Farnesyl Transferase Inhibitors

Novel agents that inhibit farnesyl transferase are potentially therapeutic in non-small cell lung cancer. Farnesyl transferase inhibitors (FTIs) have undergone studies as single agents and in combination with chemotherapy.

One such agent is R115777. In phase I studies, investigators observed responses to single-agent R115777 in breast and lung cancers. The dose limiting toxicity was myelosuppression, Other dose-dependent toxicities included diarrhea, peripheral neuropathy and elevated liver function tests.

Lonafarnib (SCH66336) another FTI, has been studied in a phase I study of 7 patients with advanced non-small cell lung cancer, investigators observed 1 partial response and 4 cases of stable disease lasting up to 63 weeks. Dose limiting toxicities include myelosuppression, peripheral neuropathy, fatigue and diarrhea.

An ongoing phase I/II trial at MD Anderson Cancer Center involving 22 advanced NSCLC patients looks at lonafarnib plus paclitaxel. In the phase I trial there were 8 partial responses; 5 of these responses were in patients with refractory disease. The phase II extension examined the combination of this lonafarnib and paclitaxel. Investigators enrolled patients with non-small cell lung cancer who had failed a taxane-containing regimen. In the first 21 evaluable patients there was 1 partial response and 11 stable disease.

Protein Kinase C Alpha

Many cancers overexpress the protein kinase C alpha enzyme which is central to the cascade of several growth factors. This enzyme is therefore an attractive target for novel treatment approaches. The agent ISIS 3521 has shown promising results in phase I and II trials.

In a phase I/II trial of patients with advanced non-small cell lung cancer ISIS 3521 was given in combination with carboplatin, paclitaxel. For 48 assessable patients, the objective response rate was 42%, with median survival of 19 months and a 75% 1-year survival rate. The results were superior to the combination of carboplatin and paclitaxel.

This led investigators to launch an ongoing randomized phase III trial of untreated patients with stage IV non-small cell lung cancer. The patients receive either carboplatin/ paclitaxel, or carboplatin/paclitaxel and ISIS 3521.

Synthetic Retinoids

In vitro, bexarotene (Targretin®) inhibits the growth of cancers including squamous carcinomas. Phase I trials show that dose limiting toxicities include desquamation, leukopenia, increased transaminases, hyperbilirubinemia and diarrhea.

A phase I/II trial included cisplatin/vinorelbine plus bexarotene in untreated advanced non-small cell lung cancer. For phase II, investigators reported an objective response rate of 25%, median survival of 14 months, and 28% 2-year survival. These results exceed what investigators report in medical literature for the combination of cisplatin/vinorelbine alone.

Bexarotene could be useful as maintenance therapy in advanced non-small cell lung cancer. A randomized trial evaluating this hypothesis was closed because patient accrual was poor. However, median time to progression for 56 patients was 128 days for high-dose bexarotene, compared with 82 days for low-dose bexarotene and 56 days for placebo. Patients who responded to induction therapy appeared to have a more robust response.