NEW DRUGS FOR NSCLC

June 30, 2010 — Two new experimental agents hold promise in the treatment of lung cancer, according to data presented here during the American Society of Clinical Oncology 2010 Annual Meeting.

The results of a phase 2 trial show that the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor PF299804 (Pfizer) appears to be more effective than erlotinib (Tarceva) in improving progression-free survival in patients with nonsmall-cell lung cancer (NSCLC) who have failed chemotherapy.

A second phase 2 study found that when ARQ197 (ArQule), a selective non-ATP-competitive inhibitor of c-MET, was combined with erlotinib, progression-free survival was prolonged in patients with advanced NSCLC, compared with those who received erlotinib alone.

However, 2 other investigational agents failed to improve outcomes. In a phase 3 trial, the addition of figitumumab (Pfizer) to paclitaxel and carboplatin did not increase overall survival in patients with advanced nonadenocarcinoma NSCLC. In addition, the trial was halted early because of serious adverse effects and increased mortality associated with the experimental agent.

In a phase 2 trial, combining mapatumumab (Genome Sciences) with carboplatin and paclitaxel as first-line therapy in advanced NSCLC did not improve response rate or progression-free survival.

PF299804

In the first study, 188 patients with advanced NSCLC who had failed at least 1 chemotherapy regimen were randomized to receive either oral PF299804 45 mg or erlotinib150 mg once daily until disease progression or toxicity.

Progression-free survival was 12.4 weeks (range, 8.3 to 16.1) for patients receiving PF299804 and 8.3 weeks (range, 8.0 to 11.4) for patients receiving erlotinib (hazard ratio [HR], 0.681; P = .019). The benefit was also consistent across several subgroups, including EGFR wild-type.

"Overall survival data are being collected, but are not yet mature," lead author Michael Boyer, MBBS, PhD, clinical professor of medicine at the University of Sydney in Australia, told Medscape Oncology. "Further follow-up will be required before we have this information."

The objective response rate also favored PF299804 over erlotinib (17% vs 4.3%; 2-sided P = .009).

Neither group has reached the median duration of response. One patient who received PF299804 achieved a complete response of 48-plus weeks, as of April 15, 2010, explained Dr. Boyer.

The number of patients achieving clinical benefit (complete response, partial response, or stable disease for 24 or more weeks) was significantly higher for those who received PF299804 than for those who received erlotinib (27.7% vs 13.8%; P = .03).

The results of this study lend support to phase 3 trials of PF299804. "A phase 3 trial of PF299804 is currently active — the CAN-NCIC-BR26 study — and is being carried out in Canada and Australia," said Dr. Boyer. "It compares single-agent PF299804 with placebo in patients who have failed erlotinib."

"The design of other potential phase 3 trials is currently under discussion," he added.

The majority of treatment-related adverse events were grade 1 or 2, although 9 patients discontinued therapy because of them: 6 in the PF299804 group and 3 in the erlotinib group. Four treatment-related grade 5 adverse events were reported: 2 in the PF299804 group (1 pneumonia and 1 pneumonitis) and 2 in the erlotinib group (1 pneumonia and 1 pulmonary embolism).

"The adverse events were easily manageable and not problematic," said Dr. Boyer, "and 94% of patients were able to continue with planned treatment, with the discontinuation rate being only 6%."

ARQ197

In the second study, Joan H. Schiller, MD, professor of medicine at Southwestern Medical School in Dallas, Texas, and colleagues conducted a randomized trial comparing erlotinib plus ARQ197 with erlotinib plus placebo. Archival tissue was collected for all patients so that KRAS, EGFR, and c-MET could be analyzed. The cohort included 167 patients with advanced EGFR-inhibitor-naïve NSCLC.

"c-MET is a receptor tyrosine kinase that is implicated in a number of abnormal cellular behaviors," said Dr. Schiller during her presentation. "c-MET amplification is associated with poor prognosis in NSCLC and resistance to EGFR kinase inhibitors."

Progression-free survival, the study's primary end point, favored the combination therapy over single-agent erlotinib in the intent-to-treat population (median, 16.1 vs 9.7 weeks; HR, 0.81; 95% confidence interval [CI], 0.57 - 1.15; P = .23).

"This was statistically significant when adjusting for key prognostic factors in Cox regression analysis," said Dr. Schiller.

Adjustment for prognostic factors such as histology and genotype yielded a progression-free survival HR of 0.68 (95% CI, 0.47 - 0.98; P < .05).

Progression-free survival was improved in patients with nonsquamous histology, EGFR wild-type status, and KRAS mutations.

"Improvements in median overall survival paralleled those of progression-free survival and were pronounced in nonsquamous patients," said Dr. Schiller.

Overall survival was 36.2 weeks in the ARQ197 plus erlotinib group and 29.4 weeks in the erlotinib group. Among nonsquamous patients, there was a 9.2 week improvement in progression-free survival in the combination group (18.9 vs 9.7 weeks) and a 13.7 week improvement in overall survival (43.1 vs 29.4 weeks).

Thus far, a preliminary safety analysis has revealed no major differences between the 2 study groups; rash was 64% in the combination group and 52% in the single-agent group; diarrhea was 48% and 53%, respectively; fatigue was 33% and 37%; nausea was 26% and 26%; and anemia was 14% and 13%.

