Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths, with adenosquamous carcinoma of the pancreas (ASCP), a rare variant, representing 1-10% of cases. Standard chemotherapy trials for pancreatic cancer exclude ASCP, leaving its optimal treatment uncertain. This report describes a 68-year-old male with metastatic ASCP and a KRAS G12C mutation, progressing through multiple lines of systemic therapy, including targeted inhibition of KRAS G12C. Notably, the patient exhibited a robust response to single-agent immune checkpoint inhibition (ICI) with pembrolizumab, despite intact mismatch repair proteins. The limited success of traditional therapies in pancreatic cancer, coupled with the rarity of ASCP, presents a challenge in establishing effective treatment strategies. While KRAS G12C inhibitors demonstrated modest benefits, this case highlights the remarkable response to ICI in a patient with squamous histology. The distinct tumor microenvironment of ASCP, characterized by squamous differentiation, may contribute to this exceptional response. This underscores the need for further research and clinical trials focused on ICI in ASCP, with an ongoing multi-center phase 2 trial investigating outcomes in this specific subset.

2024-08-01·Current Problems in Cancer

Current perspectives of KRAS in non-small cell lung cancer

Review

作者: Harris, Ethan ; Thawani, Rajat

NSCLC has a diverse genomic background with mutations in key proto-oncogenic drivers including Kirsten rat sarcoma (KRAS) and epidermal growth factor receptor (EGFR). Roughly 40% of adenocarcinoma harbor Kras activating mutations regardless of smoking history. Most KRAS mutations are located at G12, which include G12C (roughly 40%), G12V (roughly 20%), and G12D (roughly 15%). KRAS mutated NSCLC have higher tumor mutational burden and some have increased PD-1 expression, which has resulted in better responses to immunotherapy than other oncogenes. While initial treatment for metastatic NSCLC still relies on chemo-immunotherapy, directly targeting KRAS has proven to be efficacious in treating patients with KRAS mutated metastatic NSCLC. To date, two G12C inhibitors have been FDA-approved, namely sotorasib and adagrasib. In this review, we summarize the different drug combinations used to target KRAS G12c, upcoming G12D inhibitors and novel therapies targeting KRAS.

2024-04-02·Molecular Cancer Therapeutics

Cereblon-based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Inhibits Tumor Growth

Article

作者: Begovich, Kyle ; Okano, Akinori ; Chourasia, Aparajita H. ; Schoolmeesters, Angela ; Whitefield, Brandon ; Fung, Leah ; Mali, Venkat ; Huang, Shenlin ; Lai, Chon ; Martinez-Terroba, Elena ; Rajapakse, Navin ; Shakya, Arvind ; Greene, Steven ; Kumar, Maneesh

AbstractMutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, son of sevenless homolog 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target SOS1 for degradation could represent a potential pan-KRAS modality that may be capable of circumventing certain acquired resistance mechanisms. Here, we report the development of two SOS1 cereblon-based bifunctional degraders, BTX-6654 and BTX-7312, cereblon-based bifunctional SOS1 degraders. Both compounds exhibited potent target-dependent and -specific SOS1 degradation. BTX-6654 and BTX-7312 reduced downstream signaling markers, pERK and pS6, and displayed antiproliferative activity in cells harboring various KRAS mutations. In two KRAS G12C xenograft models, BTX-6654 degraded SOS1 in a dose-dependent manner correlating with tumor growth inhibition, additionally exhibiting synergy with KRAS and MEK inhibitors. Altogether, BTX-6654 provided preclinical proof of concept for single-agent and combination use of bifunctional SOS1 degraders in KRAS-driven cancers.

