Introduction
Chemotherapy is the cornerstone of treatment for patients with advanced (stages IIIB and IV) non-small-cell lung cancer.[1] In previous trials and meta-analyses of randomized trials,[13] cisplatin(Drug information on cisplatin) (Platinol)based therapy has been shown to prolong survival, relieve symptoms, and improve quality of life in a cost-effective manner. During the 1990s, the introduction of new chemotherapeutic agents—including the taxanes, gemcitabine(Drug information on gemcitabine) (Gemzar), vinorelbine (Navelbine), and irinotecan(Drug information on irinotecan) (CPT11, Camptosar)—led to small incremental improvements in survival when compared to cisplatin alone or previous cisplatin regimens.[1,46]
Combining a new agent with cisplatin or carboplatin(Drug information on carboplatin) (Paraplatin) became the most common treatment strategy worldwide. In the past 2 years, randomized trials reported that many of these new two-drug combinations have equivalent efficacy.[7,8] While toxicity rates among the regimens vary, they are sufficiently low, which makes the development of three-drug combinations feasible. The following explores the development of current and promising agents for the treatment of advanced non-small-cell lung cancer.
Current Agents
Gemcitabine
Gemcitabine is a new antimetabolite that is incorporated into DNA and inhibits DNA synthesis.[9] It was shown to produce response rates of about 20% in phase II trials in advanced non-small-cell lung cancer.[1,10] Randomized trials compared single-agent gemcitabine with the combination of etoposide(Drug information on etoposide)/cisplatin and found equal efficacy but reduced toxicity with single-agent gemcitabine. Given the excellent singleagent activity of gemcitabine, it was logical to combine it with other agents. The combination of gemcitabine and cisplatin was shown to produce response rates of about 40% in phase II trials[1] with median survival of approximately 1 year. These excellent results led to randomized trials with this doublet combination and to the incorporation of gemcitabine into triplet combinations.
Paclitaxel
Paclitaxel (Taxol) is a new taxane that works by inhibiting microtubule polymerization.[1,11] The initial trials used a 24-hour continuous infusion schedule, but subsequent studies showed that 3-hour infusions were more convenient, less toxic, and equally efficacious.[1] Single-agent paclitaxel(Drug information on paclitaxel) was shown to prolong survival when compared with best supportive care in the treatment of patients with advanced non-small-cell lung cancer.[12] It produced a 32% reduction in the hazard ratio of death in these patients. In large numbers of phase II trials, the overall response rate was 20% to 25%.[1] Many phase II studies showed that paclitaxel/cisplatin or paclitaxel/carboplatin produced high response rates.[1] In particular, the paclitaxel/carboplatin combination was extremely well tolerated and the toxicity rates, especially thrombocytopenia, were very low.
Docetaxel
Docetaxel (Taxotere) is the second commercially available taxane. It has similar single-agent activity compared with paclitaxel, demonstrating objective responses in 20% to 25% of patients.[1] A randomized trial also showed that single-agent docetaxel prolonged survival when compared with best supportive care.[13] The optimal single-agent dose is unclear, although response rates are about 20% at doses from 60 mg/m2 to 100 mg/m2. In the second-line setting, single-agent docetaxel(Drug information on docetaxel) improved survival compared with best supportive care[14] and compared with ifosfamide(Drug information on ifosfamide) (Ifex) or vinorelbine.[15] In these studies, the dose of 75 mg/m2 was preferred over 100 mg/m2 because it produced less toxicity with equal efficacy. Docetaxel has also been combined with cisplatin, carboplatin, and gemcitabine in two-drug combinations. Randomized trials show these combinations equivalent in efficacy to many other two-drug combinations. The toxicity rates may be slightly higher due to a dose of docetaxel that was too high.
Vinorelbine
Vinorelbine was the first of the new agents approved for use in the United States in the 1990s.[1] Its single-agent activity is also in the 20% range. A randomized trial showed that single-agent vinorelbine was superior to the combination of fluorouracil(Drug information on fluorouracil) (5FU)/leucovorin.[16] Vinorelbine combined with other agents, such as cisplatin, produced high response rates. These studies led to the development of triplets incorporating vinorelbine.
Irinotecan
Irinotecan is a topoisomerase I inhibitor with considerable activity in a number of solid tumors including both smallcell lung cancer and non-small-cell lung cancer.[1] It was originally developed in Japan, where most of the trials of this agent have been conducted. Although irinotecan has been combined with many other agents, most two-drug combinations have combined it with cisplatin. A small number of triplet studies use irinotecan.
