Triplet Combination Chemotherapy and Targeted Therapy Regimens

Triplet Combination Chemotherapy and Targeted Therapy Regimens

ABSTRACT: Current agents for the treatment of non-small-cell lung cancer include gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and irinotecan (CPT-11, Camptosar). Experimental agents include pemetrexed (LY231514, Alimta) and tirapazamine. Molecular and biological therapies include angiogenesis inhibitors, epidermal growth factor receptor inhibitors, HER2/neu inhibitors, and inhibitors of ras activation and function. Doublet chemotherapy is currently the standard treatment for advanced non-small-cell lung cancer. In the past 2 years, randomized trials have shown that many of the new two-drug combinations used to treat non-small-cell lung cancer have equivalent efficacy. These combinations produce 1-year survival rates of about 35% and 2-year survival rates of about 15%. Toxicity rates vary but are sufficiently low as to make the development of three-drug combinations feasible. Preliminary studies from several phase I and II trials suggest that triplet therapy can improve survival beyond that of double therapy regimens. [ONCOLOGY 15(Suppl 6):26-32, 2001]


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 (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 (Gemzar),
vinorelbine (Navelbine), and 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
(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 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/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 (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 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 (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 improved survival compared with
best supportive care[14] and compared with 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 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 (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 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 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 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

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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