CHICAGO -- The combination of two monoclonal antibodies -- ipilimumab (Yervoy) and nivolumab -- may boost response rates against metastatic melanoma without excessive toxicity, a phase I trial showed.
Concurrent therapy with the PD-1 receptor antibody and the CTLA-4 antibody produced an objective response in 40% of patients overall, Jedd Wolchok, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York City, and colleagues found.
At the maximum doses with acceptable toxicity (1 mg/kg nivolumab and 3 mg/kg ipilimumab), 53% saw their tumor burden shrink by at least 80%, including three complete responses among the 17 patients, the group reported here at the American Society of Clinical Oncology (ASCO) annual meeting.
The combination yielded "a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy," the group wrote in a paper released simultaneously online in the New England Journal of Medicine.
The speed of response was notable too, occurring within 12 weeks, commented Michael Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.
"That's something we've never seen before with an immune therapy in melanoma and it's a rare thing to see in a solid tumor," he told MedPage Today.
Both drugs target so-called immune checkpoints subverted by tumor cells.
Ipilimumab blocks the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathway used by tumors to activate immune response-limiting regulatory T cells.
Nivolumab is one of a new class of agents that block tumor cells from using programmed death 1 (PD-1) receptors to "exhaust" the killer T cell response against the cancer.
The new trial included 53 patients with unresectable stage III or IV melanoma put on intravenous nivolumab and ipilimumab given together every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses, then the two drugs together every 12 weeks for up to eight doses.
Fully 65% of these patients showed some evidence of clinical activity, whether by conventional World Health Organization response criteria, unconfirmed response, immune-related response, or stable disease for 24 weeks or more.
Another 33 patients patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses, dubbed sequential treatment.
Sequential treatment with nivolumab after progression on ipilimumab yielded an objective response rate of 20%, including one complete response.
Treatment-related grade 3 or 4 adverse events occurred in 53% of combination-group patients "but were qualitatively similar to previous experience with monotherapy and were generally reversible."
The most common of these were elevated levels of lipase (13%), aspartate aminotransferase (13%), and alanine aminotransferase (11%).
The maximum doses with "acceptable" toxicity was associated with one case of grade 3 uveitis and one case of grade 3 elevated levels of aspartate aminotransferase and alanine aminotransferase among 17 patients treated with 1 mg/kg nivolumab and 3 mg/kg ipilimumab.
The treatment-related grade 3 or 4 adverse event rate was 18% with nivolumab after ipilimumab failure.
In a separate phase I study also released at the meeting and in the NEJM, lambrolizumab, another novel PD-1 blocker, produced a 38% response rate as monotherapy after resistance to ipilimumab in advanced melanoma.
"The results of these trials are striking and complementary," James Riley, PhD, of the University of Pennsylvania in Philadelphia, wrote in an accompanying editorial.
"Surprisingly and importantly, the use of ipilimumab and either one of two PD-1 monoclonal antibodies -- whether the PD-1 and CTLA-4 antibodies were given sequentially or together -- resulted in a rate and severity of adverse events that were no higher than those observed with the individual drugs alone," he stated.
The synergy in anti-tumor effect might be due to targeting separate pathways or by preferentially impacting distinct types of immune cells to the same end, Riley noted.
The immune checkpoint blockade strategy might be effective against a wide array of other solid tumor types as well, and the results open the door to studies adding further immune modulators, he suggested.
However, not every combination appears to be as safe and effective. A phase I trial of concurrent vemurafenib (Zelboraf) and ipilimumab by Wolchok's group was halted over liver toxicity earlier this year.
The researchers acknowledged patient selection bias and the small number of patients as limitations that suggest caution in interpreting the phase I results.
The next step will be a phase III trial to formally compare ipilimumab alone, nivolumab alone, and the combination in advanced melanoma, they suggested.
Durability will also be important to follow, Atkins noted.
The study was sponsored by Bristol-Myers Squibb.
Wolchok reported receiving consulting fees from Bristol-Myers Squibb, Ziopharm Oncology, Polynoma, and Merck and grant support from Bristol-Myers Squibb, GlaxoSmithKline, and MedImmune on behalf of his institution.
Riley reported having consulted for Bristol-Myers Squibb regarding PD-1 blockade at a single 2-day meeting, having grant support from the NIH, and holding a patent with the Walter Reed Army Institute of Research regarding CTLA-4 in HIV infection.
Crystal Phend
Staff Writer
Crystal Phend joined MedPage Today in 2006 after roaming conference halls for publications including The Medical Post, Oncology Times, Doctor's Guide, and the journal IDrugs. When not covering medical meetings, she writes from Silicon Valley, just south of the San Francisco fog.
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