Use of Pemetrexed (Alimta) for NSCLC Gets ODAC Recommendation for Accelerated, Although Not Full, Approval

ROCKVILLE, MD—Pemetrexed (Alimta), a new drug for second-line treatment of non-small cell lung cancer (NSCLC), manufactured by Eli Lilly and Company, was presented to the Oncologic Drugs Advisory Committee (ODAC) at a meeting here late last month. In a pivotal Phase III trial comparing it with docetaxel, the only other agent approved for second-line treatment of locally advanced or metastatic NSCLC, pemetrexed provided only the slimmest of survival advantages. The Committee, though, voted unanimously to recommend it for accelerated approval, although not for full approval. Accelerated approval means that a drug can be marketed and prescribed as if it had full approval, but the manufacturer is required to continue Phase III trials—which should be ongoing while the agency is evaluating approval data. However, FDA rarely follows through with these requirements and has never refused to grant full approval for a drug that had received accelerated approval.Figure: Paul A. Bunn, Jr., MD: “The overall survival rate was similar, as were the response rate, progression-free survival, and time to disease progression. Pemetrexed, however, had a superior safety profile. It is a useful and safe treatment for patients with NSCLC.”Putative Advantages Lilly's Vice President for Clinical Research in Oncology, Paolo Paoletti, MD, said at the meeting that pemetrexed has a superior safety record and a better risk-benefit profile than docetaxel, and provides clinical benefit. “It is an effective and safe option,” he added The drug was approved in February of this year for use in combination with cisplatin for treatment of mesothelioma. Pemetrexed is single-agent treatment for patients with locally advanced or metastatic NSCLC after they have had prior chemotherapy. The drug is intended to be given at 500 mg/m2 in a 10-minute intravenous infusion on Day 1 of each 21-day cycle. Folic acid at 350–1,000 mg orally daily, vitamin B12 at 1,000 mg intramuscularly every three cycles, and dexamethasone at 4 mg twice a day on Days –1, 0, and +1 of each cycle should also be given to control pemetrexed's toxicity. Dr. Paoletti described for the committee the evidence of pemetrexed activity in first- and second-line treatment in seven Phase II trials conducted prior to the present Phase III pivotal trial. Three were as a single agent and four were in combination with platinum. “We found that we could suppress toxicity with folic acid and Vitamin B12 and thus decided to proceed with a Phase III study,” he explained. Lilly conducted a single-agent international study comparing pemetrexed with docetaxel because such a trial was not considered feasible in the United States alone. Moreover, combination chemotherapy is not appropriate in second-line treatment of NSCLC, and docetaxel is the only agent approved for this disease. This was the trial presented to ODAC in support of recommendation for approval. The Pivotal Trial Survival was the primary endpoint in this non-inferiority trial. Dr. Paoletti said that because there is limited historical data on the effect of docetaxel, a pure equivalency study would require upwards of 4,000 patients and would thus be unrealistic. Frances A. Shepherd, MD, the Scott Taylor Chair in Lung Cancer Research at Princess Margaret Hospital in Toronto, described two previous randomized trials in which docetaxel was compared with vinorelbine, paclitaxel, or ifosfamide.Figure: Richard Pazdur, MD: “The active control in a clinical trial, in this case docetaxel, should have a pronounced and measurable effect, and we should have multiple trials so we could perform meta-analysis. In this case, there is neither. In addition, the primary objective—survival—was not achieved, and the significant crossover from pemetrexed to docetaxel obscures the differences between the two drugs.”“They showed that second-line chemotherapy could prolong survival in NSCLC and improve performance status and symptom control,” she said. “Plus, it did not have a negative effect on quality of life. These trials subsequently led to approval in 1999 of docetaxel 75 mg/m2 for this indication.” Paul A. Bunn, Jr., MD, the Grohne/Stapp Professor and Director of the University of Colorado Cancer Center, described the pivotal Phase III study of pemetrexed (500 mg/m2 every 3 weeks plus the vitamins and dexamethasone described above) vs docetaxel (75 mg/m2 every 3 weeks plus dexamethasone), labeled by the company as JMEI. The primary endpoint was overall survival, and major secondary endpoints were progression-free survival, time to disease progression, tumor response rate, toxicity, and lung cancer symptom scale. Three major factors predicted increased survival: performance status, time since last chemotherapy, and the stage of disease. The trial was done with 571 patients at 135 sites in 23 countries. Only 21% of the study population was in US institutions. All patients had Stages III or IV disease, had only one prior chemotherapy regimen, and had adequate organ function. Median survival was 7.9 months for those receiving docetaxel and 8.3 months for those given pemetrexed. In both groups, 29.7% of the patients survived for one year. Progression-free survival was the same for both groups: 2.9 months, as was time to disease progression: 3.4 and 3.5 months for pemetrexed and docetaxel, respectively. The response rates were 9.1% for pemetrexed and 8.8% for docetaxel. None of these endpoint results was statistically significant. The only major differences between the