Eye-opening Phase III results with Bristol-Myers Squibb Co.'s Medarex Inc.-acquired immunotherapy against melanoma put ipilimumab on the skin-cancer map as the first to hit statistical significance and boost survival - even across subgroups - in a randomized, controlled trial against the challenging disease, which enrolled 676 patients who had already been treated.
A home run? Many watchers of New York-based BMS seem to think so, although the other drug in the trial was a comparatively weak peptide vaccine known as gp100.
The company has not yet filed for approval of ipilimumab and will undergo a panel review. BMS got full rights to ipilimumab in the $2.4 billion buyout of former partner Medarex, of Princeton, N.J., developer of the CTLA-4 inhibitor that has stumbled in previous studies. (See BioWorld Today, Aug. 26, 2009, and Dec. 12, 2007.)
Patients given intravenous ipilimumab plus gp100 showed a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone (p < 0.001). Compared to gp100, ipilimumab powerfully upped survival at one year (46 percent vs. 25 percent) and two years (24 percent vs. 14 percent).
Results from the study, dubbed 020, were disclosed at the American Society of Clinical Oncology meeting over the weekend, and published simultaneously online in the New England Journal of Medicine. The global trial started signing up patients in 2004 with unresectable Stage III or IV metastatic melanoma who were HLA-A2-positive because gp100 is specific to such patients, who make up about half the total population (although, as the NEJM paper points out, previous studies have shown "CTLA-4 blockade by ipilimumab is independent" of HLA-A2 status). Patients were randomized to three treatment groups to get ipilimumab plus placebo (137 patients), ipilimumab plus gp100 (403), and gp100 plus placebo (n = 136).
Although ipilimumab probably wouldn't be given with gp100 in the real world, it might go well with oral PLX4032 (RG7204) from Plexxikon Inc., of Berkeley, Calif., and Basel, Switzerland-based F. Hoffmann-La Roche Ltd., which entered Phase III trials in metastatic melanoma near the start of this year, chalking up a milestone payment for Plexxikon through the 2006 deal. PLX4032 is designed to inhibit the BRAF cancer-causing mutation that occurs in 40 percent to 50 percent of melanomas and about 8 percent of all solid tumors. (See BioWorld Insight, May 24, 2010, and BioWorld Today, Oct. 5, 2006.)
In other melanoma-related news from ASCO:
• Celldex Therapeutics Inc., of Needham, Mass., disclosed data on CDX-011 in metastatic melanoma from a Phase II study that met its primary endpoint. CDX-011 is an antibody-drug conjugate, and Celldex provided updated results from the Phase II portion of the multicenter, open-label Phase I/II study of CDX-011 in patients with unresectable Stage III/IV melanoma. A total of 34 patients were enrolled in the Phase II expansion, and the primary activity endpoint of overall response rate in the cohort was achieved with an ORR of 15 percent. Median progression free survival was 3.9 months. Celldex's shares (NASDAQ:CLDX) dropped more 21.7 percent on the news to close Monday at $5.14, down $1.42.
• Genta Inc., of Berkeley Heights, N.J., presented combined data on early endpoints from the company's randomized Phase III trials of Genasense (oblimersen) for injection plus chemotherapy in patients with advanced melanoma. The presentation included a pooled analysis that assessed combined efficacy results for the endpoints of overall response and progression-free survival from both studies. In October, Genasense missed the initial primary and secondary endpoints in a confirmatory Phase III melanoma trial, having failed to show survival efficacy in a previous Phase III study. Genta withdrew the application for approval in melanoma. The company's shares (OTC BB:GETA) fell 16.4 percent on the latest news, to close Monday at 5 cents. (See BioWorld Today, Oct. 30, 2009.)
• Myriad Pharmaceuticals Inc., of Salt Lake City, presented data from two separate Phase IIa combination drug studies of Azixa (MPC-6827, verubulin) in recurrent glioblastoma multiforme and stage IV metastatic melanoma. Azixa, in combination with standard treatments, resulted in durable responses with no added toxicity compared with chemotherapy alone in both studies. The microtubule destabilizing small molecule when combined with temozolomide in a 22-patient study found that two patients achieved partial response durations of four and 10 months. Nine patients experienced stable disease durations between three and seven months. The response rate (defined as partial response by modified RECIST criteria and stable disease) was 50 percent and the median progression-free survival was 2.9 months. Those PFS data compared favorably to temozolomide and dacarbazine in a randomized Phase III study for the treatment of patients with advanced metastatic malignant melanoma (PFS of 1.9 and 1.5 months, respectively). The combination of the drugs was shown to be safe and well tolerated at all combinations in the study, and a dose reduction of Azixa was not required when combined with temozolomide in those patients.
• Polaris Group, of San Diego, said Phase II results with ADI-PEG 20 showed the pegylated arginine deiminase targeting argininosuccinate synthetase (ASS)-negative tumors, and which is being developed and manufactured by Polaris Group, was effective in inhibiting the growth of metastatic melanoma cells in a study that involved 36 metastatic melanoma patients who were treated with ADI-PEG 20 weekly by intramuscular injection. Of the evaluable patients, 14/36 (39 percent) had a tumor response and/or clinical benefit. For 16 patients with ASS-negative tumors, 10/16 (63 percent) showed some evidence of antitumor effect, while only 1/10 (10 percent) patients had stable disease when the tumor was ASS-positive. Polaris plans to initiate its first Phase III trial with ADI-PEG 20 during the fourth quarter of this year, treating hepatocellular carcinoma, which has a high prevalence of ASS-negative tumor cells.
• Provectus Pharmaceuticals Inc., of Knoxville, Tenn., disclosed additional positive data from its Phase II trial of PV-10 for metastatic melanoma. The data, on changes in visceral and nodal metastases following chemoablation of cutaneous melanoma lesions with PV-10, showed positive improvement in those remote, untreated lesions, including metastases to the lungs, liver and brain, illustrated a potential systemic effect in visceral organs to which melanoma had spread. Updated information included data from both the initial 40 subjects and the final 40 subjects enrolled in the trial. PV-10 is a form of Rose Bengal, a small molecule used for almost 30 years by ophthalmologists to assess eye damage, as well as intravenously to diagnose liver trouble. The compound seems selectively toxic to cancer cells via chemoablation, and has a short half-life in the body without notable side effects.
• ZymoGenetics Inc., of Seattle, disclosed positive results from a Phase II trial in metastatic melanoma with recombinant interleukin 21 as a single agent. The trial met the primary endpoint of efficacy, as measured by objective response rate or lack of early disease progression. Overall response rate was 23.1 percent in evaluable patients, and median progression-free survival was 4.3 months.