项与 KRAS G12C inhibitors (Leidos Biomedical Research) 相关的新闻（医药）

2024-01-04

·GlobeNewswire-Health Care

Quanta Announces IND Clearance by U.S. FDA for QTX3034, G12D-Preferring Multi-KRAS Inhibitor, and Other Pipeline Updates

– First-in-human clinical trial evaluating QTX3034 as monotherapy and combination in patients with KRASG12D-mutated advanced solid tumors to begin in 1Q24 – – QTX3046, KRASG12D-selective inhibitor, continues advancement through IND-enabling activities; IND filing on track for 1H24 – – QTX3544, G12V-preferring multi-KRAS inhibitor, selected as development candidate and Quanta’s third KRAS-directed program – RADNOR, Pa. and SOUTH SAN FRANCISCO, Calif., Jan. 04, 2024 (GLOBE NEWSWIRE) -- Quanta Therapeutics, a privately-held biopharmaceutical company pioneering targeted therapies to treat RAS-driven cancers, today announced progress across its pipeline of KRAS-directed drug candidates, including U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) application clearance for QTX3034, a multi-KRAS inhibitor with G12D-preferring activity (G12D+ multi-KRAS), enabling the initiation of a Phase 1 clinical trial in the first quarter of 2024. Additionally, QTX3046, a KRASG12D-selective inhibitor continues its advancement through IND-enabling activities positioning the company to file an IND in the first half of 2024. Further, the company has recently selected QTX3544, a multi-KRAS inhibitor with G12V-preferring activity (G12V+ multi-KRAS), as a development candidate, representing Quanta’s third KRAS inhibitor program. “We look forward to initiating the Phase 1 study for QTX3034 in the first quarter of 2024 and evaluating this highly potent drug candidate in patients with advanced KRASG12D-mutant solid tumors as monotherapy and in combination with cetuximab, a widely used EGFR inhibitor that has shown synergy in preclinical studies with QTX3034,” said Leonardo Faoro, MD, MBA, Chief Medical Officer of Quanta Therapeutics. “Patients with KRASG12D-mutant cancers face a poor prognosis and no targeted therapy options. QTX3034 is the first of our two G12D-focused clinical approaches with QTX3046 following in the first half of 2024. We are confident that advancing two chemically distinct oral small molecules with differentiated mechanisms of action will enable us to achieve our goal of delivering a best-in-class treatment for G12D-mutant patients.” “Although RAS is one of the most clinically validated targets in oncology, the field’s understanding continues to evolve concerning the mechanisms needed to optimally target and drug KRAS-driven cancer mutations beyond G12C, including G12D and G12V,” said Perry Nisen, MD, PhD, Chief Executive Officer of Quanta. “Quanta is uniquely positioned to lead further innovation in the field with our proprietary discovery platform and our RAS biology and medicinal chemistry expertise, enabling us to identify unique chemical scaffolds with functional activity that can then be optimized for best-in-class attributes.” Dr. Nisen added, “I am proud of the team’s dedication and focus that has delivered significant progress of our pipeline, particularly advancing our first program to the clinic. Over the next 18 months, we look forward to progressing multiple novel KRAS inhibitor programs and providing data readouts from the first-in-human clinical trials for our lead programs.” About QTX3034 and the Phase 1 Clinical TrialQTX3034 is a non-covalent, potent, orally bioavailable, and allosteric multi-KRAS inhibitor with G12D-preferring activity. The QTX3034 Phase 1 clinical trial will initially enroll patients with KRASG12D mutations in dose escalation cohorts as monotherapy and in combination with cetuximab. Dose expansion cohorts consist of patients with KRASG12D-mutant pancreatic, colorectal, lung, and endometrial cancers. Endpoints include safety and tolerability, determination of the maximum tolerated dose/ recommended Phase 2 dose, pharmacokinetic properties, antitumor activity, and molecular markers. The study will be conducted at clinical sites in the US. About RAS and the MAPK PathwayThe mitogen-activated protein kinase (MAPK) pathway is a central signaling cascade that regulates cellular growth, proliferation, differentiation, and survival. When one of the proteins in the pathway is mutationally activated, it can drive tumor development and growth. RAS is the most frequently mutated oncogene in cancer, with KRAS mutations occurring in nearly one-quarter of all human cancers. RAS mutations impair the ability of RAS to convert from its active GTP-bound “ON” form into its inactive GDP-bound “OFF” state, leading to the sustained activation of the MAPK signaling pathway and ultimately driving tumorigenesis. KRAS mutations, especially G12D, G12V, and G12C, are highly prevalent in pancreatic, colorectal, and lung cancers. First-generation KRAS inhibitors have demonstrated clinical benefit, but their impact is limited to a subset of patients with a single type of KRAS mutation (G12C). About Quanta TherapeuticsQuanta Therapeutics is a private biopharmaceutical company focused on the most prevalent and elusive target in oncology—RAS. Our vision is to develop novel small molecule cancer medicines by selectively targeting protein-protein interactions that are key to oncogenic RAS activity. Driving Quanta's success is our unique high-throughput platform that applies Second Harmonic Generation (SHG) optical technology to identify allosteric modulators of protein complexes. The Quanta team has extensive drug development expertise and substantial research experience in the RAS space. By applying innovative medicinal chemistry and its unique protein conformation detection technology, Quanta aims to advance differentiated, next-generation RAS programs that address the resistance paradigms of targeted therapy in oncology. 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, a G12D-selective KRAS inhibitor, expected to enter the clinic in mid-2024; QTX3544, a multi-KRAS inhibitor with G12V-preferring activity (G12V+ multi-KRAS) projected to complete IND enabling studies in 2024. Quanta is headquartered in South San Francisco, CA, and has a site in Radnor, PA. Find more information at https://www.quantatx.com/ Follow us on LinkedIn: Quanta Therapeutics

