(Laurie Barclay, MD, Dec., 2003)

Lung cancer is the leading cause of cancer deaths worldwide, with an estimated 171,900 new cases of lung cancer and an estimated 157,200 deaths from lung cancer in the US in 2003. Although incidence appears to be decreasing among white and African-American men in the US, it continues to rise among both white and African-American women. Each year, lung cancer kills more men than does prostate cancer and more women than does breast cancer.

Non-small cell lung cancer (NSCLC), which includes squamous cell carcinoma, ademocarcinoma, and large cell carcinoma, is the most prevalent form of lung cancer. Small cell lung cancer (SCLC), or oat cell cancer, accounts for about 20% of all cases of lung cancer. SCLC metastasizes more rapidly than does NSCLC, with median survival less than one year, and overall five-year survival rate less than 5%.

Approximately 87% of lung cancer cases are related to smoking, with risk directly correlated to duration and frequency of smoking. After ten years of smoking abstinence, risk decreases to one-third to one-half that associated with continued smoking. Carcinogen exposure related to "secondhand smoke" is responsible for approximately 3,000 lung cancer deaths each year.

Radon is thought to be the second leading cause of lung cancer in the US, and it accounts for 15,000 and 22,000 lung cancer deaths annually, or 12% of all lung cancer deaths. Other causes include occupational exposure to asbestos, uranium, arsenic, petroleum products, and other carcinogens.

Carcinogen exposure induces cellular changes in the bronchial lining, which may slowly develop into a malignant tumor disrupting normal lung tissue and function. Because NSCLC is often asymptomatic initially, most NSCLC patients are in the advanced stages when diagnosed. Although combination chemotherapy regimens often produces clinical response or stabilization, there is typically little effect on overall survival.

With current therapy, metastatic NSCLC remains incurable. Response rates with some of the newer chemotherapeutics are approximately 25%, and median survival is less than six months from time to progression. Therefore, there is a great unmet need for new therapies for patients with advanced stage NSCLC, as well as for SCLC and other lung cancers.

CenterWatch has identified more than 70 agents in the pipeline, including antineoplastic agents targeting DNA replication and tumor cell growth, immune system stimulants, angiogenesis inhibitors, and novel agents derived from molecular biology and other new technologies. Most of these are still in earlier stages of development.

The only product CenterWatch identified for which phase III testing is completed is Affintak, LY900003 (ISIS-3521), an antisense inhibitor of protein kinase C-alpha (PKC-a) expression developed by Eli Lilly and ISIS Pharmaceuticals. As of March 2003, this leading drug candidate had failed its most recent human trial.

Aventis and Eli Lilly are now in phase III testing of Taxotere/Gemzar, a combination of docetaxel, a taxane which disrupts the cellular microtubular network and thereby inhibits cell division, and gemcitabine, a nucleoside analogue that interferes with DNA replication.

Taxotere is widely used in chemotherapy and is approved by the FDA to treat locally advanced or metastatic NSCLC that recurs after prior platinum-based therapy, as well as locally advanced or metastatic recurrent breast cancer. It is given every three weeks as an intravenous infusion lasting about one hour. At a dose of 75 mg/m2, the most common severe adverse events of Taxotere among advanced NSCLC patients were low blood cell count and fatigue, while less severe adverse effects included nausea and hair loss.

Gemzar is approved in more than 90 countries, either as NSCLC monotherapy and/or in combination with cisplatin. In a meta-analysis of 13 trials involving 4,556 patients with advanced NSCLC, overall survival and median progression-free survival were significantly better for Gemzar-platinum-based therapies than for other platinum-based regimens, according to a presentation at the 10th World Congress on Lung Cancer on Aug. 14, 2003. Survival benefit after one year was 38.9% vs. 35% (hazard ratio 0.90; P < .001), and median progression-free survival was 5.1 months versus 4.4 months.

In phase III trials by Eli Lilly, Alimta (pemetrexed disodium, LY231514) achieved a survival rate in NSCLC similar to that of Taxotere, but with significantly fewer adverse effects. This antifolate agent inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.

Survival, time to disease progression and response rate for Alimta are similar to those of Taxotere, but improved tolerability with Alimta led to a three-fold difference in drug-related hospitalizations, based on data presented at the recent American Society of Clinical Oncology Congress. In an international trial of patients with previously treated, recurrent NSCLC, median survival was 8.3 months with Alimta and 7.9 months with Taxotere. Severe neutropenia occurred in 5% in the Alimta arm and 40% in the Taxotere arm (P =< 0.001).

The lower toxicity profile translates into reduced costs related to fewer drug-related hospitalizations and unscheduled supportive care interventions, according to UK data from a phase III randomized study of 541 patients with second-line NSCLC presented on Sept. 24, 2003 at the 12th European Cancer Conference. Eli Lilly plans to complete its European and US submissions for Alimta in both malignant pleural mesothelioma and second-line NSCLC by late 2003.

