POTENTIAL NEW TREATMENT FOR NSCLC

Pazopanib Shows Encouraging Activity in Early-Stage Lung Cancer

Roxanne Nelson

Medscape Medical News 2008. © 2008 Medscape

September 15, 2008 (Stockholm, Sweden) — The investigational drug pazopanib (GlaxoSmithKline), a novel antiogenesis inhibitor, demonstrated single-agent activity in patients with early-stage non-small-cell lung cancer (NSCLC). Although the results are preliminary, they suggest that this agent is highly active in this setting, and might have a role in the treatment of lung cancer.

The results of this phase 2 study, which were presented here at the 33rd European Society for Medical Oncology (ESMO) Congress, showed that 30 of 35 patients experienced tumor shrinkage. In some cases, tumor size decreased by up to 85%.

"Lung cancer is difficult to treat, and new and novel agents have been slow in coming," commented Josι Baselga, MD, the current president of ESMO. "These results are encouraging."

Targeted therapies are primarily used in patients with advanced lung cancer who have already failed standard chemotherapeutic regimens, according to lead author Nasser Altorki, MD, professor of cardiothoracic surgery and director of the division of thoracic surgery at New York Presbyterian�Weill Cornell Medical Center, in New York.

"The concept that we hoped to prove is that we can use these drugs during an early stage of lung cancer, and response to these agents may be increased because there is less complexity to the genetic make-up of their cancer," said Dr. Altorki during a press conference.

Early-stage lung cancer is generally treated surgically, without any type of preoperative therapy. When preoperative treatment is used, it is generally chemotherapy, either alone or in combination with other agents, explained Dr. Altorki. "To my knowledge, this is the first time that this drug has been used in lung cancer."

Pazopanib is an investigational oral angiogenesis inhibitor that targets vascular endothelial growth-factor receptor, platelet-derived growth-factor receptor, and c-kit. The objective of this study was to use targeted therapy as a preoperative treatment, and to determine the clinical and biologic activity and the safety of pazopanib, given preoperatively, in early-stage NSCLC patients. The researchers also elected to give it as monotherapy, so that any observed response could be attributed only to this intervention.

"We thought that if pazopanib had an effect on the tumor, it may not be detectable by standard measurements," he said. "Therefore, we introduced the concept of measuring response by tumor volume."

The primary end point was tumor-volume change, which was assessed by high-resolution computed tomography performed before and after pazopanib treatment. Secondary end points included RECIST response and safety, and analysis of pre-and post-treatment plasma samples allowed the researchers to correlate cytokines/angiogenic factors with changes in tumor volume.

"Monitoring changes in plasma samples might help us predict which patients are most likely to respond to this therapy," Dr. Altorki said.

Of the 35 patients in the cohort, 60% had adenocarcinoma, 11% had squamous cell carcinoma, and 29% had another type of NSCLC. There were 29 patients with stage Ia disease, 20 with stage Ib disease, 13 with stage IIa disease, and 1 with stage IIb disease. Pazopanib 800 mg QD was administered for 2 to 6 weeks before surgery (and after biopsy), and was then followed by a 7-day washout period. The median duration of therapy was 16 days.

"Roughly 86% of patients had a reduction in tumor size, and it was as much as 85% of the tumor volume," said Dr. Altorki. "When you consider that the median duration of treatment was only 2 weeks, that amount of reduction in tumor volume is really very impressive."

The drug was generally well tolerated, with grade 3 toxicities reported in 5 patients during the study period. These included hypertension, rash, and neutropenia.

Dr. Altorki emphasized that aside from using pazopanib as preoperative monotherapy, the study was novel because innovative imaging techniques were used to measure exact tumor volume as a 3D object, and because plasma samples were collected before and after treatment.

Early-stage NSCLC can be cured with surgery, and Dr. Altorki pointed out that the patients entered the trial without any expectation of benefit, other than contributing to research. There are questions of ethics related to the delay of potentially curative surgery by a few weeks to research an experimental drug.

"You do your best to explain the underlying reasons for the study to the patient, but most of the time, their reasons for participating are altruistic," Dr. Altorki said.

Looking at these results from another angle, Dr. Baselga pointed out the benefit of shrinking the tumor before surgery: "This can really facilitate the work of the surgeons, if you can give a nontoxic therapy and then increase the ease of surgery and a cure," he said. "This study has profound implications in many areas."

On the basis of these data, more studies with pazopanib in multiple stages of NSCLC are being planned, with some aimed at using the drug in an adjuvant setting.