Experimental Agents
Pemetrexed Disodium
The multitargeted antifolate pemetrexed(Drug information on pemetrexed) disodium (Alimta, LY231514) is a novel antimetabolite that inhibits at least three enzymes involved in DNA synthesis, including thymidylate synthase, dihydrofolate reductase, and glycinamide formyl transferase.[17] Pemetrexed has demonstrated a broad range of antitumor activity against human solid tumors in preclinical models. Phase I clinical trials showed activity in mesothelioma, head and neck cancer, and lung, breast, and colon cancers. The primary toxicities were hematologic suppression, skin toxicity, lethargy, nausea, and vomiting.
Phase II trials showed a response rate of 20% in previously untreated patients with advanced non-small-cell lung cancer[18,19] and 16% in previously treated patients.[20] Phase I combination studies showed that full doses of pemetrexed could be combined safely with cisplatin and gemcitabine; phase II trials showed additive results with response rates of 40% after using pemetrexed/cisplatin.[21,22] The 1year survival rates in the two studies were 49% and 50%, respectively.
An interesting observation made during the early studies indicated that patients with folate or B12 deficiency documented by high homocysteine and/or methymalonic acid levels had far greater toxicity than patients with low levels.[23] This observation was followed by studies adding B12 and/or folate supplementation. The supplementation markedly increased the maximum tolerated dose of single-agent pemetrexed and reduced its toxicity when administered alone or in combination with other agents. The phase II studies of pemetrexed/cisplatin were completed before the observations regarding the effects of vitamin supplementation were known. The ongoing trial of pemetrexed/gemcitabine began without vitamin supplementation.[24] Subsequently, folate and B12 supplementation were added halfway through the 60 patient accrual.
The extremely low rates of severe toxicity observed when pemetrexed supplemented with folate and B12 was given in combination with other agents makes it an appealing agent for new triplet combinations for the treatment of advanced non-small-cell lung cancer.
Tirapazamine
Tirapazamine is a novel chemotherapeutic agent that is especially toxic for hypoxic cells and that synergizes with cisplatin and radiotherapy.[25] Tirapazamine has activity alone against various solid tumors, but is especially active in combination with radiation and cisplatin. Phase II studies showed high response rates with the combination of tirapazamine and cisplatin.[26]
Molecularly/Biologically Targeted Therapies
In recent years, a number of molecular and biologic targets for potential cancer therapeutics have been identified. A number of these agents have been developed to take advantage of these targets, including humanized monoclonal antibodies, tyrosine kinase inhibitors, antisense compounds, ribozymes, gene therapies, and other small molecules with specific targets. The targets that have received the most attention in lung cancer include EGF and EGF-receptor (EGFR, HER1, erb-B1), HER2/neu (erb-B2), vascular endothelial growth factor (VEGF) and VEGF receptors, and matrix metalloproteinase (MMP) inhibitors. Other targets are being developed.
Angiogenesis Inhibitors
It is well established that tumors need new blood vessels to proliferate, and that the process of new blood vessel formation (angiogenesis) is different in tumors when compared with normal tissues that often require proteins such as VEGF for tumor vessel growth.[27] Thus, angiogenesis became a target for cancer therapeutics, which differed from the usual target in that surrounding tissues—rather than the tumor cell—became the target. Many different agents that inhibit angiogenesis have been developed and have entered clinical trials.[28] These include MMP inhibitors, natural products, receptor tyrosine kinase inhibitors directed at the VEGF receptor, monoclonal antibodies directed at VEGF and its receptors, ribozymes directed at VEGF receptors, and a variety of miscellaneous agents.
Many of these antiangiogenic agents have undergone phase I and II testing in humans with advanced lung cancer and several have been studied in phase III trials. Although a thorough review of all of these studies is beyond the scope of this article, the preliminary results of several trials will be discussed briefly. Genentech has evaluated a humanized monoclonal antibody directed at VEGF. Phase I trials showed the product had a serum half-life of 2 to 3 weeks and was largely nonimmunogenic.[29] Thus, phase II trials in lung cancer were developed using intravenous infusion given every 3 weeks.
Several MMP inhibitors were entered into phase III trials after safe doses were established in phase I studies. These were done without the completion of phase II trials. Studies were conducted in both small-cell lung cancer and non-small-cell lung cancer. Several MMP inhibitors were studied in trials in which small-cell-lung cancer patients who had entered into remission after chemotherapy or chemoradiotherapy were randomized to receive maintenance MMP inhibitor or placebo. Unfortunately, there is no evidence to date that survival was improved, and it is possible that survival was compromised by one of these agents, Bay 9366.
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