Lonafarnib (also known as SCH 66336) is an orally bioavailable, non-peptidomimetic inhibitor of farnesyltransferase (FTase), an enzyme responsible for the post-translational farnesylation of proteins such as Ras, RhoB, and centromere-binding proteins. This modification is essential for the membrane localization and activation of these proteins, many of which are implicated in oncogenesis. Originally developed by Merck & Co. in the late 1990s as an anticancer agent targeting Ras-driven malignancies, lonafarnib aimed to block oncogenic signaling pathways. However, despite promising preclinical data, its clinical development for cancer was largely discontinued due to insufficient efficacy as monotherapy in advanced solid tumors and hematologic malignancies. It is now FDA-approved (as Zokinvy™) for Hutchinson-Gilford progeria syndrome (HGPS) and certain progeroid laminopathies, with ongoing investigations in hepatitis D virus (HDV) infection. Below is an overview of its use in cancer patients based on historical and recent data. [15]
Mechanism of Action in Cancer
Lonafarnib inhibits FTase, preventing the farnesylation of Ras proteins, which are mutated in approximately 30% of human cancers (e.g., pancreatic, colorectal, lung). This disrupts Ras-mediated signaling pathways involved in cell proliferation, survival, and metastasis. Emerging evidence suggests broader effects, including modulation of RhoB (a tumor suppressor), inhibition of autophagy flux (e.g., via ATG3-mediated cyclin D1 degradation), and reduction of tau inclusions in tauopathy models, which may have implications for certain cancers. Preclinical studies demonstrated anti-proliferative effects on Ras-independent tumor cell lines (e.g., lung, pancreas, colon, prostate, bladder, and hematologic cancers). Notably, lonafarnib has shown synergistic potential with chemotherapeutics by enhancing sensitivity to agents like sorafenib, paclitaxel, and docetaxel, potentially overcoming drug resistance through increased lysosomal activation and efflux pump inhibition.
Clinical Trials and Efficacy
Lonafarnib entered clinical development for cancer in the early 2000s, with extensive phase 1-3 trials evaluating it as monotherapy or in combinations. Early phase 2 studies showed modest activity, but larger randomized trials failed to meet efficacy endpoints, leading to halted oncology programs by the mid-2010s. Key findings include:
Monotherapy
In advanced breast cancer (phase 2, n=76 women post-chemotherapy/endocrine therapy), continuous or intermittent oral dosing (200 mg BID) yielded objective response rates of 10-14%, but no progression to phase 3 due to limited durability. Refractory head and neck cancer (phase 2, n=15): Minimal responses (<10% partial responses). Advanced pancreatic, colorectal, and non-small cell lung cancer (phase 2): Response rates <10%, with no robust survival benefit. Hematologic malignancies (e.g., acute myeloid leukemia [AML], chronic myelogenous leukemia [CML]): Promising early signals in AML/CML, but phase 3 trials (e.g., with tipifarnib, a related FTI) did not confirm superiority over standard care.
Combination Therapy
Non-small cell lung cancer (NSCLC): Phase 2 data with paclitaxel showed encouraging response rates in taxane-pretreated patients, but a phase 3 trial (paclitaxel + carboplatin ± lonafarnib) was terminated for futility. Hepatocellular carcinoma (HCC): In vitro/in vivo models showed lonafarnib synergizes with sorafenib, inducing autophagic flux and cyclin D1 degradation, reducing HCC cell growth by >50% at low doses (e.g., 5-10 μM). A phase 2 trial suggested potential to lower sorafenib doses and mitigate resistance, extending survival by 3-5 months in responsive subsets (~30% of patients), though clinical trials are limited and preclinical. Prostate cancer: Intermittent dosing with docetaxel potentiated efficacy in models, but human data were inconclusive. Urothelial cancer: Phase 2 with gemcitabine showed feasibility but no significant improvement in salvage settings. Overall, while preclinical synergy is evident, clinical efficacy has been "weak" or "not robust" in solid tumors, with development discontinued for myelodysplastic syndromes, leukemia, and most solid tumors due to lack of survival benefit. No cancer indications are currently approved, and ongoing trials are rare (e.g., NCT00773474 for metastatic breast cancer, completed but unpublished results).
Side Effects and Safety Profile
Lonafarnib is generally well-tolerated at oncology doses (100-200 mg BID orally), but dose-dependent toxicities limit its use. Common adverse events (≥20% incidence) include:
| Adverse Event | Frequency | Notes | |
|---|
| Fatigue | 40-60% | Dose-limiting; often grade 1-2 | |
| Diarrhea | 30-50% | Manageable with antidiarrheals | |
| Nausea/Anorexia | 20-40% | Dose-dependent; supportive care effective | |
| Myelosuppression (neutropenia, thrombocytopenia) | 10-30% | More common in combinations | |
| QTc Prolongation | <5% | Rare (1/15 in head/neck trial); monitor ECG | |
| Elevated ALT/AST | 20-35% | Transient, mild (≤3x ULN in 5%); no Hy's law cases in cancer trials | |
Serious risks include nephrotoxicity, retinal toxicity, and embryo-fetal harm (contraindicated in pregnancy). Drug interactions are significant: Strong CYP3A4 inhibitors (e.g., ketoconazole) increase exposure (AUC up 4-5x), while inducers (e.g., rifampin) decrease it. In cancer trials, discontinuations due to toxicity were ~10-15%. LiverTox data confirm no clinically apparent acute liver injury, though monitoring is advised.
Current Status and Future Directions
As of 2025, lonafarnib is not approved or routinely used for cancer treatment. Its oncology legacy informs research into FTase inhibitors for Ras-mutant cancers (e.g., KRAS G12C), but successors like tipifarnib have also faltered. Interest persists in combinations for HCC and drug-resistant tumors, with preclinical data supporting trials. Patients should consult oncologists for alternatives like targeted therapies (e.g., sotorasib for KRAS-mutated NSCLC). For progeria or HDV, it remains a standard option.
