BURROUGHS WELLCOME NAVELBINE REQUIRES ADDITIONAL STUDY FOR BREAST CANCER INDICATION, FDA CMTE. FINDS; FDA's BURKE URGES MORE FIRST-LINE COMBO THERAPY

Burroughs Wellcome will need an additional randomized trial to gain an approval recommendation for Navelbine in the treatment of breast cancer, FDA's Ontologic Drugs Advisory Committee indicated at its June 7 meeting.

Committee Member James Ingle, MD, Mayo Medical School, said: "Based strictly on Phase II data, there are interesting findings. ...One would expect there to be interest in further studies to establish the value of this agent vis-a-vis combination chemotherapy, Adriamycin [doxorubicin] and Taxol [paclitaxel]." However, Ingle said: "There is insufficient justification to approve the drug for [the breast cancer] indications based on the discussions we have had."

FDA Ontologic Drug Products Division Director Gregory Burke, MD, suggested that if B-W conducted a randomized trial of the semi-synthetic vinca alkaloid Navelbine (vinorelbine) as a first- line agent, the company could come back to the committee and get approval of "both a first- and a third-" line indication.

Burroughs Wellcome has a randomized trial ongoing for use of Navelbine in the first-line and second-line treatment of breast cancer. The study is comparing Navelbine in combination with doxorubicin versus doxorubicin alone in 300400 patients being enrolled by the National Cancer Institute of Canada. The trial is scheduled for completion during 1996.

The committee voted against recommending approval for the two indications being sought by Burroughs Wellcome for Navelbine. The committee rejected by an 8-0 vote the use of Navelbine as a treatment for patients with metastatic breast cancer who have failed standard chemotherapy for metastatic disease and for patients with metastatic breast cancer who have relapsed within six months of an anthracycline-containing adjuvant regimen. That vote was 5-2 with one abstention.

The Navelbine NDA (20-445) for breast cancer, submitted on Feb. 28, contained data from two studies, a randomized trial (P70- 01) in 179 breast cancer patients who had relapsed within six months of anthracycline-based therapy and a Phase II open-label study (P70-08) in 107 patients who had failed prior cytotoxic chemotherapy. B-W's Navelbine NDA for non-small cell lung cancer was recommended for approval by the committee in late 1993 ("The Pink Sheet" Dec. 20, 1993 p. 10) and received a Treatment IND in April ("The Pink Sheet" May 9, In Brief).

The P70-01 randomized study compared Navelbine 30 mg/m to Alkeran (melphalan) 25 mg/m given weekly every four weeks. Company consultant Stephen Jones, MD, Baylor University, said Alkeran was chosen as a comparative agent because of its clinical activity and mild toxicity. In the trial's primary endpoint, time- to-disease progression, Navelbine delayed progression for four weeks longer (twelve versus eight) than did Alkeran. Survival at one year was 36% for Navelbine and 22% for Alkeran, with median survival time extended from 31 to 35 weeks.

Although the P70-01 trial was not powered to detect response rates, 16% of Navelbine-treated patients had complete or partial responses compared to 9% of patients receiving Alkeran, Jones reported. While the company collected quality-of-life data in the study, Jones said the results were confounded by differential patient drop-out and were therefore inconclusive, showing no difference in symptom improvement between Navelbine and Alkeran.

In the uncontrolled Phase II trial (P70-08), patients were either regarded as "first-line," if they had no prior cytotoxic chemotherapy or had been disease-free for 12 months following adjuvant chemotherapy, or "second-line," if they had progressed within 12 months of prior chemo. Navelbine therapy was associated with complete or partial response rates of 35% in first-line and 32% in second-line patients. The duration of a complete or partial response was 34 weeks in both groups. The median time-to-disease progression was about 18 weeks, and the median survival ranged from 62 to 67 weeks. After eight weeks of Navelbine therapy, 42% of patients reported improvements in symptoms.

B-W Consultant Mark O'Rourke, MD, Greenville Cancer Treatment Center-South Carolina, asserted that the pooled response rate of 29% for Navelbine in the treatment of patients with prior chemotherapy was comparable to that of doxorubicin. He also pointed out that the treatment benefits of Navelbine "are not overshadowed by distressing toxicities." The major toxicity in the Navelbine trials was granulocytopenia, which occurred at a rate of 90% in the trials but only resulted in hospitalization for 9% of patients. Navelbine was associated with a low incidence of alopecia, and nausea and vomiting, which are common chemotherapy toxicities.

FDA Oncologic Drugs Division Medical Reviewer Edward Henderson, MD, and division statistician Claire Gnecco, PhD, identified several problem areas of the Navelbine NDA, including a non-standard definition for time-to-disease progression, survival analyses that were not planned, and missing documentation on time to progression for a large number of patients in the P70-01 study. "We have concerns about how the analyses were done and how indeed the protocol was conducted and whether the degree of latitude that was granted each individual physician is justified and how it impinges on the true value of the compound," Henderson said.

Committee members had particular difficulty with B-W's definition of disease progression, which included any one of the following: a greater than 50% increase in tumor size, a significant increase in nonmeasurable evaluable disease, new lesions, or a worsening in cancer symptoms or Karnofsky scale performance score.

Committee member Kathleen Pritchard, MD, Toronto Bayview Regional Cancer Center, noting that progression is often defined as a 25% increase in tumor size, maintained that "these criteria certainly aren't standard...[and have] contributed a lot to our confusion about interpreting this data." Committee Chairman Charles Schiffer, MD, University of Maryland Cancer Center, agreed that the loose definitions of progression could lead to bias by an investigator, especially in an unblinded trial such as P70-08.

Meanwhile, many of the committee members acknowledged that Navelbine had demonstrated some activity in breast cancer. Pointing to Navelbine's 35% response rate, Ingle said "that is certainly...similar to some of the combination chemotherapies." Schiffer concurred: "There is no question this stuff makes tumors shrink." Pritchard agreed that the drug "shows activity, but it is hard to know how to interpret that outside of a randomized setting." Committee consultant Craig Henderson, MD, Mt. Zion Medical Center-San Francisco, asserted that Navelbine's prolongation of survival by four weeks was significant in the anthracycline-resistant patient population, which normally has a poor prognosis. "If you look at the hundreds of randomized trials, it is rare to see any individual trial to show a change in median survival of more than 6 months."

FDA asked the committee whether a time-to-disease progression definition that relies in part on criteria such as symptom worsening would be acceptable in any setting. Committee members agreed that symptom worsening must correlate with objective measurable changes in tumor size. Conversely, Ingle asserted that response rates should be accompanied by symptom improvements and other measures. "People aren't going to buy a drug on a high response rate alone." FDA Office of Drug Evaluation I Director Robert Temple, MD, observed that this "seems intensely reasonable;" however FDA "has yet" to see a correlation between response rates and symptoms in oncology submissions.

At the end of the meeting, oncology division director Burke made a plea to sponsors of cancer INDs to move away "from trying to replicate what I consider really bad results in the third-line therapy of breast cancer and try to do innovative combinations where a new drug may be combined with current first-line therapy to try to actually improve the care of women with breast cancer." He added that "I would encourage the effort to be put into creative design to really improve the therapy of breast cancer, not just to get a drug approved."