Overhangs on the approval of the much heralded melanoma drug ipilimumab in second-line melanoma receded with the March 21 announcement of positive top-line results in the front-line setting.

The drug met a primary endpoint of overall survival in the Phase III '024 study of patients previously untreated for melanoma, said developer Bristol Myers-Squibb Co. on March 21 after the markets closed. Bristol had acquired full rights to ipilimumab in 2009 via its $2.4 billion acquisition of Medarex, a deal now viewed as prescient by many analysts ([A#0071030008]).

A CTLA-4 inhibitor, ipilimumab has a March 26 PDUFA date for second-line treatment of melanoma. Full data supporting the filing have already been reported and submitted to FDA.

The front-line study, which compared ipilimumab at a 10 mg dose in combination with the chemotherapy dacarbazine versus dacarbazine alone, however, was, until Monday, a question mark. While the data were not required for the filing, the study's results give confidence that the drug will be approved by its March 26 PDUFA date for second-line melanoma, according to Vernon Sondak, chair of cutaneous oncology at the Moffitt Cancer Center.

Sondak had been a discussant on results presented at the American Society of Clinical Oncology meeting in June, where results from the Phase III '020 study in second-line melanoma had been presented. At the time, he noted the promise of the drug but also critiqued the findings of the '020 study, which supports the application now under FDA review (Also see "Advisory Committee Review Will Test Whether One Trial Will Do The Trick For Bristol's Ipilimumab" - Pink Sheet, 18 October, 2010.).

While optimistic overall about the clinical uses for the drug, Sondak had been among those raising questions about whether the FDA would require the results from the first-line study, given its expected timing was so near the proposed regulatory action date.

At the ASCO meeting where the ground-breaking '020 results had been presented, Sondak also questioned whether the vaccine control used in the second-line study was sufficient and wondered how severe side effects would be managed (.

Certainly, the Phase III results in second-line treatment represent a breakthrough in the space and stole the show at the ASCO meeting, setting expectations that the drug would be the first new approval in the disease for more than a decade. But the unexpectedly lackluster performance of the experimental vaccine used with the trial drug and as a control created some interesting clinical and regulatory plot twists ([A#0072024002]).

In an interview with "The Pink Sheet" immediately after the front-line results broke on March 21, however, Sondak said the top-line results appear to support the idea that the drug performs well compared to a more traditional comparator such as dacarbazine. This reinforces the second-line Phase III results, which tested the drug against an experimental vaccine.

While full results from the new front-line study are still needed, Sondak said he doesn't anticipate they will be required to support the drug's approval as a second-line agent. The physician is now even more reassured that in fact the drug could be approved soon, with no need for an advisory review.

"This is wonderful news for patients," he said.

Bernstein Research's Tim Anderson in a note issued late in the day on March 21, similarly described ipilimumab as an "exciting drug," especially given the dearth of effective therapies in melanoma.

Without knowing the full details from '024, it is probably safe to assume a substantial benefit accrues to patients, the analyst wrote. If prior results are any gauge, then the drug likely gives a meaningful survival benefit compared to monotherapy treatment and will likely show again that a smaller proportion of patients (15% or so) have a near-cure like response.

"The possibility of achieving this will make many patients eager to try ipilimumab," concluded the analyst.

However, Anderson also noted that new competition is on the horizon from Roche/Plexxikon's BRAF inhibitor PLX4032. That drug was snapped up recently in one of the most valuable private biotech acquisitions in recent history (Also see "Plexxikon CEO: Expect Business As Usual, After Whopping $805 Million Daiichi Buyout" - Pink Sheet, 28 February, 2011.).

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

Hopes Rise For Approval Of Melanoma Drug Ipilimumab, With Positive Front-line Results

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