Replies to post #96811 on Biotech Values

[iwfal]

But he says the company has reviewed the data carefully for any sign that the gp100 vaccine caused undue toxicity and found none.

My first reaction was to dismiss this as overly conservative - but at least one cancer vaccine did actually seem to cause harm (CEGE's was it?).

[DewDiligence]

BMY:

But the FDA may ask: How do researchers know that the (gp100) vaccine is not toxic, and that this--not effects of ipilimumab--accounted for the difference in survival between the two patient groups?

This question is addressed by the comparison between the two Ipilimumab arms (Ipi monotherapy vs Ipi+gp100), where the hazard ratio was 1.04. If gp100 were significantly toxic and thereby reducing survival in the combination arm, the survival difference between the combo arm and the mono arm would not have turned out to be minuscule.

[turtlepower]

Ipilimumab Improves Survival for Patients with Metastatic Melanoma

At Sunday’s Plenary Session, a landmark study provided new data that have implications for changing clinical practice. Steven O’Day, MD, of the Angeles Clinic and Research Institute, reported that ipilimumab alone or in combination with vaccine increased overall survival (OS) in patients with unresectable stage III/IV melanoma for whom previous treatment had failed (Abstract 4).

“This is an historic first — the first phase III randomized study showing improvement in median and long-term survival in patients with metastatic melanoma,” Dr. O’Day said. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), is an immune therapy directed against T-cells.


Figure 1. Abbreviations: HR, hazard ratio; Ipi, ipilimumab; pbo, placebo. The study evaluated two therapeutic approaches — ipilimumab and vaccine therapy with gp100 alone and in combination. The double-blind study randomly assigned patients to receive ipilimumab (137 patients), ipilimumab and gp100 (403 patients), or gp100 alone (136 patients). All patients were required to be HLA-A2 positive. Ipilimumab 3 mg/kg was given once every 3 weeks for four cycles. The vaccine gp100 was given at a dose of 1 mg, also every 3 weeks for four cycles. The primary endpoint of the study was overall survival (OS). After 12 months, 46% of patients receiving ipilimumab alone, 44% receiving ipilimumab plus gp100, and 25% receiving gp100 were still alive. The hazard ratio (HR) for OS demonstrated a 32% to 34% reduction in the risk for death in the two ipilimumab arms compared with the vaccine arm alone (p = 0.0026 for ipilimumab alone versus gp100; p = 0.0004 for the combination versus gp100) (Fig.1.)

The disease control rate, a composite endpoint of complete response, partial response, and stable disease, was 28.5% for the ipilimumab arm (p = 0.0002 versus gp100); 20.1% for the combination arm (p = 0.0179 versus gp100); and 11% for the gp100 arm. The best overall response rates were 10.9% for patients receiving ipilimumab, 5.7% for the combination, and 1.5% for gp100 alone. For every endpoint evaluated, ipilimumab was superior to either the combination or gp100 alone.

New Treatment Option
“These results are exciting because patients with melanoma have few treatment options,” Dr. O’Day said. “After 30 years of failed studies, we finally have an option that shows a significant increase in overall survival, an endpoint that many oncology studies strive for. This new class of inhibitors that overcome T-cell suppression offers hope to melanoma patients and oncologists alike.”

Adverse events were predominantly immune response–related and included rash, colitis, diarrhea, and hepatitis. Most were manageable and reversible, Dr. O’Day said. More serious immune-related grade 3 or 4 toxicities occurred in 10% to 13% of patients receiving ipilimumab. The rates of grade 3 or 4 events at specific organ sites were dermatologic (= 2.1%), gastrointestinal (= 7.6%), liver (1.1%), and pituitary (= 2.3%). Across multiple studies, these side effects correlated with clinical outcomes and could indicate that therapy with ipilimumab is working. For patients with metastatic melanoma with few options, such as interleukin (IL-2) and dacarbazine, ipilimumab could become the standard of care, Dr. O’Day said.

Remaining Questions
Vernon K. Sondak, MD, of the H. Lee Moffi tt Cancer Center & Research Institute, was equally optimistic about ipilimumab changing the current treatment landscape. While agreeing that the data are dramatic, Dr. Sondak posed several questions that still need to be addressed by research: “Is the dose the right one? Has ipilimumab been compared with the right control? In light of these data can we still be hopeful that ipilimumab can be combined with a vaccine to provide potent immunotherapy for patients?”

Previous dose-titration studies suggested that ipilimumab may be more active at 10 mg/kg. A large, international, phase III, first-line trial for patients with metastatic melanoma that compared the combination of ipilimumab 10 mg/kg with dacarbazine to ipilimumab alone has been completed. Final data from the study, which also has OS as the primary endpoint, are due later this year. If this trial also shows ipilimumab improves overall survival (in this case when added to “standard” dacarbazine chemotherapy), the news will be of great consequence to physicians and patients alike because it will support the use of ipilimumab in the first-line setting, Dr. Sondak said.

Whether ipilimumab can be combined with a vaccine for a more potent therapy cannot yet be answered. In this current study it was hoped that ipilimumab would add to the benefits seen with gp100. The results showed that gp100 did not add any benefits to those seen with ipilimumab alone. “We were not expecting that the vaccine might actually drag ipilimumab down,” Dr. Sondak said. Physicians treating melanoma should be familiar with the side effects of therapy and how to manage them, he said. “Even at 3 mg/kg there were potentially life-threatening complications. Using ipilimumab requires a committed, multidisciplinary team at all times to address toxicity management,” he said.

Dr. O’Day said that for a disease that has had no documented improvement in survival over the past 30 years and with no new approved choices since [IL-2] over a decade ago, “ipilimumab is the light at the end of a long, dark tunnel.”

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