective KRAS G12C inhibitor. Jul 1, 2021 · Abstract. sotorasib (Lumakras) and adagrasib (Krazati), which are approved Aug 15, 2020 · The SOS1::KRAS inhibitor BI 1701963 is currently in a Phase I clinical trial. Dec 5, 2019 · An experimental drug, AMG 510, that targets a mutated form of the KRAS protein, completely shrank tumors in mouse models of human cancer, a new study shows. G12C–mutated May 31, 2023 · Results: In this systematic review, data on 2 chemotherapeutic agents Sotorasib (AMG510) and Adagrasib (MRTX849) which are Kras G12C inhibitors, are obtained from Code Break-100 and preliminary results of KRYSTAL-1 clinical trials, respectively. Allele-specific KRASG12C inhibitors are currently changing the treatment paradigm for patients with KRASG12C-mutated non–small cell lung cancer and colorectal cancer. Nevertheless, our current understanding of KRAS G12Ci in the treatment of NSCLC remains limited, with data reported from only one phase III randomized controlled trial (RCT May 9, 2024 · Comparatively, and as discussed in this review, all KRAS inhibitors that have entered clinical trials for patients with pancreatic cancer have higher ORRs and lower frequencies of TRAEs than second-line chemotherapy treatment, regardless of whether the inhibitors are in a Phase I dose escalation study or FDA-approved . Dec 15, 2023 · This serves as a rationale for combination with immune checkpoint blockade, which can provide additional combinatorial therapeutic benefit in some preclinical cancer models. A new class of drugs known as KRAS inhibitors is showing initial promise in clinical trials, but many tumors quickly develop Apr 12, 2022 · Coinhibition of CDK4/6 maximizes the therapeutic potential of KRAS G12C inhibitors in NSCLC and pancreatic cancer (pancreatic ductal adenocarcinoma) cell line models, and clinical trials are combining KRAS inhibitors with palbociclib and abermaciclib. gov. The primary objectives are to BI 1701963 is currently being evaluated in phase I clinical trials in patients with advanced KRAS-mutated cancers to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and preliminary efficacy of BI 1701963 alone and in combination with MEK inhibitors, KRAS G12C inhibitors or irinotecan. Article ADS CAS PubMed Google Scholar Hallin, J. This review aims to summarize the current clinical landscape of KRAS G12C inhibitors in colorectal cancers and to emphasize potential therapeutic strate-gies to overcome treatment challenges. May 31, 2023 · The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. et al. Jun 1, 2020 · KRas is the most frequently mutated oncogene in human cancer, and even 40 years after the initial discovery of Ras oncogenes in 1982, no approved drug directly targets Ras in Ras-driven cancer. With inhibitors to KRAS-G12D now entering clinical trials, understanding the biology of KRAS-G12D cancers, and identifying biomarkers that predict therapeutic response is crucial. gov - NCT06607185 The main purpose of the study is to assess whether the study drug, LY4066434, is safe and tolerable when administered to participants with locally advanced or metastatic solid tumors with certain KRAS mutations. GFH375/VS-7375 is identified as the lead discovery programme from the Verastem Oncology discovery and development partnership with GenFleet Therapeutics. ” The XPO1 inhibitor selinexor demonstrated efficacyinpreclinicalNSCLC models harboring various KRAS mutations. 1. NCI’s basic information about clinical trials explains the types and phases of trials and how they are carried out. 1 Research 8. However, these drugs given alone do not work in all patients. Besides, pan-KRAS inhibitors would be an alternative strategy for complement with allele-specific KRAS inhibitors to comprehensively conquer acquired resistance induced by concurrent KRAS alterations. For example, a phase 2 trial with a single group revealed that the most frequently reported AEs were diarrhea (50. