Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Antisoma’s recent late-stage study termination is another example of the obstacles to novel drug development for this disease.

The introduction of a novel drug for lung cancer was delayed yet again with another candidate touted to change the non-small-cell lung cancer (NSCLC) treatment landscape failing to show a survival benefit in Phase III. The most recent late-stage trial failure came on March 29 as Antisoma reported halting its ATTRACT-1 study testing ASA404 in previously untreated NSCLC patients. Upon the announcement, Antisoma shares fell almost 71%.

Antisoma and Novartis, the company’s development partner, believed that the addition of ASA404 to chemotherapy in Phase II trials had produced one of the largest increases in median survival ever reported in advanced lung cancer patients being studied. Based on their successful Phase II results, Novartis announced the start of the two ATTRACT trials. The ATTRACT-1 study enrolled previously untreated patients who were randomized to receive ASA404 plus chemotherapy or chemotherapy alone. The ATTRACT-2 Phase III trial with ASA404 as a second-line treatment remains ongoing.

While the mid-stage results were encouraging, industry analysts emphasized the risk in betting on Phase II data to predict what might happen in Phase III. Andy Smith, a biotechnology fund manager at AXA Framlington, said that the failure highlighted shortfalls in earlier testing. He also pointed out that Phase III studies represented a higher bar because they included more diverse and often sicker patients.

Antisoma originally licensed ASA404 from the University of Auckland in New Zealand. The small molecule drug disrupts tumor blood supply of cancerous tumors to prevent their growth. Novartis spent $75 million up front for an exclusive, worldwide license to the molecule. Antisoma earned another $25 million upon initiation of the Phase III lung cancer program. The company would have been eligible to receive $890 million in milestones as well as sales royalties and have a co-commercialization option in the U.S. had development continued.

Worldwide, lung cancer is the number one cause of death from cancer each year in both men and women. (Elnur –

ASA404’s Phase II Results

The Phase II trials with ASA404 in NSCLC patients had suggested that the addition of ASA404 to conventional treatment with carboplatin and paclitaxel could significantly enhance overall clinical effectiveness. Those in the treatment arm received a 1,200 mg/m2 dose of ASA404 in combination with chemotherapy and showed median survival of 14.0 months compared with 8.8 months in those receiving chemotherapy alone. A subsequent open-label extension to the randomized trial, which used a 1,800 mg/m2 dose of ASA404 in combination with carboplatin and paclitaxel, confirmed these findings. Median survival was 14.9 months, median time to tumor progression was 5.5 months, while the overall tumor response rate was 37.9%.

Those patients whose tumors had a squamous histology, which are typically more difficult to treat than nonsquamous tumors, had a median survival of 10.2 months when treated with the combination therapy compared with 5.5 months in the control group. Serious side effects in patients who received ASA404 and chemotherapy were not significantly different from those seen in patients who received chemotherapy only, according to lead investigator, Mark McKeage, Ph.D., of the University of Auckland.

Neal Ready, M.D., of the Duke University Comprehensive Cancer Center, who was not involved in the study, commented that the Phase II findings justified the two Phase III trials but there was no assurance that the Phase II results would be duplicated in the larger trials, particularly with regard to serious toxicities. Often in smaller trials done at academic medical centers, he noted, “you get younger and healthier patients than those who find their way into larger, Phase III trials. So sometimes you start to see toxicities that were not appreciated in Phase II trials.”

This Year’s Late-Stage Trial Failures

Antisoma’s Phase III trial discontinuation was more disappointing news for patients with NSCLC who have few novel therapeutic options. In March Pfizer halted its Phase III trial of Figitumumab in combination with other treatments for patients with previously treated, advanced NSCLC. The mAb targeted the insulin-like growth factor-1 receptor.

And in February, Novelos Therapeutics reported that the Phase III trial with its NSCLC drug did not meet its primary endpoint of overall survival. Small molecule NOV-002 was being assessed in combination with first-line chemotherapy in a randomized, controlled, open-label study in 903 patients with Stage 3b/4 NSCLC.

Betting on Arqule’s Phase II Results

Despite this spate of stunning Phase III failures, investors and Wall Street continue to reward companies that produce promising Phase II results in lung cancer. On March 31, Arqule’s stock skyrocketed on news that its lead drug, ARQ 197, in combination with Tarceva improved the median progression-free survival (PFS) of patients with advanced NSCLC by 66%. The company opened the day at $7.09, a 102.57% jump from the previous closing price of $3.50.

Arqule and Daiichi Sankyo have a license, co-development, and co-commercialization agreement for ARQ 197, a small molecule kinase inhibitor that targets the c-MET  tyrosine kinase receptor.

The difference in PFS between the two arms of Arqule’s Phase II study did not achieve statistical significance when a a log-rank test was applied. When adjusting for imbalances in the distribution of key prognostic factors, however, the difference in PFS was found to be statistically significant by applying a Cox regression analysis specified for secondary efficacy analyses.

Improvement in median PFS was more pronounced in the predefined subgroup of patients with nonsquamous histology; median PFS was 18.9 weeks in the treatment arm versus 9.7 weeks in the control arm, a 94% improvement. There were no clinically relevant differences in adverse event rates between the treatment and control arms. The majority of adverse events were mild in intensity and included rash, diarrhea, and fatigue.

“We believe the treatment benefit observed in this trial would represent a meaningful clinical improvement over standard therapy if replicated in Phase III trials,” stated Brian Schwartz, M.D., Arqule’s CMO. “We are especially encouraged by the potential benefit for the large subgroup of nonsquamous cell patients. We will thoroughly analyze our extensive database from this trial, including additional patient subgroup characteristics, to optimize ongoing and future trials of ARQ 197.”

That’s a lot of belief in Phase II study results that still must meet efficacy criteria in Phase III trials. But to analyst Andy Smith’s point that Phase III studies generally include more diverse and often sicker patients than Phase II studies, Arqule’s belief may be justified. Its Phase III trials will likely focus on patient subgroup identification to treat those mostly likely to respond to ARQ-197, thereby having a better shot at hitting an efficacy endpoint.

Meanwhile, despite the disappointment over its Phase III trial discontinuation, Antisoma will keep at it with a pipeline of diverse compounds. Antisoma CEO, Glyn Edwards, said that the focus of investment would be on Phase III leukemia treatment AS1413 and Phase II leukemia drug AS1411.

“It [drug development] is a risky business, and that’s why we try as best we can to build a portfolio of opportunities,” said Edwards. “While we will be a smaller company going forward, there is still value in our other programs.” And as long as pipeline-hungry pharma companies continue to troll for promising drug candidates, Antisoma and other firms will no doubt keep getting funding for compounds with strong Phase II results.

Patricia F. Dimond, Ph.D., is a principal at BioInsight Consulting. Email: [email protected].

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