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

Krazati: Data readout from P3 KRYSTAL-4 trial (NCT06875310) for 1L NSCLC in 2029 (Bristol-Myers Squibb) - Q1 2025 Results

P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Clinical outcomes and safety profile of adagrasib in KRAS G12C-mutated solid tumors: A single-arm meta-analysis. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical data • Retrospective data • Oncology • Solid Tumor • KRAS

First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) from the phase 2 portion of the KRYSTAL-7 study. (ASCO 2025) - P2/3 | "Clinical Trial Registration Number: NCT04613596 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Metastases • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Differential Response and Resistance to KRAS-Targeted Therapy. (PubMed, Mol Carcinog) - "The recent approval of the KRAS G12C inhibitors sotorasib and adagrasib has ushered in a new era of KRAS-targeted therapy. In this review, we summarize several major themes that have emerged from recent clinical and preclinical studies on the mechanisms of intrinsic and acquired resistance to KRAS-targeted therapy in colorectal, lung, and pancreatic cancers. We also discuss various combination strategies for targeting these mechanisms to overcome resistance to KRAS inhibitors."

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

Synthetic approaches and clinical application of KRAS inhibitors for cancer therapy. (PubMed, Eur J Med Chem) - "Inhibitors such as Sotorasib and Adagrasib have shown promise in preclinical and clinical studies by irreversibly binding to the mutant KRAS protein, locking it in an inactive state and disrupting downstream signaling pathways critical for tumor growth and survival. This review discusses the synthetic strategies employed to develop these KRAS inhibitor and also examines the clinical application of these inhibitors, highlighting the challenges and successes encountered during clinical trials. Ultimately, KRAS inhibitors represent a breakthrough in cancer therapy, offering a promising new treatment option for patients with KRAS-driven tumors."

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

OncoKBTM, MSK's precision oncology knowledge base: 2024 updates (AACR 2025) - "OncoKB promoted BRAF fusions to Level 1 following inclusion as patient eligibility criteria in the FDA drug label for tovorafenib (low-grade glioma). Additionally, OncoKB included KRAS G12C in colorectal cancer and IDH1 mutations in myelodysplastic syndromes as Level 1 following FDA approval of adagrasib + cetuximab and ivosidenib, respectively...Lastly, novel biomarkers including FBXW7 and PPP2R1A alterations (endometrial and ovarian cancer), SMARCA4 mutations (non-small cell lung cancer and esophageal adenocarcinoma) and MTAP deletions (all solid tumors) were included in OncoKB based on compelling preclinical and emerging clinical evidence in association with lunresertib + camonsertib, PRT3789, and AMG193 and MRTX1719, respectively...OncoKB also implemented major software updates to support data integration into the EPIC platform. Future OncoKB efforts are focused on whole genome/exome curation, inclusion of biomarkers for non-NGS-based precision oncology therapies,..."

Tumor mutational burden • Brain Cancer • CNS Tumor • Colorectal Cancer • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Glioma • Hematological Malignancies • Lung Cancer • Microsatellite Instability • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Intestinal Carcinoma • Solid Tumor • BRAF • FBXW7 • IDH1 • KRAS • MSI • MTAP • POLD1 • PPP2R1A • SMARCA4 • TMB

A Study of Adagrasib Plus Pembrolizumab Plus Chemotherapy vs. Placebo Plus Pembrolizumab Plus Chemotherapy in Participants With Previously Untreated Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutation (KRYSTAL-4) (clinicaltrials.gov) - P3 | N=630 | Recruiting | Sponsor: Mirati Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A cellular platform for systematic comparison of RAS inhibitors using PRISM multiplexed screening (AACR 2025) - "For example, all 10 KRAS G12C inhibitors or degraders tested showed significant selectivity for cell lines harboring the G12C mutation, with RMC-6291, adagrasib, divarasib, and sotorasib showing the greatest enrichment. Finally, we also explored orthogonal assay formats, including ultra-low adherent and extended-duration (10-day) screening, to investigate kinetic and environmental factors associated with inhibitor response. Collectively, our work provides a comprehensive profile of the cellular effects of current RAS-targeting therapeutics, and provides a foundation for the characterization of newly-emerging agents."