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRAS G12C mutated allele, which show encouraging results in clinical trials. 5 By Patient Segment 12. 8) in NCI-H358 treated with AMG-510 . Apr 18, 2024 · Herein, we outline RAS pathobiology with a focus on KRAS, illustrate therapeutic approaches across a variety of malignancies, including emphasis on the ‘on’ and ‘off’ switch allele-specific and May 31, 2023 · MSK investigators report exciting results for a new molecule that can block 16 different mutated forms of the KRAS protein. This review examines the landscape of KRAS inhibition in colorectal cancer (CRC), focusing on recent advances in therapeutic strategies targeting this oncogene. EGFR, PI3K, Nov 1, 2024 · Clinical trials of multiple KRAS G12C inhibitors have shown promising efficacy in advanced, previously treated non–small cell lung cancer (NSCLC), leading to United States Food and Drug Administration (FDA) accelerated approval of two of these therapies (adagrasib and sotorasib) and many others being investigated in this setting (9–17). Multiple early-phase clinical trials of other KRAS G12D inhibitors, including RMC9805 (NCT06040541) and HRS4642 (NCT05533463), are also ongoing. Instead of targeting a Apr 18, 2023 · Innovent Announces Updated Data of Phase 1 Clinical Trial for IBI351 (KRAS[G12C] Inhibitor) as Monotherapy for Solid Tumors at the AACR Annual Meeting 2023 today announced the updated results Apr 27, 2022 · 11. However KRAS G12C inhibitors to other KRAS variants. Farnesyl transferase inhibitors largely failed in clinical trials for KRAS or NRAS mutant cancers due to theabilityofotherenzymes,geranylgeranyltransferases,tosub-stitute forthem,although theymay havesomeutility inthe much rarer HRAS mutant cancers. Nov 7, 2023 · The pan-RAS inhibitor RMC-6236 generated preliminary signals of durable clinical efficacy and displayed a manageable safety profile in patients with KRAS-mutant non–small cell lung cancer (NSCLC Apr 10, 2024 · Patients with advanced NSCLC with KRAS G12C mutations showed favorable outcomes when treated with KRAS G12C inhibitors in several clinical trials [4, 5, 9]. Therefore, there is a need for KRAS inhibitors that can treat other cancer types. 4%) [ 5 ]. Sep 20, 2020 · Results showed that a KRAS G12C inhibitor produced durable clinical benefit with mainly low-grade gastrointestinal and hepatic toxic effects in a heavily Phase I Clinical Trials Program Sotorasib is the first specific inhibitor of KRAS G12C to enter clinical trials. 6 days ago · However, KRAS G12C inhibitors’ clinical trials have revealed clinical efficiency variations between patients with KRAS G12C-positive NSCLC and those with CRC. These inhibitors demonstrated clinical activity primarily in non-small cell lung cancer (NSCLC), where the KRAS G12C mutation frequency is highest (14,15). 46 Addition of MEK or ERK inhibitors to KRAS-G12C inhibitors has been explored pre-clinically and in early-stage clinical trials. Researchers involved in NCI’s RAS Initiative, as well as others, have also made progress designing pan-KRAS inhibitors—drugs that work against several different KRAS mutant proteins. Methods: NCT04111458 is a first-in-human trial of BI 1701963 in patients aged ≥18 years with tumors harboring KRAS mutations. 2,5,6 While KRAS G12C inhibitors have received regulatory approval in certain countries, a significant unmet need persists for other KRAS mutant alleles, such as KRAS G12D, G12V, and G13D, which account for over 100,000 annual diagnoses in the United States alone. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p. Pan-KRAS SOS1 inhibitors exhibit activity against a broad spectrum of KRAS alleles, including the major G12D/V/C and Sep 19, 2024 · Alongside, we also profiled the covalent inhibitor of KRAS G12C Sotorasib or the noncovalent KRAS G12D inhibitor MRTX-1133 as appropriate (Fig. