Genentech/OSI should study sequential dosing of its epidermal growth factor receptor inhibitor Tarceva and Lilly's Gemzar , FDA and Oncologic Drugs Advisory Committee members suggested in recommending supplemental approval of erlotinib for treatment of pancreatic cancer Sept. 13.

Genentech/OSI are seeking an indication for Tarceva for treatment of advanced pancreatic cancer in combination with Gemzar (gemcitabine). The sponsors have proposed a dosing schedule of 100 mg erlotinib once-daily and 1,000 mg/m² gemcitabine weekly.

During the meeting, FDA Office of Oncology Drug Products Director Richard Pazdur questioned whether "this is the best route to use this drug as far as schedule. Should this drug be perhaps given in sequential use?" he suggested.

In voting against approval, committee member Bruce Cheson (Georgetown University Hospital) said that he had "no confidence" that the proposed schedule was "the optimal combination of these two drugs."

"We're doing a disservice putting out a drug combination that is getting us 10 days, when, if it were thoughtfully constructed better, it might give us several months of benefit," Cheson said.

Pazdur responded that the drug approval process is "dynamic" and that more appropriate dosing could be determined through continued study while the agent is marketed.

OSI VP-Medical Affairs & Translational Research Pablo Cagnoni said the company is in discussion with potential investigators about how to design sequential dosing studies.

"Patients with pancreatic cancer progress very quickly and building sequential regimens is not a simple way to address this issue," he noted. The average survival time of a patient diagnosed with pancreatic cancer is about six months.

OSI is studying sequential dosing of Tarceva in lung cancer, Cagnoni noted. FDA first approved erlotinib in 2004 for treatment of refractory non-small cell lung cancer (¹ [A#00660480002], p. 4).

Pazdur acknowledged that "patients with pancreatic carcinomas have short survivals and, hence, second-line therapies don't have the same meaningfulness because many of these will have very rapid progressions."

However, the question remains, "are we using this drug appropriately." Pazdur said.

"I am bothered, I guess, from the lung cancer data. I never got a satisfactory explanation of why those first-line trials were negative," Pazdur said.

"The issue of the use of the drug, Tarceva, with chemotherapy" is the "glaring elephant in the room," he said.

Pazdur noted that all four first-line trials of EGFR inhibiting small molecules in combination with chemotherapy - two each for Tarceva and AstraZeneca's Iressa - failed to show a survival advantage in lung cancer patients.

"This caused many in the field to say maybe many of these drugs shouldn't be used with chemotherapy," he said. "And now, granted it's a different disease, we do have a trial now combining this drug" with chemotherapy, "albeit a different chemotherapy gemcitabine."

Cheson suggested that scientists be brought in "to tell us how to" more appropriately use anti-EGFR agents, "rather than making the Iressa mistake again, which is what we're doing - except for here there is a little bit of difference; there it was verstunken."

FDA limited use AstraZeneca's lung cancer therapy Iressa to patients already benefiting from gefitinib following a failed confirmatory study (² Also see "Iressa Gets Narrowed Indication Instead Of Withdrawal: New Model For FDA?" - Pink Sheet, 27 June, 2005., p. 18).

The committee voted 10 to 3 that Tarceva should receive approval for treatment of advanced pancreatic cancer in combination with Gemzar.

[Editor's Note: To ³ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

"This is a positive study in a tough disease," panelist Maha Hussain (University of Michigan) noted.

OSI found on a 20% reduction in risk of death (hazard ratio of 0.80) with Tarceva (erlotinib) plus gemcitabine compared with gemcitabine and placebo. One-year survival was 23% for Tarceva plus gemcitabine, compared with 17% for gemcitabine plus placebo.

Instead of hazard ratios, FDA focused on median survival, which it found to be 6.37 months for the Tarceva combination compared with 5.95 for gemcitabine plus placebo. The agency emphasized that the difference was only 12 days.

An OSI analysis of median survival based on updated information submitted to the agency in June, found a greater difference in median survival of approximately five weeks, or 8.7 months for the Tarceva combination versus 7.6 months for gemcitabine plus placebo.

The committee voted unanimously that the data presented by OSI were "statistically persuasive" and 11 to two that the size of the survival difference was "clinically important." Tarceva's survival benefit in pancreatic cancer may be modest, but the benefit is still clinically meaningful, committee members said.

"If there is an improvement of one month...then I think that is valuable," committee member Alexandra Levine (University of Southern California Norris Cancer Center) said. "It is not negligible," she added.

Committee member Michael Perry (University of Missouri) noted that Tarceva is priced at approximately $100 a day, working out to - under "the most optimistic scenario" of a 21-day survival benefit - $550 per day of added survival.

"Can society afford this amount of money for this amount of gain or should we keep looking until we find something that's a better drug?" Perry asked.

Pazdur resisted the discussion concerning cost-effectiveness. "That is a separate issue from the regulatory decision that is being made here," he said.

In addition, the FDAer cautioned that it may not be an "appropriate conversation" to discuss whether "X amount of days is benefit and X minus two days is not benefit....The question here is do we truly have a true finding and given the relative prospectiveness of that finding in terms of the toxicity in a risk/benefit relationship."

Committee chair Silvana Martino, who voted against approval, disagreed, asserting that "the real issues here have to with 'is it 2.5 minutes, is it 12 days, is it five weeks and though we're pretending that those numbers are the same, they are not the same."

"The very fact that I have to use the word days still bothers the hell out of me," she said.

Unless the short survival advantage and "quality of life are the issues, then it's very unclear to me why I am sitting here. I could be having a cappuccino somewhere," Martino said.

The only statistically significant endpoint in quality of life was an increase in diarrhea among Tarceva patients. In the pivotal trial, 5.8% of patients receiving the erlotinib/gemcitabine regimen exhibited severe diarrhea compared to 2% of placebo patients.

"Generally speaking quality of life was not altered, with some exceptions - the exceptions beings there was more diarrhea and little bit more rash," Martino observed.

"If I could summarize that I would say, 'gee, maybe I get to live a little bit longer, but from a clinical perspective - other than counting whatever those days are...all I am going to do during those days is have rash and diarrhea," she said. "That bothers me a bit."

Some committee members agreed with Martino that the increased duration of survival might not outweigh the risk of added toxicities with Tarceva therapy, which included, in addition to diarrhea, possible interstitial lung disease and stroke.

Severe ILD-like events were reported in 2.3% of patients in the Tarceva regimen vs. 0.4% of patients in the gemcitabine alone arm. Stroke was also increased in the Tarceva arm (2.3% vs. 0%).

The survival benefit "doesn't come without a price," Cheson said. "You're coming with increased toxicity and no improvement in quality of life. If it was 10 days and the drug was innocuous - slam dunk."

The committee voted 12-1 that the sponsor should not be required to conduct a second pivotal trial in advance of approval. It would be unethical to randomize patients to placebo when an available treatment regimen has been shown to improve survival, committee members said.

The six-month user fee date for the Tarceva sNDA is Nov. 2; the application was submitted on April 29.

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