Oncology • KRAS

RAS inhibitors as payloads of ADCs to treat RAS-mutant tumors (AACR 2025) - "Recent breakthroughs in regulating the activity of RAS proteins have led to the discovery of several clinical therapeutic molecules, such as Sotorasib and Adagrasib. ADC containing RAS inhibitor is a new approach to treat RAS mutant tumors. It has shown good selectivity and potency in both in vitro and in vivo studies on a variety of tumors. It exhibits good PK and physicochemical properties."

Oncology • CLDN18 • KRAS

RV-1521: A broad-spectrum mRNA vaccine targeting KRAS mutations in cancer (AACR 2025) - "While KRAS G12C inhibitors, such as sotorasib and adagrasib, have made significant progress, their mutation-specificity excludes up to 85% of KRAS-mutant cancers, including those with G12D, G12V, and G13D mutations...Its ability to synergize with anti-PD-1 therapy and elicit a robust, multi-faceted antitumor immune response positions it as a promising strategy for treating KRAS-driven cancers. Ongoing studies will evaluate its safety and adaptability across diverse microenvironments and patient populations."

IO biomarker • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD4 • CD8 • EGR1 • GZMB • IFNG • KRAS

Identification of a potent KRAS (ON) inhibitor with selectivity for mutant KRAS over HRAS and NRAS (AACR 2025) - "Early successes in the discovery of mutation specific therapeutics for KRAS led to the development of marketed agents adagrasib and sotorasib, which selectively inhibit KRASG12C. This lead series exemplar has a differentiated mechanism of action compared to the tri complex multi RAS inhibitors currently in development, with selectivity over HRAS and NRAS. In vivo characterization to be presented includes pharmacokinetics, pharmacodynamics measuring inhibition of pERK, and efficacy in KRAS mutant tumor bearing mouse models."

Oncology • Pancreatic Cancer • HRAS • KRAS • NRAS

Development of a novel selective CDK4 inhibitor for HR+/HER2- breast cancer (AACR 2025) - "In MCF7-xenograft mouse model, TY-2072 showed significant suppression of tumor growth in a dose-dependent manner at 20 and 40 mg/kg BID, TY-2072 exhibited synergetic effects with Fulvestrant on anti-tumor growth inhibition with good tolerance, evidenced by the maintenance of body weight of the animals throughout the study. TY-2072 demonstrates high selectivity against CDK4, and more than 17-fold selectivity against CDK6 compared to palbociclib, proving that TY-2072 is a CDK4 inhibitor rather than a CDK4/6 dual inhibitor. Western blot assays showed a dose-dependent reduction in phosphorylated RB (Ser780) in breast cancer cell lines after 48 hours TY-2072 treatment. The anti-proliferation effects of CDK4 inhibitors were assessed with MCF7 (breast cancer, CDK4 sensitive), JEKO-1 (mantle cell lymphoma), and MOLM13 (acute myeloid leukemia, CDK6 sensitive) through a CTG cell viability assay after 5-day incubation."

Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Leukemia • Lung Cancer • Lymphoma • Mantle Cell Lymphoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2 • KRAS

Developing KRASG12C inhibitor-resistant tumor models for efficacy evaluation of next-generation anticancer therapies (AACR 2025) - "Cell viability was assessed by CellTiter-Glo (CTG) with AMG510 and MRTX849 (Adagrasib, KrazatiTM). CRISPR/Cas9-engineered KRAS secondary mutations cell lines displayed differentially resistant profile to KRASG12C inhibitors, and drug-induced resistant cell models developed in vitro displayed KRAS-independent mechanisms of resistance. These novel cell models offer a valuable preclinical platform to evaluate therapeutic strategies to overcome resistance to KRAS-targeted therapies."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FGFR1 • KRAS • MET

Integrative analysis of acquired drug resistance to KRAS(G12D) inhibitors (AACR 2025) - "Novel therapeutic approaches such as RAS(ON) inhibitors like RMC-6236 or specific KRAS(G12D) PROTAC degraders can significantly inhibit cell proliferation in vitro not only in MRTX1133 acquired resistance but also in adagrasib resistance models. Complex transcriptomic reorganization shows the upregulation of CD24 -a potential cancer stem cell related gene- and the epithelial to mesenchymal signature highlight the difficulty to target drug resistant cells. These findings emphasize the necessity to design combinatorial treatments to prevent and delay the acquisition of drug resistance in KRAS-driven cancers."

Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AVEN • CD24 • HRAS • KRAS • NRAS

Overcoming sotorasib acquired resistance in KRASG12C mutant NSCLC by TUSC2 gene therapy (AACR 2025) - "The resistant cell lines also showed resistance to adagrasib, another KRASG12C inhibitor...The H23AR tumors, which exhibited no significant sensitivity to sotorasib, showed robust antitumor effects of quaratusugene ozeplasmid, a lipoplex gene therapy containing the TUSC2 gene in both H23AR and TC314AR PDXs...This antitumor effect was correlated with significant infiltration of human CD8 T, NK, DC, and M1 MQ, and downregulation of MDSCs and exhausted T cells. TUSC2 therapy, alone or in combination with sotorasib, induced apoptosis, inhibited colony formation, and showed significant antitumor efficacy in KRASG12C AR tumors"

Gene therapy • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ANXA5 • CD34 • CD8 • KRAS • TUSC2

Combining RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitors overcomes sotorasib resistance driven byKRASG12C amplification or NRASG13R mutation (AACR 2025) - "Amplification of the KRASG12C mutant allele and acquisition of NRAS mutations have been reported as resistance mechanisms in tumors progressing on sotorasib and adagrasib...We generated five sotorasib-resistant cell lines from relapsed tumors of sotorasib-treated H358 xenografts (MR1-MR5) and two vehicle-treated tumors (MV1 and MV2). We created an additional isogenic cell line model, H358-MX1, by treating H358 cells with sotorasib and a SHP2 inhibitor, RMC-4550...In H358-MX1 mouse xenografts, RMC-7977 + RMC-4998 significantly inhibited tumor growth compared to single-agent treatments or other combination regimens. These preclinical data suggest that combination of RAS(ON) mutant-selective and RAS(ON) multi-selective inhibitors overcome resistance to KRASG12C (OFF) inhibitors driven by KRASG12C amplification and secondary NRASG13R mutation in KRASG12C mutated lung cancer models."

Lung Cancer • Oncology • Solid Tumor • KRAS • MX1 • NRAS

An integrated end-to-end platform facilitating the evaluation of next generation KRAS inhibitors (AACR 2025) - "In addition, to allow researchers to have a better understanding of the biological basis of drug resistance, we have established and validated a panel of lung and pancreatic cell models that are resistant to AMG510 and MRTX849 through CRISPR-Cas9 editing and drug-induced approaches. Our continuously evolving assay platform facilitates the discovery and development of new generation KRAS inhibitors and combinational strategies."

Oncology • Solid Tumor • CDKN2A • KEAP1 • KRAS • SMARCA4

A patient-derived organoid screening platform as a powerful tool to study efficacy of KRAS inhibitors (AACR 2025) - "Recently, advances have been made in this area, with the development and approval for clinical use of the KRASG12C inhibitors (Sotorasib and Adagrasib). In conclusion, our PDO platform effectively captures the efficacy and specificity of KRAS inhibitors in models with different KRAS mutations. The HUB PDO platform is valuable for studying combinatorial treatments to overcome KRAS inhibitor resistance, highlighting the potential of PDOs in developing novel KRAS inhibitors."

Clinical • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • KRAS

Adagrasib (ADA) as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring KRASG12Cand STK11 mutations: KRYSTAL-1 phase 2 cohort (AACR 2025) - "Abstract is embargoed at this time."

Clinical • Metastases • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • STK11

Suppression of TNFα and IFNγ signaling are key molecular events in KRASG12C mutant cancer cells to confer therapeutic resistance to Sotorasib and promote immune evasion (AACR 2025) - "The groundbreaking development and FDA approval of the mutant and cancer selective KRASG12Cis Sotorasib and Adagrasib to treat NSCLC and CRC patients have revolutionized the field of cancer biology. In vitro, single-cell imaging flow cytometry revealed that Sotorasib-tolerant cancer cells displayed remarkable reduction in nuclear translocation of NFkB and STAT1 as compared to parental cells, highlighting the importance of TNFα and IFNγ signaling to maintain optimum immune modulatory response of KRASG12C mutant cancer cells to KRAS inhibition. Collectively, our findings uncovered cancer cell-intrinsic and extrinsic molecular mechanisms underlying clinical resistance to Sotorasib and provide a comprehensive profiling of tumor/immune microenvironment ecosystem in refractory tumors to lay the groundwork for developing promising treatment platforms to overcome this inevitable resistance and achieve optimum clinical outcome."