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. Feb 26, 2024 · Indeed, various clinical trials have been executed to explore the efficacy of combining MEK inhibitors with PI3K/AKT pathway inhibition in PDAC by using a pan-PI3K inhibitor (NCT01155453 Oct 14, 2023 · “Given KRAS G12C mutations are the most common KRAS mutation in NSCLC and acquired mutations and amplifications occur upon clinical progression to KRAS G12C inhibitor monotherapy, the results of the RAMP 203 trial are important in understanding potential new treatment approaches for patients. All in all, clinical trials investigating the efficacy of KRAS downstream inhibitors in monotherapy provided limited clinical benefit and substantial toxicity in most studies [11, 65] Yet, recent preclinical studies with patient-derived xenograft tumors highlighted the need for combination therapy in order to fully block KRAS signaling in lung Notably, similar clinical trials of MEK inhibitors for KRAS-mutant PDAC, CRC and NSCLC have shown no benefit over the standard of care 147,154–156. Researchers have developed a KRAS inhibitor, BI-2852, that inhibits ERK phosphorylation and reduces proliferation of KRAS-mutant cancer cells. 10, 11, 12 There are essentially four novel approaches to target KRAS that can be divided into targeted therapies and immunotherapies, potentially in combination with one Dec 31, 2024 · The efficacy of the first-generation KRAS inhibitor is modest, but with scientific advancement, KRAS G12C inhibitors with higher potency are on the horizon. Nov 5, 2023 · The research team already has developed two additional RAS(ON) inhibitors, also now in clinical trials—RMC-6236 for patients with advanced solid tumors harboring select KRAS G12 mutations and a mutant allele specific-inhibitor, RMC-9805, targeting KRAS G12D (ON), the most common KRAS mutations in patients with pancreatic or colorectal cancer. 242 is a neoadjuvant platform trial for molecularly defined non-small cell lung cancer. Reminiscent of BRAF inhibitor trials however, 23, 24 KRAS inhibitors appear less effective as monotherapy in CRC than in NSCLC. May 10, 2023 · Recent studies reveal that nearly one in seven human cancers exhibit KRAS alterations, contributing to an estimated 19. Dec 18, 2024 · The KRAS G12C inhibitor prior-treated Stage I Part B cohort is still enrolling patients and is anticipated to complete enrollment in early 2025. 8%), nausea (31. Jan 19, 2022 · Adagrasib (MRTX849) and other direct KRAS G12C inhibitors are currently being investigated in multiple clinical trials. Adagrasib and sotorasib, two FDA-approved agents specifically targeting this mutation, have shown promise in clinical trials. Methods: This is a first-in-human, multicenter, open-label phase 1 study in adult patients with advanced solid tumors with KRAS G12D mutations, without prior direct KRAS inhibitor treatment (NCT06227377). 2 Additionally Jun 25, 2021 · In fact, several KRAS G12D inhibitors are in development and, according to Dr. Dec 13, 2024 · The group will start a phase 1 trial of its “G12V-preferring” multi-KRAS inhibitor QTX3544 in January, according to the latest listings on clinicaltrials. However, in clinical trials, combination of KRAS G12C inhibitors with PD-(L)1 blockade has yet to show improved outcome, in part due to treatment toxicities. May 27, 2021 · This result strongly suggests the potential of ASP2453 to be the best-in-class compound among KRAS G12C inhibitors and provides confidence on an advancement of ASP2453 to clinical trials. May 2, 2024 · This review article summarizes the latest evidence from the clinical trials of KRAS G12C inhibitor combinations and discusses other possible combinations with their preclinical evidence. Here we discuss Prior treatment with any KRAS G12C small molecule inhibitor, except in certain scenarios where such prior therapy is allowed as per protocol; The following patients will be excluded from some parts of the study: Experienced certain serious side effects with prior immunotherapy Sep 13, 2024 · Background: The KRAS G12C mutation, prevalent in various malignancies, including non-small cell lung cancer (NSCLC), represents a unique therapeutic target. Feb 27, 2024 · Apart from Revolution only one other company, 280Bio, has a pan-KRAS inhibitor in the clinic; 280Bio is the US subsidiary of China’s Shanghai Yingli, and presented a poster at last year’s AACR showing that the molecule YL-17231 overcame resistance in KRAS-mutant tumours resistant to G12C inhibition. