By Edward B. Garon, MD
Immune checkpoint inhibitors have dramatically changed the treatment of patients with lung cancer. The degree of efficacy seen with these agents would have been nearly unimaginable a decade ago. We now have long term follow-up data demonstrating that a substantial percentage of patients are alive 5 years or more after receiving an immune checkpoint inhibitor.1,2 Of particular note, the patients with these impressive outcomes are often not the patients with targetable driver mutations—patients who had previously constituted a disproportionate percentage of our 5-year survivors. The fact that those benefiting appear to be more consistent with the “typical” patient with lung cancer is reflected by data showing that outcomes for lung cancer in general have substantially improved.3 In advanced disease, there are few settings remaining in which immune checkpoint inhibitors are not currently approved. Perhaps the most satisfying results of these advances is that our clinics look quite different than just a few years ago.
Yet, despite all of our reasons for enthusiasm, the data do not support the idea that immune checkpoint inhibition is a cure for these patients. Although there are many patients in our clinics who received a limited course of an immune checkpoint inhibitor and have had persistent disease control since, that is not necessarily the rule. In fact, most of the patients at our institution with continued disease control from our original clinical trials assessing immune checkpoint inhibitors have had at least one local treatment since achieving disease nadir. Although these data are anecdotal, the CheckMate 153 study randomly assigned patients with disease control after several months of nivolumab to either discontinuation of nivolumab after a year or continuous treatment.4 The PFS strongly favored continuation. Perhaps more concerning, survival appeared to be lower among patients who discontinued at a year.
When I think of a cure, I think of antibiotics for bacterial infections such as pneumococcal pneumonia. Patients who are cured of pneumococcal pneumonia do not have limited recurrences long after treatment, and persistent treatment is not considered helpful. Perhaps one could argue that the CheckMate 153 data are consistent with the idea that a year of immune checkpoint inhibition is analogous to a course of antibiotics that is “too short”; however, if we accept that explanation, we then have no prospective data to guide us as to what duration of immune checkpoint inhibition would be sufficient.
When describing the promise of immunotherapy to prospective clinical trial participants in years past, I generally described how we are hoping to have the immune system recognize the tumor and eliminate it the way that it eliminates chickenpox (varicella). I would explain that the immune system is able to recognize the virus, eliminate it, and prevent the person from getting chickenpox again. From what we see in the clinic, my chickenpox explanation has turned out to be a particularly good analogy, although not for the reason I had intended: While the immune system prevents recurrence of chickenpox, a substantial percentage of patients do have sequelae of the virus again, in the form of shingles (herpes zoster). Although some of the patients in our clinic who have disease recurrence after a great response to immune checkpoint inhibitor therapy develop widespread disease, we frequently see a more limited recurrence.
Regardless of the terms that we use to describe the long-term outcomes of our patients treated with immune checkpoint inhibitors, compared to the therapies that preceded them, immune checkpoint inhibitors’ outcomes have had a major impact. We now have many patients who are alive and thriving many years after starting an immune checkpoint inhibitor. This has changed the face of lung cancer substantially. When asked by other providers whether a mutual patient can be cured, it may seem discouraging that we can’t definitively say yes. Still, I don’t think that this detracts from the success of immune checkpoint inhibitors. Although many people consider it depressing to state, 100% of people will die. As oncologists, the best that we can hope for is to have our patients die of something other than their cancer or its treatment. We have now started to see this happen in our clinics. Although the data to date, in my opinion, are not clearly supportive of the disease being cured the way a bacterial infection is, something very substantial is happening. We now view a “good” outcome in our patients tremendously differently than we did prior to immune checkpoint inhibitors. We are moving toward viewing advanced lung cancer as a part of the overall medical situation in a substantial percentage of our patients rather than the only relevant condition. In my opinion, it is much more appropriate to focus on what has been accomplished than to perseverate on what may not yet have been achieved.
References:
- Garon EB, Hellmann MD, Rizvi NA, et al. Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J Clin Oncol. 2019;37(28):2518-2527.
- Gettinger S, Horn L, Jackman D, et al. Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: Results From the CA209-003 Study. J Clin Oncol. 2018;36(17):1675-1684.
- Howlader N, Forjaz G, Mooradian MJ, et al. The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med. 2020;383(7):640-649.
- Spigel DR, McCleod M, Hussein MA, et al. Optimizing duration of nivolumab treatment (tx): randomized results of fixed-duration (1-yr) vear continuous nivolumab in patients (pts) with advanced (adv) non-small cell lung cancer (NSCLC): Abstract 12970. Presented at: European Society for Medical Oncology Congress; September 8-12 2017; Madrid, Spain.
About the Author:
Dr. Garon is associate professor of medicine at the Geffen School of Medicine at UCLA in the Department of Medicine, Division of Hematology/Oncology.
