An FDA advisory committee review in early December of Bristol-Myers Squibb Co.'s application for ipilimumab for second-line melanoma based on one pivotal trial will test the current climate for oncology drug approvals.

FDA has made clear in certain cancer settings that it prefers to see evidence from two clinical trials, and the importance of a confirmatory trial has been underscored by recent developments, like the withdrawal of Pfizer Inc.'s Mylotarg (gemtuzumab) (Also see "Mylotarg Pulled Off Market, But Pfizer Continues Search For Appropriate Population" - Pink Sheet, 21 June, 2010.).

Roche/Genentech's Avastin (bevacizumab) gained accelerated approval in breast cancer based on progression-free survival results, ibut it failed to show a survival benefit in a confirmatory trial. The clearance in breast cancer is now under review by FDA (Also see "Roche Gets Reprieve On Avastin For Breast Cancer With Delay At FDA" - Pink Sheet, 17 September, 2010.).

Bristol has an advantage in that ipilimumab, or Yervoy, has shown a survival benefit, which should ease a lot of concerns about anti-cancer effect. The ipilimumab application is supported by only one Phase III MDX010-020 trial in almost 700 patients with metastatic melanoma, but that trial showed an impressive survival benefit of four months.

But wary regulators and oncologists could be interested in a separate ongoing, frontline Phase III study that has not yet reported out.

Bristol had submitted the application for full approval (meaning a confirmatory study is not necessarily required) for second-line use in July and it was accepted for priority review, which means a six-month review schedule (Also see "BMS Files Ipilimumab With FDA And EMA, Positioning It For Launch Next Year" - Pink Sheet, 22 July, 2010.). Ipilimumab is already being made available through an expanded access program.

FDA's Oncology Drugs Advisory Committee will consider Bristol's BLA for the anti-CTLA-4 monoclonal antibody on Dec. 2.

The melanoma community is expecting a positive outcome from the panel review based on the strong survival benefits demonstrated in the pivotal '020 study, commented Vernon Sondak, chair of cutaneous oncology at Moffitt Cancer Center and chair of the melanoma group of the Southwest Oncology Group. Sondak had discussed the trial when it was presented at the plenary session of the 2010 American Society of Clinical Oncology meeting in June.

However, the advisory committee members are likely to question whether one trial is enough to support approval and to seek reassurance that the company has a robust plan for managing the significant toxicity, Sondak said during an interview.

The three-arm '020 study tested a 3 mg/kg dose of ipilimumab plus Bristol's experimental gp100 vaccine (403 patients) against monotherapy with ipilimumab and placebo (n=137), and the gp100 vaccine with placebo (n=136).

Median overall survival was 10.1 months for patients who received ipilimumab alone, 10 months for those on ipilimumab plus the gp100 vaccine, and only 6.4 months for those who got the vaccine without the drug.

With few options for these patients available, the results represented a major achievement. During his discussion of the trial at the ASCO plenary session, Sondak had described it as the first light at the end of a dark tunnel that has characterized melanoma therapy.

Careful Plan Needed to Manage Severe Side Effects

But along with the efficacy results came serious issues with toxicity that are likely to face scrutiny during the panel review (Also see "Ipilimumab Boosts Survival, But With Adverse Events That Need Strict Oversight" - Pink Sheet, 6 June, 2010.).

The overall rate of severe adverse events (Grade 3 to 4) was 17% in the ipilimumab/vaccine arm compared to 23% in the ipilimumab-alone arm and 11.4% in the vaccine arm. The most important side effects were immune-related. There were 14 treatment-related deaths in the study, or 2% of the study population. Of these, 7 were immune-related, including five in the ipilimumab/vaccine arm and two for ipilimumab monotherapy.

A committed multidisciplinary medical team is needed to manage use of the drug, Sondak had emphasized during the ASCO plenary discussion.

In the interview, Sondak noted that the agency's advisors are likely to expect a careful, well-thought out plan for educating health professionals and patients about the management of side effects in order to get the best outcome possible with the new drug.

Certain side effects such as hypophysitis, or inflammation of the pituitary gland, are unique to the drug. Other events, including diarrhea and hepatic toxicity, are the same as those experienced with chemotherapy and will be familiar to oncologists. However, importantly, the causes differ and the treatment needs to be more aggressive in patients treated with ipilimumab, Sondak commented.

"The side effects seem familiar, but the management is totally different and indeed unique," he explained.

Bristol would not speculate on the possibility for a Risk Evaluation and Mitigation Strategy while discussions with regulators are ongoing.

Another issue that could get some attention during the panel review is the use of the vaccine as a control arm. Contrary to expectations, the vaccine did not show modest activity and there were concerns that it may have actually dampened response. The imbalance in the immune-related deaths could also be an impediment to FDA approval, if panelists consider the vaccine to be the source of toxicity without conferring any benefit.

At the time of the ASCO meeting, analysts said that the regulatory outlook partly depends on how well Bristol can sell the proposition that the vaccine arm is much like a placebo control (Also see "Ipilimumab Data Impress, But Vaccine Control Could Complicate Review" - Pink Sheet, 14 June, 2010.).

On the other hand, options are very limited in this setting, so it's unclear whether another more suitable control could have been selected. Bristol has argued that there is no clear single standard of care for patients with advanced melanoma who have received prior therapy nor are there generally accepted therapeutic options.

Leerink Swann analyst Seamus Fernandez pointed out in an interview at the time of the release of the results that it is important to keep in mind that the 12-month and 24-month survival rates were greatly higher in the two ipilimumab arms.

Similarly, Sondak noted that the survival benefit was shown in hundreds of patients in the two treatment arms including ipilimumab in the pivotal study. There is no evidence to show that the control was anything but reasonable, he said.

"I do not expect this to be a make or break issue," he said.

Second Study In First-Line Setting Continues

Panelists may consider whether it would be better to hold off on approval until results are available from another Phase III trial in advanced melanoma. The primary completion date listed for that trial of 500 patients is November, just before the panel date. A Bristol spokesperson pointed out that this is an event-driven study so it's difficult to project a precise timeline for completion, but the company expects to have results early in 2011.

But waiting for these results may not be appropriate. Compared to the second-line study, the design of the ongoing first-line study differs in important ways: the double-blind study tests a 10 mg/kg dose of ipilimumab (much higher than what was tested in the second-line study) added to the approved chemotherapy dacarbazine in high-risk, untreated, unresectable advanced melanoma.

Appropriate dosing and combination with other therapies are unanswered questions at this point for physicians treating melanoma, Sondak said, so practitioners will be interested in seeing the results of the trial.

Sondak expects that in light of the differences in trial design, advisors and the agency will ultimately decide to clear the drug for the particular dose and dosing schedule tested in the second-line melanoma trial, and handle the first-line indication separately at a later date.

"Assuming the panel decides to base their decision on the results of the second-line trial, since those results are published and have been widely discussed, I don't think there will be too many curveballs there," Sondak said.

The first-line trial does not include the concomitant gp100 vaccine, however, so if that is an issue for the advisory committee, then waiting for the other trial could be an option to gain further confidence in the drug's effect.

- Emily Hayes (e.hayes@elsevier.com)

Advisory Committee Review Will Test Whether One Trial Will Do The Trick For Bristol's Ipilimumab

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