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Dr West

How long should we continue immune checkpoint inhibitor therapy in patients who respond?

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Over the past several years we have seen some great triumphs  in a subset of patients with advanced cancers who received an immune checkpoint inhibitor like Opdivo (nivolumab), Keytruda (pembrolizumab), or a growing list of other agents that act by removing a braking mechanism on the immune system and can stimulate it to recognize and attack the cancer.. In some patients, we can see the cancer shrink to the point of actually having no evidence of disease (NED) on post-treatment scans.  In many other patients. the cancer will shrink (sometimes immediately, sometimes after a delay of a few months), then remain visible but smaller for a long time.  In the original trials, most treatment protocols plan to have patients continue on ongoing IV therapy with these therapies meant to be given every 2 or 3 weeks, without any endpoint until their cancer shows significant progression or the patient develops significant side effects.  There are reasons to be tempted to discontinue treatment at some point: many of the leading experts with the most experience in immunotherapy have seen side effects that seem to be cumulative, raising the question of whether continued treatment with an immune checkpoint inhibitor for more than 6 or 12 months adds anything other than risk, inconvenience of coming in for infusions every few weeks, and major expense.  Many patients are also inclined to not be tethered to the clinic for regular visits and infusions every few weeks if they add no real value. And one of the basic tenets of immune response is that the immune system has a memory and may continue to respond to a recognized target or a very long time, even without ongoing active stimulation.

Moreover, many of these trials often allow patients to continue on immunotherapy after scans show evidence of tumor growth, based on the concept of pseudo-progression that I described in detail previously. I noted the potential harm of having patients continue on immunotherapy while their cancer was actually progressing, but how long should we continue a patient on immunotherapy when they’re doing well? Is there any end, or should we have them continue on immunotherapy indefinitely?  

The short answer is that we really don’t know.  In general, companies that sell expensive immunotherapy treatments have little incentive to spend money to design and run trials that try to determine whether patients will do just as well or better with less of the product they sell vs. more. However, in a competitive environment in which there are many remarkably similar drugs, a company could be very shrewd by demonstrating that 6 months of their immunotherapy is as effective as treatment well beyond 6 months with another therapy — the health care system would reward the limited duration therapy with the vast majority of the market share; moreover, the many patients who were not destined to respond would just get a few months of treatment, but now they’d receive the agent that is given for just a few months instead of a competing option.

There are some clinical trials being done that are trying to ask this by testing a fixed duration of 6 or 12 months  of immunotherapy, then stopping, vs. ongoing immunotherapy, we won’t have results of these trials for years. At the same time, people working on these trials note several major challenges. 

1) These trials need to enroll very large numbers of patients, because only a minority will have a very good response and get to the point where they would split between those stopping treatment after several months and those who continue until progression.  To end up with 400 patients randomized, a trial in many cancer settings would need to enroll well over 1000 patients.

2) Patients (and potentially their oncologists) may end up unwilling to follow their assigned treatment duration. Some patients assigned to ongoing treatment may become weary of ongoing visits and infusions every few weeks and decide to stop after many months rather than continue without an endpoint. Others assigned to a fixed duration may reach that point and then have misgivings about stopping.  When these drugs are commercially available, patients and their doctors can end up doing what they want, short-circuiting the trial and muddying the results.

We can hope to gather limited information from retrospective findings. Some patients who are responding may stop due to side effects, insurance issues, or just weariness of coming in for regular treatments that may or may not still be helpful.  We know that at least some of these patients can continue to do well, showing no evidence of progression for at least 6-9 months, but most of these agents haven’t been in use long enough to really get a sense of how long these responses after treatment discontinuation might be sustained. We also don’t yet have a sense of whether patients who develop progression after discontinuing immunotherapy can be “rescued” and respond again if they resume immunotherapy. 

In the meantime, we are left to our best judgment, and different oncologists follow different approaches. Some continue immunotherapy without any break, as long as a patient is doing well. Others stop it after a fixed period, whether that is 6 or 12 or 24 months or some other one — we don’t have an evidence-based endpoint. The approach I tend to favor is one in which I discuss the options with the patient, who may have a personal preference, but I recommend increasing the interval between treatments starting around 6 months in, gradually increasing from 2 or 3 to longer intervals of 4-6 weeks for the next year, then eventually out to 6-8 weeks. This is based on a principle that the immune system may benefit from a “refresher” repeat stimulation intermittently, but treatment every 6-8 weeks is a much more convenient interval of follow up than a shorter one, and this reduces cumulative exposure and risk of side effects, while also reducing cost of treatment.  However, if a patient has significant side effects or a clear preference to stop, I would be far more inclined to hold treatment and follow the patient and their scans closely, leaving open the option of resuming immunotherapy later.

Melanoma is likely to be the first setting that gives us some answers, as immunotherapy has been studied for longer and has more patients doing well for  years than other cancer settings. We can rightly say that there may be differences between melanoma and other cancers, but without any real direct evidence to answer the question for most settings, even indirect insights from other cancers can add to what we rely on now, which is primarily our best judgment and preferences.

What do you think? 


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