乌鸦传媒

CHICAGO -- A therapy aimed at reviving the immune response to advanced melanoma generated durable responses in long-term follow-up of an early clinical trial, a researcher said here.

About a third of the 107 patients in the dose-finding trial had an objective response to the monoclonal antibody nivolumab, and the rate reached 41% among patients who got the dose now being studied in phase III trials, according to Mario Sznol, MD, of the Yale Cancer Center.

In contrast, historical response rates to immunotherapy in advanced melanoma have been no better than 10%.

"We're really in an era of remarkable advances in melanoma," Sznol told reporters at the annual meeting of the American Society of Clinical Oncology.

The drug targets a molecule dubbed PD-1 -- part of a so-called immune checkpoint -- on the surface of killer T cells. PD-1 is activated by a corresponding molecule, PD-L1, on the surface of tumor cells, with the effect of turning off the immune response to the cancer.

Nivolumab is one of several drugs under investigation whose goal is to interrupt that activation and keep the immune response active. The meeting is expected to see reports on others that block PD-1, as well as some that block PD-L1 on the tumor side of the interaction.

For the near future, the study emphasizes the importance of getting patients into clinical trials of new drugs, commented Lynn Schuchter, MD, of the University of Pennsylvania in Philadelphia, a melanoma expert who speaks for ASCO.

"Patients with melanoma getting access to these new agents is really the most critical part of care," she told reporters.

But "when PD-1 antibodies get approved, it will definitely be practice-changing," she said.

"Melanoma patients are living longer and better with these new treatments," she said in a statement.

The industry-sponsored study tested nivolumab in several types of advanced disease, but for this report, Sznol and colleagues focused on the 107 patients with advanced melanoma.

All patients had disease that worsened despite earlier standard systemic treatment. Indeed, 25% had three or more prior therapies and 63% had two or more, Sznol reported.

The drug was given intravenously every 2 weeks at doses ranging from 0.1 to 10 mg per kg of body weight.

Overall, 31% of the patients -- 33 of the 107 -- saw their tumors shrink by at least 30%, with at least some responses at each dose level.

The researchers chose a dose of 3 mg per kg for further study because of a 41% response rate, including one patient with a complete response, Sznol reported.

That dose also had a median overall survival rate of 20.3 months, compared with 16.8 months for the study as a whole.

The drug caused adverse events in 82% of patients, with grades 3 and 4 events in 21%, most commonly lymphopenia, fatigue, and increased lipase.

"The high level of activity observed with this drug opens up a number of avenues for future research to understand and challenge the ways tumors evade the immune system," Sznol said in a statement.

"We're very excited that there is potential for even more activity in combination with other drugs," he said.

He noted that the study was not randomized, but "it had a considerable number of patients and the durability of responses is a sign of very promising clinical activity."

He also said that patients were representative of typical patients with advanced melanoma, rather than being selected for the best chance to respond.

The findings are a "real breakthrough in the treatment of melanoma and possibly other cancers," commented Michael Atkins, MD of Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

Physicians have been able to stimulate the immune system in nonspecific ways for several years, he told 乌鸦传媒, but the treatments were associated with "a lot of toxicity." The highly specific nature of the PD-1 antibody approach appears to yield better efficacy with lower toxicity, he said.

But he cautioned it remains unclear if the approach will work in all patients and in all tumor types.

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