Zarnestra (tipifarnib) / Kura Oncology - LARVOL DELTA

FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors (AACR 2024) - P1, P2 | "Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes...In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models...Other combination arms may also be considered. The study began accrual in October 2023."

Clinical • Combination therapy • First-in-human • IO biomarker • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS • KRAS

Tipifarnib (TIP) and alpelisib (ALP) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase I results from KURRENT-HN (ESMO 2025) - P1/2 | "8 pts not evaluable: inability to swallow (n=2); toxicity (n=2); death, clinical progression, withdrew consent, tumor hemorrhage (n=1 each) † Of 6 pts with CR/PR, 5 pts had 1 prior tx and 1 pt had 3 prior tx ‡ Off tx prior to confirmatory scan due to: disease progression (n=2), withdrawn consent and cardiac event (n=1 each) Conclusions TIP + ALP was well tolerated with a manageable toxicity profile – noteworthy considering the known challenges of PI3Kαi combos with other targeted tx. Durable antitumor activity was observed in heavily pretx molecularly selected R/M HNSCC pts, supporting that combos (eg, FTI + PI3Kαi) targeting synergistic pathways may improve modest single tx activity."

Metastases • P1 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CA

Integrated multi-omics analysis indicates MARCO and ZBTB20 as candidate biomarkers in rheumatoid arthritis and tuberculosis. (PubMed, Front Immunol) - "Computational drug-repurposing analysis identified Tipifarnib as a candidate compound, and molecular docking and molecular dynamics simulations predicted potentially stable interactions with MARCO and ZBTB20...The clinical findings provide preliminary support for MARCO as a marker associated with RA-TB comorbidity, whereas the translational relevance of ZBTB20 requires further validation. These findings provide a molecular framework for further investigation of RA-TB comorbidity and may inform the future development of tissue-specific biomarkers and targeted interventions."

Biomarker • Journal • Immunology • Infectious Disease • Inflammatory Arthritis • Pulmonary Disease • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Tuberculosis

Phase 2 Trial of the Farnesyltransferase Inhibitor Tipifarnib for Relapsed/Refractory Peripheral T Cell Lymphoma. (PubMed, Blood Adv) - P2 | "Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pre-treated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. ClinicalTrials.gov NCT02464228."

Journal • P2 data • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia • DNMT3A • IDH2 • RHOA

Plasmodium-induced disruption of brain endothelial barrier integrity in vitro and in mice is prevented by inhibitors of farnesyltransferase. (PubMed, Malar J) - "Inhibitors of farnesyltransferase protect human endothelial cell barrier integrity from disruption induced by P. falciparum in vitro and decrease mortality in mice with experimental cerebral malaria, indicating a role for farnesylation in the regulation of barrier integrity during cerebral malaria and identifying a potential drug target for the protection of the endothelium during severe malaria."

Journal • Preclinical • Infectious Disease • Malaria

Dissecting PCD-driven molecular landscapes in AML: a multi-omic framework for prognostication and therapeutic targeting. (PubMed, Clin Exp Med) - "As an exploratory analysis, subtype-specific therapeutic vulnerabilities were revealed: Subtype A displays predicted sensitivity to immune checkpoint inhibitors (anti-PD-1) and tipifarnib, whereas Subtype B responds better to cytarabine/doxorubicin. Crucially, experimental validation confirmed significant upregulation of key model genes (HIP1, SQLE, VNN1) in AML patient samples and cell lines (P < 0.05), reinforcing the model's biological relevance. These findings establish PCD dysregulation as a central axis of AML heterogeneity, providing a framework for precision risk stratification and hypothesis-generating immunophenotype-guided therapy."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DNMT3A • FLT3 • HAVCR2 • HIP1 • NPM1

Renaissance of farnesyltransferase inhibitors in cancer. (PubMed, J Transl Med) - "The "second chance" for FTIs is here but the successful clinical implementation of FTIs can only be achieved if the design of the new clinical trials do not repeat mistakes of the past: application of these drugs without predictive markers."

Journal • Review • Head and Neck Cancer • Infectious Disease • Oncology • Respiratory Syncytial Virus Infections • Solid Tumor • EGFR • HRAS • KRAS

Tipifarnib Suppresses Exosome Biogenesis/Secretion in Aggressive Prostate Cancer Cells: Working Toward an Adjuvant Strategy to Overcome Enzalutamide Resistance (AUA 2026) - "The findings indicate that blocking exosome biogenesis and release with tipifarnib may offer an effective strategy for interrupting the exosome-driven signaling network underlying ENZ resistance in CRPC. Although further validation of cell viability is warranted, tipifarnib's ability to inhibit exosome output reinforces its potential as a repurposed adjuvant to existing androgen receptor–targeted therapies and as a clinically feasible exosome biogenesis inhibitor."

Clinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Clinical trial in progress: BCC022 a phase II trial of tipifarnib and naxitamab for relapsed/refractory neuroblastoma (AACR 2026) - P2 | "A projected 90 evaluable subjects (70 in cohort 1 and 20 in cohort 2) will be enrolled at up to 30 Beat Childhood Cancer Research Consortium hospitals. As of January 2026, enrollment is ongoing at 9 hospitals, with approximately 3% of the planned population enrolled."