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. The current Patent Highlight presents compounds that directly bind to KRASG12D, selectively inhibiting its activity. Aug 20, 2024 · More than 90% of pancreatic tumors carry a cancer-fueling change in the KRAS gene. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, today announced a trial to investigate the ERK1/2 inhibitor ERAS-007 in combination with a KRAS G12C ways controlled by RAS. These compounds possess a Dec 1, 2021 · Table 1 summarizes major clinical trials for KRAS mutant tumors. 4 By Indication 11. , KRAS G12D), as well as pan-KRAS inhibitors or RAS(ON) multiselective inhibitors, are entering clinical trials and demonstrating promising results. Overview of KRAS G12C inhibitors and other KRAS inhibitors As of December 2023, two KRAS G12C inhibitors (sotorasib and adagrasib) have been approved by the FDA. This Sep 6, 2023 · MRTX1133 is a highly selective inhibitor of KRAS G12D mutation, being studied in a phase I/II clinical trial (NCT05737706) for safety, tolerability, and anti-tumor activity in patients with advanced solid tumor malignancy with this mutation. A separate Phase 1 trial Dec 21, 2021 · The rapid progression of KRAS(G12C) inhibitors from preclinical characterization to the clinic has radically changed the perception of the KRAS oncogene as an undruggable target. Here, we report preliminary results of the dose escalation part of a first-in-human phase 1 study of HRS-4642 in patients (pts) with advanced KRAS G12D mutant solid tumors. Here, we present pre-clinical data showing May 13, 2024 · The inhibitors currently in early-phase clinical trials include MRTX1133 (ClinicalTrials. However, clinical trials showed that nearly 20% of patients with NSCLC and mutated KRAS G12C are insensitive to KRAS inhibitors and are clinically non-responders. However, the development of resistance necessitates BI 3706674, a KRAS multi-inhibitor, is currently undergoing clinical investigation as a monotherapy in patients with unresectable metastatic KRAS wild type amplified and KRAS G12V mutated solid tumors including gastric, esophageal, and gastroesophageal junction adenocarcinoma, and PDAC, respectively. Dec 21, 2022 · KRAS p. Aug 17, 2023 · Other KRAS-G12C inhibitors, GDC-6036 (NCT04449874), RG6330, and D-1553 (NCT04585035), are under phase I/II clinical trials, and their results have not been published. Preclinical studie Aug 24, 2023 · Researchers at The University of Texas MD Anderson Cancer Center have uncovered a functional role for KRAS mutations in pancreatic cancer and rapidly translated these findings into a novel therapeutic approach combining a KRAS G12D inhibitor with immune checkpoint inhibitors for early- and late-stage KRAS G12D-mutant pancreatic cancer. Oct 12, 2024 · It highlights recent clinical trials evaluating the efficacy of KRAS inhibitors either as monotherapy or in combination with other agents, such as anti-EGFR antibodies. 