This changes everything about how these patients are treated, Australian expert says.
Ten-year data for treatment of metastatic melanoma with combination nivolumab plus ipilumab immunotherapy continues to bring good news.
The phase III results, published in the NEJM, show that patients with a deep response to immunotherapy are now more likely to die from something other than metastatic melanoma.
“Twenty years ago, there were virtually no patients with advanced melanoma who died of anything else except advanced melanoma,” Professor Mark Shackleton, director of oncology at Alfred Health, told Dermatology Republic.
“So the fact is quite remarkable that we’re now having to consider that these patients might develop or even die from other illnesses after having achieved deep responses and durable remissions from immunotherapy treatment.”
In this multinational trial, 1296 adults with unresectable, advanced, stage III or IV melanoma were equally randomised to receive either nivolumab, an anti–PD-1 antibody, (1mg/kg) plus anti–CTLA-4 agent ipilimumab (3mg/kg) every three weeks for four doses, followed by nivolumab (3mg/kg) every two weeks; or nivolumab (3 mg/kg) every two weeks plus placebo; or ipilimumab (3mg/kg) every three weeks for four doses plus placebo. Treatment was discontinued if toxicity became unacceptable, the patient’s disease progressed, or they wished to stop.
Median overall survival was 71.9 months for nivolumab+ ipilumab, 36.9 months for nivolumab alone, and 19.9 months for ipilumab alone.
Patients were 47% less likely to die during follow-up in the combination group than in the ipilumab group and 37% less likely to die in the nivolumab monotherapy group than in the ipilumab group.
Melanoma-specific survival was over 120 months for the combination group, with 37% still alive at the end of the trial; 49.4 months in the nivolumab arm; and 21.9 months in the ipilumab arm of the trial.
“Through 10 years, the results for melanoma-specific survival had continued to separate from the results for overall survival, more so in the nivolumab-plus-ipilimumab group … This trend suggests that the patients with advanced melanoma were living long enough to die from other causes,” the authors write.
Progression-free survival plateaued at three years. The most common site for first recurrence was the lymph nodes (in 18% of the nivolumab ipilimumab group, 25% in the nivolumab group, and 35% in the ipilimumab group), followed by the central nervous system (5%, 6% and 9% respectively).
Adverse events were more severe and frequent in the combination arm, but even those who stopped treatment early for this reason could achieve long term survival, the researchers said.
“As a career oncologist, immunotherapy has completely changed the way that I practice,” said Professor Shackleton.
“When I was training in the 1990s, a diagnosis of stage IV advanced melanoma was essentially a death sentence that often portended a very rapid downhill clinical course and frequently affected young people. Nowadays it’s one of the ‘best’ advanced cancers to have – not that there is any such thing as a ‘good’ advanced cancer – and the data from this study show why.”
Proactive support and management of patients with melanoma- or treatment-related complications is a much greater part of modern melanoma management than it used to be, said Professor Shackleton.
“I can’t think of many patients in the 1990s that I would have sent to intensive care for very high acuity supportive care during a treatment complication or interim problem, because you just knew that even if you could keep them alive, they would soon die from melanoma anyway, so referring them to ICU was almost never worth it in terms of quality of life,” he said.
“Now we have no qualms at all in referring such patients to receive whatever care they need to support them particularly during that initial period of treatment, which can be associated with substantial and even life-threatening side effects,” he said.
Caring for these patients now requires an extended multidisciplinary approach, frequently involving specialists from other disciplines to manage organ-specific complications, and intensive care colleagues to support patients who are acutely unwell.
“Managing treatment toxicities without reducing the anti-melanoma effectiveness of immunotherapy is an important next frontier for innovation, said Professor Shackleton.
“One challenge is that our standard treatment options for treating immune-associated toxicities are very broadly immunosuppressing medicines,” said Professor Shackleton.
“But, of course, the same generic immune responses that is causing toxicity might also be linked to an anti-cancer effect at that time. In most cases, our immunosuppressing drugs are not selectively able to distinguish between those two. There are major opportunities for our field to innovate in this area, with several promising ideas already in development.”
The news is good for patients who respond to this kind of treatment.
“Among patients across all three trial groups who had a depth of response of at least 80%, both median overall survival and median melanoma-specific survival were more than 120 months,” the authors write.
However, 30-40% of patients do not seem to have a good response to immunotherapy, said Professor Shackleton.
“It is not yet clear why some patients respond while others don’t, but both tumour cell intrinsic and extrinsic factors will be involved to varying degrees.
“In some instances, there will be something in the tumour cells that renders the immune system incapable of recognising them as bad and in need of elimination. In other cases where there is an initial immune response, tumour cell-related factors inhibit or prevent that immune response beyond the current therapies that we use.
“On top of that, across populations, there are a differing abilities to mount immune responses to a given antigen, based on our genetic make-up, as well as our environmental exposures during life. For example, there’s compelling evidence that gut bacteria have a role in influencing immune responses and even in whether a patient responds to immunotherapy at all,” said Professor Shackleton.
Trying to predict whether a patient will respond is a very active area of research, he said, with a lot of work going into trying to identify predictive biomarkers, including at The Alfred.
“If there’s a biomarker that predicts with 100% confidence whether a patient will respond to immunotherapy, believe me, that would be rapidly incorporated into routine clinical care. But we just don’t have that for cancer immunotherapy at the moment.
Given that immunotherapy is still the best and often only standard of care option for most patients with advanced melanoma, even if a biomarker predicted a low but non-zero chance of success, patients would understandably still choose to have it, he said.
“However, patients with biomarker profiles that indicated a primarily low chance of responding to immunotherapy, even if that chance were not zero, might be more inclined to think about participating in a clinical trial of new treatments where the benefit is not well known but at least in theory might offer a better chance than standard immunotherapy,” he said.
“And specific biomarker profiles might be linked with specific likelihoods of response to available and emerging immunotherapy combinations. For example, backbone anti-PD1 therapy might be most effectively combined with either anti-CTLA4, anti-LAG2, RP1, TIL, or other emerging agents based on tumour- and patient-related biomarkers.”
