There are survival results, but they are relatively short, which is a consequence of having results that are so spectacular that you are compelled to present them so early.
— Kim A. Margolin, MD
In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.
Much of the news about immunotherapy that came out of the 2013 ASCO Annual Meeting focused on agents that target immune system checkpoints and block pathways for receptors that suppress T-cell activity. This approach is more direct than other immunotherapeutic strategies and, at least for now, seems to hold the most promise.
“It is simple, it is relatively nontoxic, and it is well defined, which is not the case with many of the other immunotherapies. And it seems to work really well,” Kim A. Margolin, MD, told The ASCO Post. Dr. Margolin, whose clinical expertise is in immunotherapy for treating melanoma and kidney cancer, is Professor of Medical Oncology at the University of Washington, a member of the Fred Hutchinson Cancer Research Center, and a physician with the Seattle Cancer Care Alliance.
Results of trials using these immunotherapeutic agents in patients with melanoma and some other cancers have shown improved treatment outcomes, but survival data so far are limited. “There are survival results, but they are relatively short, which is a consequence of having results that are so spectacular that you are compelled to present them so early,” Dr. Margolin stated. She pointed out that in many cases, these “are the results of phase I studies, and that’s pretty amazing, to have such promising results in phase I that you make a huge splash, not only at a meeting, but in The New England Journal of Medicine.”1
Objective Response Rate
One of the phase I studies found the combination of ipilimumab (Yervoy) and nivolumab produced an objective response rate of 40% in patients with previously treated stage III/IV melanoma.1,2 Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and has been approved by the FDA for the treatment of unresectable or metastatic melanoma. The investigational drug nivolumab is an antibody that blocks programmed death 1 (PD-1) receptor. “Responses were durable, although longer follow-up is needed in some cohorts,” the investigators wrote in The New England Journal of Medicine.1 “The effect of the combination regimen on long-term survival remains to be defined.”
“There are other combinations that also have either checkpoint blockers together or a combination of checkpoint blockers with other immunostimulants—like cytokines, vaccines, or other accessory molecules like CD137—that have promise,” Dr. Margolin said, but haven’t come as far as the combination of ipilimumab and nivolumab. “Of course, that is in great part because the same company makes nivolumab and ipilimumab, so the hurdles associated with having more than one company work together on novel combinations were not present when that combination was able to be studied.” Both drugs are from Bristol-Myers Squibb, which also provided funding for the study.
In an expanded phase I study of nivolumab, 33 of 107 patients (31%) treated with five different doses of the drug experienced tumor shrinkage of at least 30% by RECIST criteria. The median overall survival across all doses was 16.8 months, which the investigators noted “compares favorably with historical data.” 3
“A very interesting thing is that responses don’t necessarily have to be maintained by continuing the drug,” reported study lead author Mario Sznol, MD, Professor of Medicine at Yale Cancer Center in New Haven, Connecticut, at a press conference held during the 2013 ASCO Annual Meeting. Among the 17 responders who stopped taking nivolumab for reasons other than disease progression, “12 continued to respond for at least 4 months after stopping the drug,” Dr. Sznol stated.
Asked whether that kind of carryover effect could be an expected feature of immunotherapy agents or is unique to nivolumab, Dr. Margolin responded, “I don’t think either one of those ends of the spectrum is necessarily the answer. We have learned the lessons from transplantation immunology [and other areas] that you probably cannot cavalierly assume that whatever therapeutic manipulation you make in the immune system is going to last unless you continue to actively pursue it. So, yes, there are some long-term responses after stopping the drug, but I think until we have more data, it would be a little too rosy to expect that.”
Patients with advanced melanoma who have experienced initial benefit from ipilimumab therapy and then had disease progression, can safely be retreated with ipilimumab, according to an analysis of patients treated in an ipilimumab expanded access program.4 These patients had unresectable stage III/IV melanoma, had progressed following one or more systemic therapies, and had no alternative treatment options. The potential benefit of retreatment on overall survival is being prospectively evaluated in an ongoing phase II study randomizing patients to ipilimumab retreatment or the physician’s choice of an alternative therapy.
“People who get retreated are, by definition, people who (A) did well for some period of time, then stopped doing well, and then were well enough to get the drug, (B) did not experience severe toxicities from treatment the first time around, and (C) lasted long enough to get to that point. Those are all relatively high bars,” Dr. Margolin said. “So you are looking at a highly selected, very biased group of patients. That having been said, it is very encouraging to know that you may be able to recapture responses that have been lost if the patient has been off therapy.”
‘Used to Failure’
A New York Times article5 on immunotherapy trials results from the 2013 ASCO Annual Meeting quoted Dr. Margolin as saying, “We’re so used to failure, we get excited very easily.”
In an interview with The ASCO Post, Dr. Margolin elaborated on that thought. “In some historical phase I studies, surely in the age of cytotoxics when we didn’t have agents that were molecularly or otherwise tailored to the patient, we had drugs that were tested in phase I across a broad spectrum of different tumor types. Patients were often heavily pretreated and not good candidates for likelihood of benefit. You were looking for toxicities, and maybe if you saw a little signal, you would then pursue that drug in those patients at that dose,” she said.
“Times have changed dramatically since then,” she continued. “In the area of targeted therapies, they’ve changed in the direction of picking patients based on molecular target expression, and often treating in earlier stages, in patients who haven’t been so heavily pretreated. Some of these immunotherapies are restricted to certain histologies. So we have an opportunity to see these efficacy signals earlier in groups of patients who are better characterized and in narrower histologic groups,” she added.
“That is why I could say we are used to failure, certainly in the phase I setting. The old way of doing phase I studies pretty much guaranteed failure,” she said. “Melanoma is a highly complicated malignancy, and it has taken decades of work and perseverance, but now we are seeing some pretty amazing turnaround of those results.” ■
Disclosure: Dr. Margolin receives research support from Bristol-Myers Squibb. Dr. Sznol is a paid consultant for Bristol-Myers Squibb.
1. Wolchok JD, Kluger H, Callahan MK, et al: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. June 2, 2013 (early release online).
2. Wolchok JD, Kluger HM, Callahan MK, et al: Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9012. Presented June 2, 2013.
3. Sznol M, Kluger HM, Hodi S, et al: Survival and long-term follow-up of safety and response in patients with advanced melanoma in a phase I trial of nivolumab (anti-PD-1, BMS-936558, ONO-4538). 2013 ASCO Annual Meeting. Abstract CRA9006. Presented June 1, 2013.
4. Margolin KA: Ipilimumab retreatment following induction therapy: The expanded access program (EAP) experience. 2013 ASCO Annual Meeting. Abstract 9041. Presented June 1, 2013.
5. Pollack A: Promising new cancer drugs empower the body’s own defense system. NY Times. June 3, 2013.
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