Clinical • P2 data • Hematological Malignancies • Neuroblastoma • Oncology • Solid Tumor • HRAS

A newly developed patient-derived culture panel identifies precision therapies and pan-effective agents for head and neck squamous cell carcinoma (AACR 2024) - "Subsequent high-content imaging cell death assay further demonstrates a dose-dependent tipifarnib-induced cell death in HRASp.G13R-mutated PDC, but not in SNU-899; 2) TP53-EP300 co-mutated HNSCC-PDCs are most sensitive to cisplatin with ~340 nM sensitivity (mean IC50) among all PDCs tested, which is 22 times more sensitive than that reported in Genomics of Drug Sensitivity in Cancer (GDSC) HNSCC cell lines; 3) EGFR-AS1 (c.2361G>A)-germline mutated PDCs, and MAPK1-mutated PDCs, are both hypersensitive to EGFR inhibitors (EGFRi: erlotinib and mobocertinib), which independently credentialed gene-drug sensitivity relationships reported in exceptional responders in HNSCC clinical trials. These include 3 FDA-approved agents, TAK-981, Selinexor (a novel XPO1 inhibitor), and trametinib, as well as the preclinical agent JQ1. In conclusion, our pilot HNSCC-PDC drug screen identifies new gene-drug sensitivity relationships for HNSCC PM development and new pan-effective agents..."

IO biomarker • Late-breaking abstract • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP8 • EP300 • HRAS • MAPK1 • PIK3CA • SHH

Wild-type RAS signaling is an essential therapeutic target in RAS-mutated cancers (AACR 2024) - "The mutant HRAS inhibitor tipifarnib blocked PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cancer cell lines; covalent KRASG12C inhibitors blocked MEK signaling and synergized with PI3K inhibitors in KRASG12C- mutated cell lines...Dual knock-out of WT RAS isoforms in KRAS- and HRAS-mutated cancer cell lines reduced PI3K signaling in KRAS-mutant cell lines and MAPK signaling in HRAS-mutant cell lines and reduced proliferation, confirming our findings in MEF cells. Overall, our data highlight the critical role of WT RAS isoforms in supporting mutant RAS signaling and should be considered when designing combination therapies in RAS-mutated cancers."

Oncology • HRAS • KRAS

Farnesyltransferase inhibitors show synergistic anticancer effects in combination with novel KRAS G12C inhibitors (AACR 2024) - "Clinically approved farnesyl-transferase inhibitors (tipifarnib and lonafarnib) were combined with, novel KRAS G12C inhibitors (sotorasib and adagrasib) using human lung-, pancreatic and colorectal- adenocarcinoma cells in vitro and in vivo. Our findings suggest the potential clinical applicability of the combination of KRAS-G12C inhibitors and farnesyl-transferase inhibitors. Furthermore, our preliminary data suggest that the synergistic effect of FTIs on KRAS-G12C inhibitors can be projected to G12D inhibitors as well."

Combination therapy • IO biomarker • Late-breaking abstract • Bladder Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • RHEB

Model-Based Patient Selection and Dosing Strategies for HRAS and PIK3CA Dysregulated HNSCC: A QSP Model for Alpelisib and Tipifarnib Combination. (PubMed, Clin Pharmacol Ther) - P1/2 | "Global sensitivity analysis identified compensatory feedback, tumor proliferation rate, and PI3K-mTOR crosstalk as key determinants of tumor response. This novel QSP application exemplifies an innovative bottom-up modeling approach to support patient selection and dosing strategies for future clinical studies."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS • PIK3CA • RHEB

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=1376 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: May 2026 ➔ Jan 2027

Biomarker • Trial completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • High Grade Glioma • Langerhans Cell Histiocytosis • Lymphoma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

Combined Inhibition of HRAS and MEK Induces Tumor Regression and Restores Myogenic Differentiation in HRAS-Mutant Rhabdomyosarcoma. (PubMed, Cancer Res) - "Farnesyltransferase (FTase) inhibitors (FTIs), such as tipifarnib, inhibit HRAS membrane localization and blunt RAS effector signaling, leading to an antitumor effect in HRAS-mutant FN-RMS preclinical models...Co-targeting FTase and MEK restrained tumor progression and induced terminal myogenic differentiation. These findings highlight an effective combinatorial strategy and support its preclinical translation for patients with HRAS-mutant RMS."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FOXO1 • HRAS • KRAS • NRAS • PAX3

Bioinformatics analyses reveal the autophagy-related feature biomarkers in dilated cardiomyopathy with heart failure. (PubMed, Front Cardiovasc Med) - "A doxorubicin (DOX)-induced cardiomyocyte injury model was established to evaluate hub gene expression in vitro and in vivo studies. This study provides novel evidence that CTSD and SOD2 potently contribute to autophagy regulation in DCM with HF. These findings highlight their diagnostic potential for DCM with HF and lay a foundation for exploring targeted small-molecule therapies (e.g., QL-XII-47, tipifarnib-P2) to improve the disease's clinical management."