22 Using a disulfide-fragment-based screening approach, a library of 480 tethering compounds was screened for covalent binding to KRasG12C. A Study of the Pan-KRAS Inhibitor LY4066434 in Participants With KRAS Mutant Solid Tumors J5Q-OX-JRDA - ClinicalTrials. Mar 5, 2023 · For the extensive unmet needs of targeting numerous KRAS mutations, more efforts in developing allele-specific KRAS inhibitors are needed. This study aims to compare their efficacy in treating KRAS G12C-mutated NSCLC, drawing insights from pivotal Sep 30, 2024 · A notable difference is that the Pfizer and BeiGene trials both exclude patients who have been previously treated with any RAS or KRAS inhibitor. To date, no marketed mutant-selective and potent KRASG12D inhibitors are available. Hence, further data are imperative to broaden the scope of patients with CRC poised to reap the rewards of Mar 11, 2024 · In melanoma, MEK inhibitors are now routinely added to BRAF inhibitors, providing a significant, although modest, delay in the onset of development of drug resistance. 3 Phase I 8. Sep 24, 2023 · The oral, covalent, mutant-selective KRAS inhibitor, RMC-9805, has been dosed for the first time in a patient with a KRAS-G12D-mutant solid tumor, marking the beginning of a phase 1/1b clinical trial (NCT06040541). Nature 575, 217–223 (2019). Dec 27, 2024 · Numerous combinatorial therapies involving KRAS inhibitors are in clinical trials aiming to overcome therapy resistance. 5 Compared to NSCLC, colorectal cancer with KRAS G12C mutation showed a limited objective response to the KRAS G12C inhibitors, indicating resistance to the therapy. Chair: Kiyoko Kato. 3A and fig. As was the case with the now-abandoned LY3499446, combinations look set to be central to Jan 3, 2024 · The United States Food and Drug Administration (FDA) has cleared the investigational new drug (IND) application for BBO-8520, a first-in-class orally bioavailable and potentially highly potent small molecule direct inhibitor of KRASG12C that binds to the Switch II pocket in both the GTP-bound (ON) and GDP-bound (OFF) state conformations of KRASG12C BBO-8520 is expected to significantly […] It has shown promise in NSCLC including a partial response in 50% who had been previously treated with a KRAS inhibitor . Several additional clinical trials of glecirasib are currently ongoing or planned: Jun 1, 2020 · There are now several KRAS allele-specific inhibitors in late-phase clinical trials, and many newer agents and targeting strategies undergoing preclinical and early-phase clinical testing. There are numerous clinical trials of KRAS G12C inhibitor agents ongoing . It is an oral, small molecule, highly selective inhibitor of KRAS G12C by covalently and irreversibly binding to the S-IIP, locking KRAS in its inactive GDP-bound state and inhibiting KRAS oncogenic signaling. Jun 4, 2021 · The highly selective and irreversible KRAS G12C inhibitor sotorasib showed clinical efficacy with reversible toxic effects, the SELECT-1 randomized clinical trial. More than 90% of PDAC cases involve KRAS mutations. Aug 24, 2024 · Citation 55 Several inhibitors of KRAS G12C have been developed to date. Colorectal cancer , another malignancy with a high incidence of KRAS mutations, has also shown responsiveness to these inhibitors. 7 Phase III Oct 23, 2023 · NEW YORK – Drugmakers at the European Society for Medical Oncology Congress presented data on next-generation KRAS inhibitors from early-stage clinical trials, hoping to demonstrate enhanced KRAS G12C inhibition, initial evidence of efficacy in solid tumors, and the ability to target a variety of KRAS variants. Aug 23, 2023 · Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. Potential explanations for this phenomenon include tissue-specific differences in KRAS dependence, clonal Nov 7, 2023 · The pan-RAS inhibitor RMC-6236 generated preliminary signals of durable clinical efficacy and displayed a manageable safety profile in patients with KRAS-mutant non–small cell lung cancer (NSCLC Mar 5, 2023 · For the extensive unmet needs of targeting numerous KRAS mutations, more efforts in developing allele-specific KRAS inhibitors are needed. With publication of CodeBreaK 100 and KRYSTAL-1 trials, two inactive-state RAS (off)-selective KRAS G12C inhibitors, sotorasib and adagrasib, have now demonstrated clinical efficacy in patients with advanced cancer (7, 8, 20). 