Like Taxotere, epothilone (BMS-247550) targets microtubules and thereby blocks cell division. However, because this microtubule-stabilizing agent is not a taxane, it has potential activity against taxane-resistant tumors. In three phase II studies by Bristol-Myers Squibb presented on June 2, 2003 at the American Society of Clinical Oncology annual meeting, activity was encouraging against taxane-sensitive, refractory and insensitive NSCLC tumors.

In a randomized study, patients with advanced NSCLC who received prior platinum-based therapy had an acceptable toxicity profile with epothilone, 32 mg/m2. Objective responses occurred in 10 patients (13.1%), including four patients who had previously received taxanes.

An innovative technology to inhibit tumor growth is to block production of Raf-1 protein with LErafAON, a NeoPharm drug using NeoLipid liposomes to facilitate intracellular delivery of c-raf antisense oligonucleotide. In phase I/II clinical trials, LErafAON is being tested for use as monotherapy or as adjuvant therapy. Based on preclinical studies, LErafAON may improve sensitivity to radiation therapy and chemotherapy.

An alternate approach to cancer therapy is to stimulate the immune system to attack the tumor rather than to prevent DNA replication within the tumor. ImClone Systems is developing BEC2, a monoclonal anti-idiotypic antibody in phase III testing for NSCLC and in phase II testing for SCLC. When used with Bacillus Calmette Guerin (BCG) as an immune stimulant, the BEC2 antibody mimics the cell surface tumor antigen ganglioside GD3, thereby stimulating a stronger immune response to cells expressing natural GD3.

In pilot studies, BEC2 appeared to stimulate the immune system to identify and eliminate residual tumor cells, prevent recurrence of tumors, and prolong survival in patients with limited disease SCLC. International phase III clinical trials are underway for this indication in conjunction with Merck KGaA.

Cell Genesys is in phase II development of another immune system stimulant, the Gvax vaccine modified to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) and to induce a systemic immune response against the patient's specific lung cancer. After surgical removal of a patient's tumor, the cells are cultured, genetically modified to secrete GM-CSF, and irradiated to prevent division before vaccinating the patient.

In a phase I/II trial in 33 patients with advanced NSCLC, most of whom had failed prior chemotherapy and/or radiation therapy, three patients (9%) had complete responses after receiving Gvax as outpatients over a three-month period. Median duration of response was 17.8 months, and one of the complete responses was ongoing at 21.7 months. Median survival of all 33 treated patients was 11.6 months from the initiation of vaccine manufacturing. In seven patients (21%), disease did not progress, with a median response duration of 7.7 months.

In 10 patients with early stage lung cancer who received Gvax following surgery, seven were reported to be disease free for a median follow-up time of at least 16 months, and they did not receive further treatment.

Two randomized phase II trials of Gvax, with or without low- dose cyclophosphamide, are underway in approximately 100 patients with NSCLC, including patients with bronchial alveolar carcinoma who may have a more favorable prognosis. A phase III trial of Gvax in all types of NSCLC is planned to begin in late 2003 or early 2004.

Using molecular biology to target SCLC, ImmunoGen is developing HuN901-DM1 (BB-10901), a tumor-activated prodrug (TAP) created by conjugating the effector molecule, DM1, with the humanized monoclonal antibody, huN901, which binds to a surface antigen on SCLC cells. In preclinical studies, huN901-DM1 eradicated SCLC tumors under conditions in which cisplatin and etoposide interrupted tumor growth only temporarily. Phase II trials are underway, treating relapsed SCLC patients at the maximum tolerated dose as defined in phase I trials testing the safety, tolerability, and pharmacokinetics of increasing doses of huN901-DM1.

In phase I development by ImmunoGen, cantuzumab mertansine is also a TAP, combining the the DM1 effector molecule and the huC242 antibody targeting CanAg, which is found on multiple cancers including NSCLC.

A third drug incorporating monoclonal antibody is SGN- 15/Taxotere from Seattle Genetics. This antibody-drug conjugate is composed of the chimeric monoclonal antibody BR96 chemically linked to eight doxorubicin drug molecules per antibody. In combination with Taxotere, SGN-15 is being tested in an open label, randomized phase II study for Taxotere-naive patients with documented NSCLC.

Novacea and Aventis are pursuing a novel approach to NSCLC with DN-101, a drug containing high amounts of calcitriol, the biologically active form of vitamin D. In laboratory models, higher levels of calcitriol are associated with anti-cancer effects synergistic with those of other classes of chemotheraputic agents.

The clinical use of calcitriol has been limited by hypercalcemia at doses required for anti-tumor activity, until the discovery of high dose pulse administration (HDPA) allowing high oral doses of calcitriol to be given safely once weekly. With HDPA, more than 90 patients have tolerated doses of of DN-101 that were 60 to 100 times the currently approved dose for calcitriol, and they have achieved plasma levels within the range needed for anti-tumor activity.

Although developing new technologies have spawned a host of new agents targeting lung cancer, these are still in early stages of development. Time and continued research will tell whether they can improve the still dismal prognosis of NSCLC and SCLC.