IASLC: Continued Poor Prognosis Spurs Therapy Development for NSCLC

SEOUL, South Korea, Sept. 5 -- The lack of long-term survival benefit for current non-small-cell lung cancer drugs continues to drive development of new therapies and new formulations of existing drugs.

The new therapies include immunotherapeutic and targeted agents, investigators reported here at an industry-sponsored symposium held during the International Association for the Study of Lung Cancer's world conference.

Antigen-specific cancer immunotherapy (ASCI) offers one example of the emerging strategies, said Joan Schiller, M.D., of the University of Texas Southwestern Medical Center in Dallas. The therapy combines a recombinant form of a tumor antigen with an immunologic adjuvant to stimulate the patient's immune system to mount an attack against cancer cells.

The tumor-specific antigen MAGE-A3 has formed the basis for one such strategy. Expressed in as many as 50% of non-small-cell lung cancers, MAGE-A3 confers a poor prognosis, and its expression increases with worsening disease stage.

"Although it is expressed in other types of tumors, MAGE-A3 is not expressed in normal cells, making it very tumor specific," said Dr. Schiller.

Dr. Schiller reviewed data from a randomized, placebo-controlled phase II clinical trial of MAGE-A3 antigen-specific immunotherapeutic agent involving 182 patients with stages IB-II disease. All tumors were MAGE-A3+.

Following recovery from complete resection, patients were randomized 2:1 to MAGE-A3 antigen-specific therapy or placebo. Treatment started with five induction doses administered in each arm every three weeks, followed by eight maintenance doses, given three months apart.

The primary objective was the disease-free survival (time from surgery to relapse), and secondary objectives were disease-free survival, overall survival and safety.

Analysis performed after a 28-month median follow-up showed a non-significant trend for efficacy of the MAGE-A3 product: group comparisons of disease-free interval, disease-free survival, and overall survival gave, respectively, a hazard ratio (HR) of 0.74 (95% CI: 0.44-1.20, P=0.107), 0.73 (95% CI: 0.45-1.16) and 0.66 (95% CI: 0.36-1.20).

"Although these differences were not statistically significant, I think they were hypothesis generating," said Dr. Schiller.

The findings provided the impetus for a randomized phase III trial with an accrual target of 2,270 patients with stage IB, II or III disease. Patients will receive platinum chemotherapy or no chemotherapy, and then both arms will be randomized to MAGE-A3 antigen-specific therapy or placebo. Final results are not expected until 2012.

In a different tack, an oral formulation of topotecan has been developed to make administration more convenient and make the drug more amenable to use in combination therapy, said John R. Eckardt, M.D., of the Center for Cancer Care and Research in St. Louis.

Intravenous topotecan (Hycamtin) is approved for use in relapsed ovarian cancer and small-cell lung cancer. The oral formulation is being evaluated in both small-cell and non-small-cell disease.

In one of the best-known studies of oral topotecan, the agent was compared with best supportive care in patients with relapsed small-cell lung cancer. The oral formulation almost doubled median survival, making it the first chemotherapeutic agent to demonstrate a survival advantage over best supportive care for patients with relapsed small-cell disease, said Dr. Eckardt.

Earlier this year, Dr. Eckardt reported findings from a multinational phase III trial comparing oral and intravenous topotecan for small-cell lung cancer. The results demonstrated comparability with respect to response rate, stable disease, stable disease, time to progression, and median, six-month, and one-year survival. Oral topotecan was the better tolerated of the two regimens.

A study that compared cisplatin with oral topotecan or etoposide in extensive small-cell disease resulted in a similar median survival, one-year survival, and time to progression. Both regimens demonstrated good tolerability. A comparison of oral topotecan and intravenous docetaxel in patients with relapsed non-small-cell lung cancer also provided evidence of comparability with respect to survival, time to progression, and response rate. Tolerability was favorable and similar.

Although not yet approved in the U.S., "oral topotecan has shown activity in both small-cell and non-small cell lung cancer in large phase III clinical trials and has the advantages of convenience and tolerability," Dr. Eckardt concluded.

Interest in angiogenesis inhibitors in lung cancer continues to fuel development of novel therapies such as the investigational multikinase inhibitor pazopanib, said Alex A. Adjei, M.D., Ph.D., of Roswell Park Institute in Buffalo, N.Y. Pazopanib targets VEGF receptors 1, 2, and 3, PDGF receptors ? and ?, and the c-kit family of kinases.

"By targeting multiple receptors, pazopanib inhibits several pro-angiogenic signaling pathways simultaneously," said Dr. Adjei.

Interim results from various clinical trials have indicated that pazopanib has activity in renal cell carcinoma, ovarian cancer, and sarcoma. The angiogenesis inhibitor is undergoing phase 2 evaluation as presurgical therapy for patients with stage I/II non-small-cell lung cancer. By Aug. 1, the trial had accrued 16 of the 33-patient target enrollment.

The trial has multiple objectives that should provide insight into the activity and potential role of pazopanib in non-small-cell disease, said Dr. Adjei. Principal study objectives are tumor volume reduction, identification of predictive markers of clinical benefit, identification of early biomarkers of response, and to establish a basis for development of pazopanib monotherapy for early-stage lung cancer.

Dr. Adjei and Dr. Eckhardt had no disclosures. Dr. Schiller reported relationships with Genetech, AstraZeneca, Pfizer, and Merck.