3 By Company 11. Feb 29, 2024 · Session 3 Current Status and Future Prospects of Clinical Trials in Japan. Several other KRAS G12C inhibitors are being tested in late-stage clinical trials. PCM Trials outlines how adopting decentralised clinical trial methods such as mobile research nurses can speed up medical discoveries and treatments. KRAS G12C Inhibitors as Monotherapy To date, the KRAS G12C allele is the only KRAS variant with Jul 11, 2024 · Delhi, July 11, 2024 (GLOBE NEWSWIRE) -- Global KRAS Inhibitors Market and Clinical Trials Future Outlook 2030 Report Highlights: Global KRAS Inhibitors Sales Growth In 2023: 10% Nov 21, 2024 · While KRAS G12C inhibitors have demonstrated remarkable clinical benefits, only a few clinical trials have reported related adverse events (AEs) [5, 6]. Aug 12, 2024 · Background: Pancreatic ductal adenocarcinoma (PDAC) is a challenging cancer with a 5-year survival rate of under 12%. Jan 4, 2024 · Quanta’s KRAS inhibitor pipeline includes three programs: QTX3034, a multi-KRAS inhibitor with G12D-preferring activity (G12D+ multi-KRAS), anticipated to enter clinical trials in 1Q24; QTX3046 Oct 29, 2024 · Prior to adagrasib, AMG510 (sotorasib) was the first KRAS G12C-targeted inhibitor that entered clinical trials (CodeBreaK 100 / NCT03600883) and was approved by the FDA on May 28, 2021, for patients with locally advanced or metastatic KRAS G12C-mutated NSCLC who had received prior systemic therapy. 4 Phase I/II 8. , 2020). 3B and fig. All trials on the list are NCI-supported clinical trials, which are sponsored or otherwise financially supported by NCI. Nov 4, 2023 · RMC-4550, an SHP2 inhibitor, is currently undergoing several combinational clinical trials after showing strong synergy and significant improvements in anti-tumor capabilities with several direct KRAS G12C inhibitors [96, 105] as well as the highest synergy score (22. May 13, 2024 · pan-KRAS and pan-RAS inhibitors are in clinical trials with promising efficacy. S4, B to D) and DUSP6 (Fig. The IND. com's offering. g. Glecirasib Ongoing Clinical Trials. Potential explanations for this phenomenon include tissue-specific differences in KRAS dependence, clonal KRAS G12D mutation is one of the most prevalent subtypes in RAS mutant cancers. A couple of assumptions were included in the model due to the lack of available data at the time of model development. Apr 4, 2024 · Subsequent to the success of the KRAS G12C inhibitor, acquired resistance to the inhibitor has become a clinical problem and the underlying mechanisms have been explored. 17 While more potent ERK pathway inhibition is Dec 18, 2024 · Verastem Oncology Provides a Clinical Update for RAMP 203 Trial in Advanced KRAS G12C Mutant Non-Small Cell Lung Cancer The KRAS G12C inhibitor prior-treated Stage I Part B cohort is still Nov 1, 2023 · Activating mutations in codon 12, especially G12D, have the highest prevalence across a range of carcinomas and adenocarcinomas. Similar to Aug 26, 2022 · Nevertheless, this approach of combining a KRAS G12C inhibitor with an ICI is being evaluated in several clinical trials across KRAS G12C-mutant solid tumours (Supplementary Table 1), including Discovery of switch-II pocket binders The starting point for the development of KRasG12C inhibitors currently being investigated in clinical trials was the discovery of the so called switch-II pocket in 2013 by the Shokat Laboratory. Expansion cohorts in pancreatic, colorectal, and lung cancer are part of the design of this trial. 61 Aurora kinase A (AURKA) may also help cells to escape drug-induced quiescence by adaptive Jun 21, 2024 · Clinical trials have shown promising results, with patients exhibiting significant tumor shrinkage and prolonged progression-free survival when treated with KRAS G13C inhibitors. 2 . llwpef qoed xtg ouuwvgt azpbq fuqya cfb dobq zthkf fsyxow