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Concurrent treatment with two antibodies that boost the immune response to tumors in distinct ways appears to be highly effective against metastatic melanoma

Jun 2, 2013 | 1:05 pm

A one-two punch against cancer

June 2, 2013, New York, NY—A team of researchers led by Jedd Wolchok of the Ludwig Center at Memorial Sloan-Kettering Cancer Center (MSKCC) presented data today at the 2013 Annual Meeting of the American Society of Clinical Oncology showing promising results from a Phase I clinical trial evaluating the concurrent use of two immunotherapies for the treatment of advanced melanoma. The study is published in this week’s issue of the New England Journal of Medicine. Wolchok and his colleagues found that a regimen of two antibody therapies—ipilimumab (Yervoy) and the investigational drug nivolumab—led to strong and durable tumor regression in patients with inoperable, metastatic melanoma, which is highly resistant to treatment.

The trial results reveal that 40% (or 21) of the 52 evaluated patients who received the combined therapy showed objective responses in measurable tumors. Notably, 31% (or 16) of the evaluated patients had tumor regressions greater than 80% compared with baseline, and in five of those patients detectable tumors regressed completely. About 90% of responding patients continued to respond to the therapy as of February 13, after 13 months of median follow-up. In all, 65% appeared to have demonstrated clinical activity with stable or improved findings on imaging.

“We were pleasantly surprised by both the speed and sheer depth of the response to this combination of antibody therapies,” says Jedd Wolchok, MD, PhD, director of immunotherapy clinical trials and monitoring at the Ludwig Center at MSKCC. “Though this is a modest-sized Phase I trial and its results need to be confirmed in larger studies, our data indicate that when given concurrently the two drugs could be more effective against metastatic melanoma than either appears to be alone.”

Patients who received the dosages of the two-drug regimen selected to move forward into later stage trials (ipilimumab at 3mg/kg and nivolumab at 1mg/kg) had an objective response rate of 53%, defined as at least a 50% confirmed reduction of measurable tumors on CT scans. Ultimately, all of these responding patients experienced better than 80% tumor regression, and many achieved that response within 12 weeks of treatment. By contrast, ipilimumab, the first approved drug shown to extend survival of people with metastatic melanoma, has an objective response rate of about 11% when used alone. Recent studies of nivolumab, meanwhile, suggest it has an objective response rate of up to 41%.

“The results buttress a growing conviction among researchers that the immune system can be effectively harnessed to control cancer and that such treatments can induce durable regressions,” says Wolchok. “Further, they suggest that two distinct immune modulating pathways can be safely engaged concurrently and that doing so may yield results superior to those obtained using either approach alone.”

The antibody therapies illustrate the point perfectly. Ipilimumab interferes with a normal process by which the immune system controls the activation of T cells that destroy diseased tissues. The antibody blocks a protein switch on the T cell surface known as CTLA-4 that, when turned on, dampens the cell’s activation. Nivolumab, meanwhile, targets a protein known as PD-1 that is also found on the T cell surface. PD-1 too functions as a brake on T cell activation—but one that is aberrantly engaged by tumors themselves to shut down a T cell attack.
“In a sense,” explains Wolchok, “ipilimumab boosts the general activation of T cells involved in destroying tumors, while nivolumab disrupts a cellular interaction that allows tumors to sabotage that attack.”

Interestingly, however, patients responded to the concurrent therapy regardless of whether they had biomarkers that have previously been found to correlate with positive responses to each of the therapies.

The clinical trial enrolled 86 patients with inoperable, advanced melanoma who had previously been treated with three or fewer drugs into six cohorts. Fifty-three of these patients were divided into four cohorts that received four doses of ipilimumab and nivolumab every three weeks, and then four doses of nivolumab alone every three weeks. After week 24, they received a combined treatment of the drugs every three months. Each cohort that got the combination therapy received a different dosage of the two drugs, with nivolumab ranging between 0.3-3 mg/kg, and ipilimumab ranging between 1-3 mg/kg. In addition, 33 patients who had received ipilimumab before joining the trial were divided into two cohorts and given nivolumab alone at one of two dosages every two weeks. About 38% of these patients had objective responses to the sequenced therapy. “This provides hope for patients whose disease has progressed after ipilimumab. Alternative immunotherapies can still work for them,” says Wolchok.

Researchers affiliated with Bristol-Myers Squibb, Yale Cancer Center and Dako North America collaborated with Wolchok and his Ludwig colleagues to conduct this trial. Side effects of treatment in the trial were, in most cases, relatively easily managed and reversed. No deaths resulted from the treatment. Wolchok is now working with BMS to evaluate the combined immunotherapy in a large, randomized, double-blind, placebo controlled Phase III efficacy trial. This work was funded by Bristol-Myers Squibb Inc. and Ono Pharmaceutical Company Ltd. (NCT01024231).

About The Ludwig Institute for Cancer Research
The Ludwig Institute for Cancer Research is an international non-profit organization committed to improving the understanding and control of cancer through integrated laboratory and clinical discovery. Leveraging its worldwide network of investigators and the ability to sponsor and conduct its own clinical trials, Ludwig is actively engaged in translating its discoveries into applications for patient benefit. Since its establishment in 1971, the Ludwig Institute has expended more than $1.5 billion on cancer research. For more information, go to www.licr.org. For additional background on the Ludwig Center at Memorial Sloan-Kettering Cancer Center, go to www.mskcc.org/research/ludwig-cancer-immunotherapy.