Can patients with cancer and preexisting autoimmune disorders safely benefit from immunotherapy? The answer has been unclear, with only retrospective studies and anecdotal reports guiding oncologists. This subpopulation of patients has largely been excluded from clinical trials out of concerns over the risk of severe immune-related adverse events or worsening of their underlying disease. “As a result, we have very little information about immunotherapy in those individuals,” said Elad Sharon, MD, MPH, Senior Investigator in the Cancer Therapy Evaluation Program at the National Cancer Institute (NCI).
“Take a patient with BRAF wild-type melanoma. Essentially, we’d be telling that patient we have nothing to offer them because we don’t have data on how well that patient may do on these therapies…. Going forward, this is something the U.S. Food and Drug Administration, Friends of Cancer Research, and the NCI are interested in correcting,” he said.
Dr. Sharon enlightened listeners on this topic—and described an NCI-sponsored trial addressing this issue—at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium.1
Checkpoint Inhibitors in Patients With HIV
Single-agent pembrolizumab was evaluated in a phase I study of 30 patients with advanced cancer (variety of tumor types) who were receiving antiretroviral treatment for human immunodeficiency virus (HIV).2 Cohorts had CD4 thresholds of 100 to 199, 200 to 350, and > 350 CD4-positive T cells/μL. All patients were considered healthy, from an HIV perspective, as a result of antiretroviral therapy.
Among 30 patients, there was 1 complete response, 2 partial responses, and 2 case of stable disease for more than 24 weeks. Activity was noted in patients with lung cancer, non-Hodgkin lymphoma, Kaposi sarcoma, and liver cancer. There was no worsening of HIV and no significant increase in CD4 counts, reported Dr. Sharon, a co-investigator of the study.
One severe adverse event was observed in a 61-year-old man with non-Hodgkin lymphoma and Kaposi’s sarcoma—polyclonal KS herpesvirus (KSHV)-associated B-cell lymphoproliferation. After the second cycle of pembrolizumab, the patient developed polyclonal KSHV-associated B-cell lymphoproliferation and died. This type of adverse event was not observed in any of the five other patients with Kaposi sarcoma or in the two patients with primary effusion lymphoma.
Without a dedicated trial like CITN-12, this patient’s case could have ended up in the literature as a case report, Dr. Sharon proposed, and the ensuing recommendation by some experts would be to withhold effective immunotherapy from all patients who are HIV-positive. This would have been an unfortunate mistake, in his opinion: “This illustrates why we need to think about prospective clinical trials” in immunocompromised populations, he emphasized.
“Our hope with this study was to influence not only NCI trials, but also trials being conducted by industry,” stated Dr. Sharon, adding that the overwhelming majority of NCI-sponsored immune checkpoint inhibitor trials already allow enrollment of patients with HIV. Prospective evaluation of pembrolizumab as first-line systemic therapy for Kaposi sarcoma is ongoing.
Small Study in Patients With Autoimmune Disorders
Although not a prospective study, an analysis of 39 patients with cancer who had autoimmune disorders, presented at the Symposium by investigators from Ochsner Health System, New Orleans, found a potential increase in the odds of antitumor response among patients experiencing a disease flare. “However, the confidence interval is wide,” said study presenter Karine Tawagi, MD.3
A flare of autoimmune disorders or a new immune-related adverse event was observed in 8 patients (21%) and 9 patients (23%), respectively, and were generally manageable. The response rate was also higher among these patients (combined, 43%) than among those with no flares or immune-related adverse events (12%; P = .0475). Patients who experienced an autoimmune disorder flare or immune-related adverse event were more than five times as likely to have a radiographic response (odds ratio = 5.5; 95% confidence interval = 0.87–40.3).
“Patients with autoimmune disorders should be considered for checkpoint inhibitors, if that is the best course of recommended treatment, and should also not be excluded from clinical trials involving checkpoint inhibitors,” Dr. Tawagi concluded.
Checkpoint Inhibitors in Patients With Autoimmune Disorders
“Patients with autoimmune disease are, in a sense, similar to those with HIV…. However, I don’t think we have the same level of confidence to allow these patients on all of our trials,” Dr. Sharon continued.
Retrospective analyses of the use of checkpoint inhibitors in patients with cancer and various autommune diseases were performed and published in several papers. In a landmark retrospective analysis, one multinational study team evaluated the use of agents targeting the programmed cell death protein 1 (PD-1) in 52 patients with advanced melanoma and a variety of autoimmune disorders.4 Half had some type of rheumatologic disease; others included mostly dermatologic, neurologic, and endocrine diseases. Clinically active disease was reported by 29% of patients; 62% were not receiving immunosuppression, whereas others were receiving steroidal and nonsteroidal agents.
The study found the response rate to anti–PD-1 treatment to be 33%, and the incidence of flares requiring immunosuppression was 38%. “Flare” was evaluated in terms of the time to flare, grade, and disease-specific types of flares. Almost all these flares were grade 1 or 2 and were easily managed. The results support the safe and effective use of anti–PD-1 agents in patients with preexisting autoimmune disease, the authors concluded.
One recent publication noted by Dr. Sharon showed the occurrence of an erosive deforming inflammatory arthritis in a patient with cervical adenocarcinoma, which emerged after the first infusion of nivolumab.5 Unfortunately, for this patient and others like her who develop unusual symptoms during treatment, baseline images have not been available for comparison, he added. These findings suggest a need for prospective evaluation of immune checkpoint inhibitors in patients with preexisting autoimmunity and a diagnosis of cancer, to better assess the risk for this vulnerable population of patients.
Prospective Clinical Trial Underway
Retrospective studies have looked at symptoms and outcomes among patients with cancer who have autoimmune disease and been treated with checkpoint inhibitors, but they have suffered from heterogeneity, recall bias, differences in disease severity at baseline, inconsistent definitions of “flare,” and lack of consistent management guidelines. “We elected to try something different,” Dr. Sharon said.
Dr. Sharon and Hussein Tawbi, MD, of The University of Texas MD Anderson Cancer Center, are therefore spearheading a prospective multicenter NCI-sponsored study of nivolumab in patients with preexisting autoimmune disease. Included in the study are cohorts with dermatomyositis/systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, and a variety of less common disorders. These separate cohorts are being overseen by experts in those particular diseases. The trial (ClinicalTrials.gov identifier NCT03816345) is now open and active.
The study’s primary objective is to understand the toxicities associated with nivolumab in patients with these autoimmune disorders. It also aims to provide specific management recommendations based on autoimmune disease severity; determine the efficacy of nivolumab in the individual cohorts; and determine the pharmacodynamic impact of nivolumab on serum chemokines, circulating immune cells, and other potential biomarkers of response and toxicity. Ultimately, these findings could set the stage for future combinatorial therapy in the autoimmune population, he said.
Dr. Sharon concluded: “Our goal is to bring these particular fields together to better understand what’s happening from the autoimmune disease perspective and from the cancer perspective…and to arrive at a point where, when we have patients with autoimmune disease in whom immunotherapy is appropriate, we never turn them away simply because we don’t know enough about how their immune system will react.”