Bristol-Myers Squibb's immunotherapy Yervoy (ipilimumab) will enter the market positioned for wide use, with a broad label for its approval for metastatic melanoma and positive Phase III results for front-line patients.

A CTLA-4 inhibitor, ipilimumab was cleared by FDA on March 25 for unresectable or metastatic melanoma. Though the NDA was based on a study in refractory patients, the indication does not specify second-line use (Also see "Bristol Basks In Broad Ipilimumab Label, Sets High Price" - Pink Sheet, 25 March, 2011.).

Just days before the approval, Bristol announced positive top-line findings in Study 024; widespread adoption in clinical practice is sure to follow once the full data are released.

The drug has now been shown to work in all lines of therapy for advanced malignant melanoma. And with FDA-approved labeling that does not limit use to patients with advanced metastases or who have failed earlier treatment, Bristol has little left than to launch. Though the first-line results will need to be submitted to FDA and added to labeling, ipilimumab has few obstacles to reaching its full commercial potential.

Bristol said it was pleased with the broad label for ipilimumab.

Making Headway In Metastatic Melanoma

Approval was supported by the pivotal Study 020, which had included mostly very late-stage melanoma patients. All of the patients had been pretreated with other drugs. As there have been no approvals for metastatic melanoma in 13 years, the arrival of ipilimumab has been eagerly awaited.

Even before the full data from study 024 come out, doctors who take a more aggressive approach to treatment are likely to consider the therapy as a first-line treatment, based on the announcement that Yervoy improved survival, commented Tim Turnham, executive director of the Melanoma Research Foundation.

And importantly, the wording of the label does not specify the extent of metastases, paving the way for broader use in patients with Stage III disease, in which patients may only have metastases to the lymph nodes, Turnham said.

Off-label use in the first-line setting had already been expected, and at the beginning of the year, Leerink Swann's Seamus Fernandez reported that feedback from a key opinion leader suggested that ipilimumab would be used in about 70% of patients.

Supporting The Front Line

The drug met a primary endpoint of improving overall survival in study 024, which included 500 patients with previously untreated Stage III or Stage IV melanoma. Few other details on performance are available until the full results are presented at the American Society of Clinical Oncology annual meeting in June. Secondary endpoints in the study included progression-free survival, disease control rate, safety profile and quality of life.

Bristol had acquired full rights to ipilimumab in 2009 via its $2.4 billion acquisition of Medarex ([A#0071030008]).

The front-line study compared ipilimumab at a 10 mg dose in combination with the chemotherapy dacarbazine versus dacarbazine alone. The study used a higher dose of ipilimumab and included maintenance dosing after induction therapy.

Although the full details from the ‘024 study are unknown, it is probably safe to assume ipilimumab demonstrated a substantial survival benefit, based on results from other trials, Bernstein Research analyst Tim Anderson wrote in a March 22 note. Based on prior results, he expects maybe double the survival benefit versus the chemotherapy and a near-cure-like response in 15% of patients.

Labeling does not specify use in refractory patients, and with the release of positive front-line data just days before, ipilimumab is likely to be used for the full spectrum.

“The possibility of achieving this will make many patients eager to try ipilimumab,” Anderson commented, but he also pointed out by the end of the year it could face competition from Roche/Plexxikon's BRAF inhibitor vemurafenib (RG7204/PLX4032).

Ipilimumab is also likely to be used in combination with vemurafenib, which is slated for filing this year. Genentech confirmed that it is in talks with Bristol regarding a combination study. “We are considering a broad development program with vemurafenib that may include combinations with other medicines, both approved and investigational, from Genentech and other companies, as well as studies in other tumor types,” the company said.

Comparing The Comparators

Top-line results from the first-line trial are reassuring given that the drug was tested against a traditional comparator like dacarbazine, commented Vernon Sondak, chief of cutaneous oncology at the Moffitt Cancer Center.

There had been concerns about the adequacy of the comparator in the refractory trial.

The application in second-line melanoma was supported by only the one Phase III 020 trial in 676 patients with metastatic melanoma that showed a survival benefit. The data represented a breakthrough in the space and stole the show at the American Society of Clinical Oncology 2010 meeting, setting expectations that the drug would be the first new approval in the disease for more than a decade.

But there had been some doubts about the use of Bristol’s experimental gp100 vaccine in the study.

The three-arm study tested a 3 mg/kg dose of ipilimumab with the gp100 vaccine (403 patients) against monotherapy with ipilimumab and placebo (n=137) and gp100 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.

There were some questions about whether the vaccine actually had a negative effect, because it did not add a benefit to the test drug and on some measures appeared to dampen response. If so, it would have pulled down the control arm results, making the test drug look better than perhaps it was. There was concern that the gp100 results would be a complicating factor for FDA, if the agency wouldn't view the gp100 arm as a placebo control ([A#0072024002]).

Sondak, who had been a discussant on the 020 study at ASCO, had questioned whether panelists at a scheduled meeting for the Oncology Drugs Advisory Committee would want to hold out for the results from the first-line study (Also see "Advisory Committee Review Will Test Whether One Trial Will Do The Trick For Bristol's Ipilimumab" - Pink Sheet, 18 October, 2010.). However, FDA cancelled the advisory committee review in a move that was widely interpreted as a positive sign for the drug’s approval (Also see "Advisory Panel For Bristol's Yervoy Is Called Off, Which May Bode Well" - Pink Sheet, 23 December, 2010.).

At $120,000 per patient, Bristol's pricing for ipilimumab is higher than expected.

Gauging The Ipilimumab Market

Bristol's pricing for ipilimumab is higher than had been expected. The drug is administered in 3 mg/kg injections every three weeks for four doses. It will be priced at $30,000 per injection, for a total price of $120,000.

Bernstein had been projecting sales of $1.7 billion for ipilimumab in 2015, based on an assumption of a $100,000 per-patient per-year price. The firm said it is not changing its estimates for now, even though the actual price is higher. A number of variables could affect estimates in the near future, including the full dataset at ASCO's 2011 meeting.

Assuming a price of $50,000, Leerink Swann had projected $100 million in 2011 and $925 million in 2017. But in light of the positive results in the front-line study, Fernandez thought the price could increase by 50%. In that case, the firm’s 2017 sales estimate would rise by $600 million.

By Emily Hayes

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