"Benefits in EGFR wild-type and KRAS-mutation-positive patients were intriguing and merit further investigation, and have been submitted for presentation at the upcoming European Society for Medical Oncology meeting," she concluded.

In a Highlights of the Day session, Charles Rudin MD, PhD, from Johns Hopkins University in Baltimore, Maryland, noted that "the results are exciting but clearly need confirmation."

The investigation showed a hint of benefit for overall survival, he said. "The results were interesting overall for a phase 2 trial, with a very intriguing exploratory subset analysis."

Figitumumab

The insulin-like growth-factor type I receptor (IGF-IR) plays an important role in normal cellular growth and development, and is implicated in the regulation of tumor growth. Figitumumab is a monoclonal antibody that targets the IGF-IR. In this study, a planned enrollment of 820 patients were to be randomized in a 1:1 manner to receive paclitaxel (200 mg/m2), carboplatin (area under the curve [AUC] 6), and figitumumab (20 mg/kg), or paclitaxel and carboplatin alone.

However, accrual was permanently suspended at 681 patients because of a lack of efficacy and the serious adverse effects and death associated with figitumumab.

"The study was stopped early by the Independent Data Monitoring Committee due to excessive deaths," said Dr. Rudin. "It was not predicted or seen in the phase 2 trial, and it is disappointing and concerning."

Dr. Rudin noted that "many of us in the lung cancer community were hopeful about figitumumab" because of the results of the earlier phase 2 trial. It had "striking data for a phase 2 trial in NSCLC, with an overall response rate of 64%," he said, but then the drug went on to fail in a phase 3 trial.

"But does this mean we should be give up and go home?" he asked. "Not yet. This target is too clearly implicated in disease to not be further explored."

The researchers, led by Jacek Jassem, MD, professor of medicine and at the Medical University of Gdansk in Poland, observed serious adverse effects in the experimental group, which included dehydration, hyperglycemia, and hemoptysis. In addition, there was an excess of treatment-related deaths in group receiving figitumumab (8 vs 0).

"There were also more cardiac events in the experimental group (15 vs 5)," explained Dr. Jassem.

The overall survival showed a trend toward the control group, which was close to being significant (10.3 vs 8.5 months; P = .051), said Dr. Jassem during his presentation.

However, survival HR estimates favored patients with low baseline insulin-like growth factor (IGF)-1 levels in the standard chemotherapy group, but favored those with high baseline IGF-1 levels in the experimental group.

The study closed permanently after a planned interim analysis at 225 events because of a survival HR that "showed there was no sense in continuing the study," he said. "Biomarker analysis continues to design possible future studies."

"There is probably some potential benefit of figitumumab, but it is highly compromised by its side effects," Dr. Jassem said. "The risk/benefit of figitumumab in addition to standard chemotherapy appears to be related to the levels of circulating free IGF-1."

He added that additional research is needed to verify the potential benefit in patients with high levels of free IGF-1.

Mapatumumab

In the fourth trial, Joachim von Pawel, MD, from the Asklepios Klinikum Gauting in Munich, Germany, and colleagues evaluated the efficacy and safety of mapatumumab, in combination with carboplatin and paclitaxel, as first-line therapy in patients with advanced NSCLC.

Mapatumumab is a fully human agonist monoclonal antibody that targets and activates the death receptor TRAIL-R1. In this study, 119 patients with stage IIIB or IV advanced primary NSCLC were randomized to 1 of 3 study groups: paclitaxel 200 mg/m2 + carboplatin AUC 6.0; the same dose of paclitaxel/carboplatin plus mapatumumab 10 mg/kg; or the same dose of paclitaxel/carboplatin plus mapatumumab 30 mg/kg.

The patients completed up to 6 cycles in the absence of evidence of disease progression or unacceptable toxicity, and participants in the groups receiving mapatumumab could receive additional cycles of the drug in the absence of disease progression.

The researchers found that adding mapatumumab to paclitaxel/carboplatin therapy did not improve either the response rate or progression-free survival.


"It's a pity that we have no benefit from adding mapatumumab to paclitaxel/carboplatin in unselected patients with advanced NSCLC," said Dr. von Pawel.

Overall, the combination was well tolerated. "The adverse-event profile of the combination was similar to chemotherapy alone, and there were some numerical differences across treatment groups," he said.

"The pharmacokinetic and biomarker analyses are ongoing, as are clinical trials in other indications," Dr. von Pawel added.

This trial was similarly disappointing, said Dr. Rudin. "Again, it had a great clinical suggestion of efficacy; unfortunately, there did not appear to be a benefit."

Dr. Boyer reports relationships with Human Genome Sciences, AstraZeneca, Lilly, Merck, Roche, and Bristol-Myers, Squibb. The ARQ197 study was funded by ArQule and Daichi Sankyo Co. Dr. Schiller reports relationships with Celegene, Genentech, Geron, Novartis, Pfizer, Synta, ArQule, AstraZeneca, Bayer, Biodesix, Daiichi Sankyo, GSK, Merck, Onyx, and Syndax. Dr. Jassem reports a relationship with Pfizer. Dr. von Pawel reports relationships with Genentech, Lilly, Merck Serono, Pfizer, Roche, and AstraZeneca.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstracts 7500, LBA7501, LBA7502. Presented June 5, 2010. Abstract LBA7523. Presented June 7, 2010.