National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 26, 2010 • Volume 7 / Number 2

Special Report

UPDATE

The ATTRACT-1 trial testing the drug ASA404, also called vadimezan, in patients with previously untreated, advanced non-small cell lung cancer was halted after a planned interim analysis showed that there was little or no prospect of demonstrating a survival benefit. Read the full article about the trial’s termination in the April 6, 2010 NCI Cancer Bulletin.

Trials Point to Potential Advances in Lung Cancer Treatment

These FLT-PET scans show a 43-year-old nonsmoker, whose lung tumor was positive for an ALK gene rearrangement. The image on the left shows the primary tumor in the left lung, as well as disease in regional lymph nodes (green areas). The image on the right, taken after 4 weeks of treatment with PF-02341066, reveals marked tumor shrinkage. These FLT-PET scans show a 43-year-old nonsmoker, whose lung tumor was positive for an ALK gene rearrangement. The image on the left shows the primary tumor in the left lung, as well as disease in regional lymph nodes (green areas). The image on the right, taken after 4 weeks of treatment with PF-02341066, reveals marked tumor shrinkage. [Enlarge]

Results from two early phase clinical trials suggest that patients with advanced lung cancer may have new treatment options that improve their survival. The results were reported recently at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer in Coronado, CA.

The findings, said Dr. Paul Bunn of the University of Colorado and a leading expert on lung cancer treatment, are part of an encouraging trend. “Almost every year now we’re getting new drugs that improve survival in lung cancer patients,” he said during a press briefing. “But we have a long way to go.”

The larger of the trials, dubbed ATTRACT-1, was a phase II study with more than 100 patients who had advanced non-small cell lung cancer (NSCLC) and had not yet received treatment. Patients were randomly assigned to receive one of two doses of the investigational targeted therapy vadimezan, also called ASA404, along with standard chemotherapy or chemotherapy alone. Patients who received the combination therapy had improved overall survival compared with those who received only chemotherapy. Those patients whose tumors had a squamous histology, which are typically more difficult to treat than tumors with nonsquamous histology, had a median survival of 10.2 months if they were treated with the combination therapy compared with 5.5 months if they were treated with chemotherapy only.

Serious side effects in patients who received vadimezan and chemotherapy were not significantly different from those seen in patients who received chemotherapy only, reported the trial’s lead investigator, Dr. Mark McKeage of the University of Auckland in New Zealand.

Vadimezan works by attacking the tumor vasculature but in a different way than angiogenesis inhibitors. Drugs like bevacizumab (Avastin) work predominantly by halting the growth of new blood vessels to a tumor. Vadimezan, on the other hand, is referred to as a “vasculature disrupting agent” because it causes established blood vessels that feed tumors to collapse, prompting cells to die within the tumor.

The phase II findings “are quite promising” and justify the two ongoing phase III trials of vadimezan in patients with advanced NSCLC being conducted by the drug’s manufacturer, Novartis, said Dr. Neal Ready of the Duke University Comprehensive Cancer Center, who was not involved in the study. But, he added, there is no guarantee that the phase II results will be duplicated in the larger trials, particularly with regard to serious toxicities, which are a common challenge when treating patients with squamous cell lung cancer.

Often in smaller trials done at academic medical centers “you get younger and healthier patients than those who find their way into larger, phase III trials,” Dr. Ready said. “So sometimes you start to see toxicities that were not appreciated in phase II trials. Certainly we would like to have better treatment options, particularly in patients with squamous cell histology. But we’ll have to wait to see what the phase III trials show.”

The other trial, a phase I study that began nearly 3 years ago, involved the experimental agent PF-02341066, which targets two genes, ALK and cMET. The trial initially included patients with a wide range of tumors to determine the highest tolerable dose. However, based on laboratory studies suggesting that certain molecular markers were associated with greater sensitivity to the drug, the investigators added an “expansion cohort” of patients whose lung tumors had specific molecular characteristics, including the fusion, or rearrangement, of ALK with other genes. In 2007, one study described the rearrangement of ALK with the gene EML4 in a small percentage of NSCLC tumors, and further investigation showed that the genetic abnormality itself could fuel tumor growth.

At the AACR-IASLC conference, Dr. Ross Camidge of the University of Colorado reported data on 31 patients whose tumors had the EML4-ALK rearrangement and were treated with PF-02341066. There was a 65 percent response rate (tumor shrinkage), including complete tumor eradication in some patients. Nearly two-thirds of patients in the trial had already received at least two different treatment regimens.

In some NSCLC tumors, Dr. Camidge explained, fusion of ALK with another gene—most often EML4, but other fusions have been identified—is required to ramp up its activity and drive tumor growth. Rearrangements involving ALK are seen in 3 to 6 percent of patients with NSCLC, particularly in nonsmokers or light smokers, and in those with the adenocarcinoma type of lung cancer.

The trial is “a nice story,” said Dr. Camidge, “of flexible and rapidly responsive clinical investigators in close partnership with the pharmaceutical industry.” Because it was a smaller trial, the researchers could “react quickly to the emerging data” about the gene rearrangement, he said.

The adaptations made during the trial (which is ongoing and also includes an expansion cohort, planned from the trial’s initiation, of patients whose tumors overexpress the cMET gene) are representative of an important shift in the conduct of clinical trials, said Dr. Ravi Salgia, a trial co-investigator from the University of Chicago.

“This sets up a new paradigm, where early on we have a molecular signature of a tumor that defines the best population for a drug, and we have rapid translation into the clinic,” Dr. Salgia said. “It’s an imatinib type of story, where we are making advances in the lab and quickly translating them into the clinic and vice versa.”

The drug’s manufacturer, Pfizer, has already launched a phase III trial that will include only patients with NSCLC whose tumors have the EML4-ALK rearrangement.

Pointing to the new data on the ALK rearrangements and to previous findings showing that EGFR gene mutations predict response to erlotinib (Tarceva) in NSCLC patients, Dr. David Carbone of the Vanderbilt-Ingram Cancer Center said that testing for these mutations should now become “part of standard therapy” for lung cancer patients.

“It’s clear that most patients with adenocarcinoma of the lung should now have genetic testing of their tumors performed on a routine basis,” he said at the press briefing. “None of these patients can be identified by clinical parameters. It’s the mutations that identify these patients, and more and more of these drugs are going to become available.”

Abbott is collaborating with Pfizer to develop a “companion diagnostic” test that would be used to screen patients for gene rearrangements that make them more likely to benefit from treatment with PF-02341066.

Carmen Phillips