临床1期临床申请

2023-12-26

·Firstwordpharma

Amgen fails in bid for full FDA approval of KRAS inhibitor Lumakras

The FDA rebuffed Amgen’s attempt to gain full approval of Lumakras (sotorasib), with the agency asking the company to conduct a new confirmatory study for the KRAS inhibitor. The decision - detailed in a complete response letter - had been expected after a recent negative advisory panel vote on the application.Lumakras gained accelerated FDA approval in 2021 for patients with KRASG12c-mutated non-small-cell lung cancer (NSCLC) who had received at least one prior systemic therapy. The decision was based on objective response rate data from the CodeBreaK 100 study, with Amgen later submitting results of the Phase III CodeBreaK 200 to support the drug's conversion to traditional approval. While CodeBreaK 200 met its primary endpoint with a significant 34% progression-free survival (PFS) benefit for Lumakras versus docetaxel, an FDA advisory panel voted 10 to 2 that the data could not be reliably interpreted. Ahead of the vote, agency staff released briefing documents saying that survival data from the trial were "uncertain," and that the study may not be considered "adequate and well-controlled."Larger study sizeAmgen said Tuesday that the new confirmatory study must be completed no later than February 2028, although it did not reveal further details. However, speaking at the recent advisory panel meeting, committee chair Ravi Madan highlighted the small size of the CodeBreaK 200 trial, which enrolled 345 patients.The next key catalyst in the KRAS inhibitor space is likely to be PFS and interim overall survival data from the confirmatory KRYSTAL-12 study of Mirati Therapeutics’ Krazati (adagrasib) in the first half of 2024. The drug has accelerated approval in the US for the second-line treatment of adults with KRAS G12C-mutated locally advanced or metastatic NSCLC.Despite the promise around KRAS inhibitors, sales of Lumakras have failed to take off as expected, with revenue from the product falling quarter-over-quarter in Amgen’s most recent financial results. For a deeper look, read Vital Signs: Do KRAS blunders weigh down targeted therapy in lung cancer?

临床3期临床结果上市批准加速审批

100 项与 KRAS G12C inhibitors (Leidos Biomedical Research) 相关的药物交易

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