IO biomarker • Colon Cancer • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IFNG • KRAS • STAT1 • TNFA

A 1st in class pan-RAS inhibitor with robust antitumor activity in PDAC models and advantages over other RAS inhibitors to escape resistance (AACR 2025) - "Growth assays involving direct comparison of ADT-007 with mutant-specific KRASG12C inhibitors (sotorasib), pan-KRAS inhibitors (BI-2865), or other pan-RAS inhibitors (RMC-6236) revealed more complete cancer cell killing by ADT-007. Finally, cancer cell lines resistant to KRASG12C and KRASG12D inhibitors retained complete sensitivity to ADT-007 but showed resistance to MRTX849 and MRTX1133, respectively. These results show the unique advantages of ADT-1004 over mutant-specific KRAS, pan-KRAS, and other pan-RAS inhibitors to escape resistance that limits the efficacy of RAS inhibitors FDA-approved or in clinical trials."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRAF • EGF • KRAS

Discovery and characterization of BAY 3498264: a small molecule inhibitor targeting the RAS-SOS1 interaction (AACR 2025) - P1 | "Recent regulatory approvals of KRAS G12C selective inhibitors (KRAS G12Cis) including sotorasib and adagrasib have offered clinical advances to patients with cancer harboring the KRAS G12C mutation. Our findings support the clinical exploration of BAY 3498264 in combination with KRAS G12Cis, and other therapies targeting the MAPK pathway, potentially offering a more durable blockage of the pathway and greater benefit for patients. BAY 3498264 is now in the early stages of a novel phase I study (NCT06659341)."

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

AN9025, an orally bioavailable pan-RAS(ON) inhibitor with potent, broad-spectrum anti-tumor activity (AACR 2025) - "Additionally, AN9025 demonstrated cytotoxic activity in cell models resistant to KRAS(OFF) G12C inhibitors sotorasib and adagrasib, while showing no cytotoxicity in BRAF-mutant, RAS-independent cell lines. In summary, AN9025 is a highly potent pan-RAS(ON) inhibitor that forms a tri-complex with CypA and RAS, effectively blocking downstream signaling and demonstrating robust antitumor efficacy, including in models that are resistant to mutant-selective RAS(OFF) inhibitors. Preclinical studies support its advancement into clinical development as a promising targeted therapy for RAS-driven cancers."

Oncology • BRAF • DUSP6 • KRAS

PHI-501 as a potent pan-RAF/DDRs inhibitor suppresses lung cancer cell proliferation and overcomes KRAS G12C inhibitor resistance (AACR 2025) - "The growth inhibitory activity of PHI-501 in KRASG12V, KRASG12S, KRASQ61H and NRASQ61K lung cancer cells was superior to that of G12Ci (sotorasib and adagrasib) and BRAF inhibitors (encorafenib and avutometinib). The treatment of PHI-501 alone showed robust growth inhibition in lung cancer cells harboring KRAS wild-type or KRAS and NRAS mutation. Our results suggest that PHI-501 as the pan-RAF/DDRs dual inhibitor is beneficial for the treatment of lung cancer and even helps overcome the resistance of previous G12Ci treatments."

Lung Cancer • Oncology • Solid Tumor • DDR1 • EGFR • KRAS • NRAS

Ficerafusp alfa reverses acquired resistance to the KRAS-G12C inhibitor sotorasib in KRAS-G12C-mutated lung tumors (AACR 2025) - "Recent approvals of KRAS-G12C inhibitors (G12Ci) such as sotorasib (AMG510) and adagrasib have improved treatment responses and overall survival rates2...The combination of sotorasib with ficerafusp alfa resulted in a significant reduction in sotorasib-resistant NCI-H1373 tumors over sotorasib in combination with cetuximab.This study reinforces the hypothesis that TGF-β plays an important role in acquired resistance to G12Ci. Our findings suggest that combining G12Ci with ficerafusp alfa could overcome G12Ci drug-resistance in KRAS-G12C-mutated lung cancer."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • TGFB1