two drugs were in toxicity. Docetaxel patients had significantly more neutropenia, febrile neutropenia, neutropenic infection, diarrhea, and alopecia. There were significantly fewer hospitalizations due to adverse events and on-study deaths with pemetrexed, and less use of supportive care. Dr. Bunn summarized the trial: “The overall survival rate was similar, as were the response rate, progression-free survival, and time to disease progression. Pemetrexed, however, had a superior safety profile. It is a useful and safe treatment for patients with NSCLC.” He also said that advanced-stage NSCLC patients are living longer and better lives; therefore they are good candidates for second-line therapy. He urged the committee members to recommend full approval because, “making available a safer, effective treatment will improve the physician's ability to make treatment decisions for patients with this devastating disease.” FDA Is Not So Sure Martin H. Cohen, MD, Medical Officer in the FDA Division of Oncology Drug Products, summarized the pivotal trial. He mostly agreed for the most part with Lilly's data and presentation but said the number of crossover patients was a problem. Thirty-two percent of pemetrexed patients crossed over to the docetaxel arm after tumor progression. “In addition, more than 30% of pemetrexed patients received post-study chemotherapy, which confounds the survival results. Patients who did not receive post-study chemotherapy had shorter survival.” He added that the toxicity spectrum between the two drugs differed and was not as benign as the company claimed. Docetaxel produces more neutropenia and neutropenic complications, but pemetrexed results in significant thrombocytopenia, skin rash, fatigue, and nausea and vomiting. Folic acid and vitamin B12 are known to decrease pemetrexed toxicity, but the trial did not determine whether they would do the same for docetaxel. Richard Pazdur, MD, Director of the FDA Division of Oncology Drug Products, added his concerns: “The active control in a clinical trial, in this case docetaxel, should have a pronounced and measurable effect, and we should have multiple trials so we could perform meta-analysis. In this case, there is neither. In addition, the primary objective—survival—was not achieved, and the significant crossover from pemetrexed to docetaxel obscures the differences between the two drugs.” Yong-Cheng Wang, PhD, Statistical Reviewer for the FDA Division of Oncology Drug Products, concluded that the pivotal study failed to demonstrate superior efficacy or the non-inferiority of pemetrexed to docetaxel. It was obvious that FDA did not think much of the trial or the drug and that non-inferiority was not demonstrated. First, there is only one small historical study of 104 patients from which to estimate the survival effect of docetaxel, thus making it impossible to estimate docetaxel's efficacy in this disease, to evaluate interstudy variability, and to assess constancy. A meta-analysis of several historical studies is ordinarily required for non-inferiority. Second, in the pivotal study, comparison of survival is confounded by the crossover rate and the significant number of docetaxel patients who did not receive post-study chemotherapy. On the positive side, there is evidence of anti-tumor activity in pemetrexed, which could be interpreted as a surrogate reasonably likely to predict clinical benefit, and the drug has a definite safety advantage. FDA asked members of ODAC if they believe that pemetrexed has a more favorable toxicity profile than docetaxel. The Committee members answered unanimously in the affirmative. The FDA has never refused to grant full approval for a drug that had received accelerated para. The agency then asked if supporting efficacy data on tumor response and progression-free survival outweigh the uncertainly about loss of docetaxel survival effect by using post-study pemetrexed. Again, the members voted unanimously in the affirmative. However, when FDA asked if, given the potential confounding effect of crossover and the problem of estimating control effect, there is sufficient evidence to warrant regular approval, members of the committee were less certain: The vote was 8 no and 5 yes. They thus recommended that pemetrexed be given accelerated but not full approval. STAR Enrollment Ends Ahead of Schedule The Study of Tamoxifen and Raloxifene (STAR) reached its goal of enrolling 19,000 women in the trial in June—a month earlier than originally expected. Women still being evaluated for the study will be allowed to join the trial until October. A news release from the National Surgical Adjuvant Breast and Bowel Project (NSABP) said that the results are expected in about two years. More than 500 sites in the United States, Canada, and Puerto Rico are involved in the study. “It's a remarkable achievement,” said NSABP Chairman Norman Wolmark, MD. “Women at increased risk for developing breast cancer chose to be proactive about finding options to prevent the disease. We owe a debt of gratitude to these women who are leading the charge in preventing breast cancer.” “Data from these large-scale clinical trials in breast cancer prevention is critically important and will help women at increased risk for breast cancer make choices about their health,” stated Leslie Ford, MD, Associate Director for Clinical Research in the National Cancer Institute's Division of Cancer Prevention. “The women who have chosen to join this trial are advancing the medical frontier and should be congratulated.”

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