By Jarushka Naidoo, MB, BCH
Posted: April 1, 2019
The U.S. Food and Drug Administration (FDA) has approved immune checkpoint inhibitors for multiple cancer types, including stage III and IV NSCLC, and now SCLC. As approvals have expanded, so too has access to these agents for patients who would not have been eligible to receive them as part of a prospective clinical trial. Patients with active or prior autoimmune conditions, hepatitis B or C, and HIV, as well as those receiving corticosteroids at baseline, may now have access to these agents. This raises important questions regarding safety, appropriate monitoring, and the likelihood of sustaining a successful anticancer response in these patient populations. Several publications have provided guidance in these situations, and future studies are likely to address questions that remain outstanding.
Patients with Known/Active Autoimmune Conditions
In a retrospective multicenter study of 56 patients with NSCLC with known autoimmune conditions who were treated with anti–PD-1 therapies, 26% developed a high-grade immune toxicity, and 13% had a high-grade flare of their known condition.1 However, these patients still sustained a response to therapy comparable to those without autoimmune conditions (22%, mainly second-line NSCLC). Patients who were symptomatic from their autoimmune condition at the start of immunotherapy had a greater chance of a flare of the autoimmune condition. No extra care for these patients, such as a pre-immunotherapy consultation with an organ specialist as is done in some centers, was noted in the study.
In a similar retrospective study in patients with metastatic melanoma, 52 of 119 patients treated with an anti–PD-1 therapy had a known autoimmune condition. Thirty-eight percent had a flare of their known condition requiring immunosuppression, but only 8% overall discontinued treatment for toxicity, and 33% of those who had a known autoimmune condition sustained an antitumor response.2 Although patients with inactive autoimmune disease at the start of treatment were less likely to have a flare than those with active disease, 30% of these patients still had an exacerbation of their underlying disease.
A prospective clinical trial by the National Cancer Institute (primary investigators: Hussein Tawbi, MD, PhD, and Elad Sharon, MD) is being planned to assess the safety of anti–PD-1 in patients with advanced-stage solid malignancies and selected autoimmune conditions, including rheumatoid arthritis, infl ammatory bowel disease, systemic lupus erythematosus, dermatomyositis, and scleroderma.
Hepatitis B and C
In a phase I/II trial (CheckMate 040), nivolumab was administered to patients with advanced hepatocellular carcinoma with or without hepatitis B or C.3 Patients had Child-Pugh scores of less than 7 (dose-escalation) and less than 6 (doseexpansion). Patients with hepatitis B infection were receiving antiviral therapy (viral load < 100 IU/mL). Antiviral therapy was not required for patients with hepatitis C infection. Toxicity profiles were similar and acceptable in both infected and non-infected groups. Patients in both groups responded to therapy, with response rates of 20% (with HCV, 10 of 50) and 14% (with HBV, 7 of 51) respectively, which was similar to the overall response rate in the study population of 20% (42 of 214). These response rates also are comparable to those for uninfected patients who were treated with sorafenib (21%, 12 of 57), as well as for those who were sorafenib naive (23%, 12 of 56). Anti–PD-1 therapy displayed limited antiviral activity, with some changes in hepatitis C virus RNA, and no cases of hepatitis B reactivation or antihepatitis B seroconversion.
It remains an open question as to whether it is safe to administer immune checkpoint blockade to patients with HIV. A prospective clinical trial in France is underway to assess this question in patients with NSCLC (NCT03304093). In addition, other trials are aimed at identifying whether HIV-related malignancies may be responsive to anti–PD-1+/– CTLA-4 (NCT02408861) therapy.
In 640 patients with NSCLC treated with anti–PD-1/-L1 therapy, 88 patients received baseline steroids greater than or equal to 10 mg/day of prednisone or its equivalent.4 Progression-free survival and overall survival were poorer in those receiving baseline steroids versus those receiving no steroids or less than 10 mg/ day of prednisone or equivalent, although it is unclear if there may have been other confounding factors that might have contributed to poorer outcome in this population that required steroids.
These data have supported the cautious use of immune checkpoint blockade in circumstances that would have precluded inclusion into clinical trials. While we await prospective data to support these approaches, it may be clinically appropriate for patients with active autoimmune conditions to be co-treated by their relevant medical subspecialist during immunotherapy, in anticipation of a potential flare of their conditions.
In patients with hepatitis B or C, a hepatology consult prior to treatment and assessment of a Childs-Pugh score is likely to be relevant. In patients already receiving corticosteroids at a dose of 10 mg/day or more of prednisone/equivalent, it may be prudent to reduce this to less than 10 mg/day prior to treatment start, if clinically appropriate. Monitoring of these patients must also be adapted. In certain situations, the patients mentioned above or those receiving combination immune checkpoint inhibition are likely to require more frequent monitoring in an attempt to identify an immune-related adverse event early, for example, by weekly visits or provider phone calls for the first 4 to 6 weeks of therapy. The value of this approach and effects on early diagnosis of an immune-related adverse event must be prospectively assessed, with the knowledge that immune toxicities may occur at unpredictable times in a patient’s treatment course. ✦
About the Author: Dr. Naidoo is an assistant professor of oncology at Johns Hopkins University.
1. Leonardi GC, Gainor JF, Altan M, et al. Safety of Programmed Death-1 Pathway Inhibitors Among Patients With Non-Small-Cell Lung Cancer and Pre-existing Autoimmune Disorders. J Clin Oncol. 2018;36(19):1905-1912.
2. Menzies AM, Johnson DB, Ramanujam S, et al. Anti-PD-1 therapy in patients with advanced melanoma and pre-existing autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28(2):368-376.
3. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502.
4. Arbour KC, Mezquita L, Long N, et al. Deleterious effect of baseline corticosteroids on efficacy of PD-(L)1 blockade on patients with NSCLC. J Clin Oncol. 2018;36(suppl; abstr 9003).