Biomarker • Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • CDKN1A • CTSD • DDIT3 • EP300 • SOD2

KURRENT-HN: Combination Trial of Tipifarnib and Alpelisib in Adult Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) (clinicaltrials.gov) - P1/2 | N=45 | Completed | Sponsor: Kura Oncology, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Jul 2025 | Trial primary completion date: Dec 2025 ➔ Jul 2025

Biomarker • Trial completion • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS • PIK3CA

NOXA modulates tipifarnib sensitivity in myeloid leukemia cells. (ASH 2025) - "This is consistent with clinical data in angioimmunoblastic T-cell lymphoma that suggested responses were enriched in IDH2 mutated cases. Ongoing studies will include sequencing samples from patients treated with tipifarnib in the cooperative group phase 3 study (NCI 2009-00535) to determine the incidence of IDH2 and other mutations in responders vs. non-responders."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • T Cell Non-Hodgkin Lymphoma • Targeted Protein Degradation • BCL2 • IDH2 • PMAIP1

Prevalence of HRAS mutations in metastatic head and neck squamous cell carcinoma: A preliminary study from India (ESMO Asia 2025) - "Tipifarnib, a FTase inhibitor, has been given FDA approval for high VAF HRAS positive HNSCC. HRAS mutations have been shown to have poor response to cetuximab in first-line recurrent metastatic setting... This preliminary study demonstrates a notably high prevalence (20%) of HRAS mutations among Indian patients with metastatic HNSCC highlighting the potential for integrating HRAS-targeted therapies into future clinical management protocols in India."

Metastases • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS

Using single-cell and transcriptome data to identify prognostic genes associated with SUMO-ylation and their molecular regulatory mechanisms in breast cancer. (PubMed, BMC Cancer) - "In this study, 8 SUMO-ylation related prognostic genes were identified in BRCA, namely GPC1, CAPZA1, NUDCD1, MTDH, COX7A1, PLK3, FAM43A and CEBPD, offering fresh perspectives on the prognosis of BRCA."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BRCA • CD8 • FAM43A • GPC1 • MTDH

Integrative computational approach to farnesyltransferase inhibition toward anti-liver cancer drug candidate from Syzygium cumini essential oils. (PubMed, Mol Biol Res Commun) - "However, MD simulations confirmed that both essential oil compounds exhibit binding stability comparable to that of Tipifarnib. Finally, α-humulene epoxide II and bornyl acetate from S. cumini exhibit favorable drug-like properties, high predicted safety margins, and a lack of organ-specific toxicity, underscoring their suitability for further drug development."

Journal • Liver Cancer • Oncology • Solid Tumor • FNTB • HIF1A • MMP9

Farnesyltransferase inhibitors decrease matrix-vesicle-mediated mineralization in SaOS-2 cells. (PubMed, Mol Biol Rep) - "Our findings demonstrate that FTIs Lonafarnib and Tipifarnib impair MVM, highlighting the essential role of farnesylation in biomineralization."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • COL1A1 • RUNX2

Comprehensive bioinformatic analysis of HTR7: A potential biomarker for diagnosis, survival, and immunotherapy in pan-cancer. (PubMed, PLoS One) - "Furthermore, our study showed that aberrant methylation of HTR7 was associated with the infiltration of many immune cells, including Th1, Th17, DC, macrophages, etc. In cancer pathways, HTR7 could inhibit the cell cycle, DNA damage, and hormone AR pathways and activate the EMT and RAS/MAPK pathways. GO and KEGG enrichment analyses revealed that HTR7 could participate in the G protein-coupled receptor signaling pathway, serotonin receptor signaling pathway, hormone signaling, cAMP signaling pathway, etc. Several drugs, including 5-fluorouracil, gemcitabine, sunitinib, tipifarnib, and trametinib, may be sensitive to high HTR7 expression in tumors."

Biomarker • IO biomarker • Journal • Pan tumor • Oncology • CTLA4 • HAVCR2 • HTR7 • PD-1 • PD-L1 • PD-L2 • TIGIT

A phase I study of the next-generation farnesyltransferase inhibitor (FTI) KO-2806 as monotherapy in advanced solid tumors (ESMO 2025) - P1 | "The FTI tipifarnib demonstrated promising clinical activity among m HRAS tumors, supporting the potential utility of KO-2806 in these settings. Encouraging antitumor activity was observed in advanced m HRAS solid tumors with a broad therapeutic window. These data support further exploration of its combinatorial potential."

Metastases • Monotherapy • P1 data • Colorectal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thyroid Gland Carcinoma • HRAS • KRAS

Identification of Potential Biomarkers and Drugs for Papillary Thyroid Carcinoma Using Computational Analysis and Molecular Docking. (PubMed, Curr Med Chem) - "The hub gene CCND1 and its targeting drug candidate Tipifarnib may contribute to PTC treatment."

Biomarker • Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CCND1 • LYVE1 • SOX4 • TCF4 • YBX1