Anti–PD-1 antibodies appear safe in patients with pre-existing autoimmunity

Anti–PD-1 antibodies may safely and effectively treat patients with advanced melanoma who have pre-existing autoimmune disorders or who experienced major toxicity with prior ipilimumab treatment, according to results of a retrospective study.

Although anti–PD-1 antibodies have demonstrated clinical activity and favorable toxicity profiles in various malignancies, occasionally immune-related toxicity can be severe.

Clinical trials designed to evaluate checkpoint immunotherapies have excluded patients with significant pre-existing autoimmune disorders, and only one trial included patients who experienced immune-related adverse events when treated with ipilimumab (Yervoy, Bristol-Meyers Squibb).

“Anti–PD-1 antibodies are more effect and less toxic than ipilimumab. Thus, these agents may be safer to use in patients who are at high risk for autoimmune complications,” Alexander M. Menzies, MD, medical oncologist and senior research fellow at the Melanoma Institute Australia, and colleagues wrote. “However, currently no data exist regarding the safety and efficacy of anti–PD-1 antibodies in patients with pre-existing autoimmune disease, who are at increased risk for developing cancer, and there are minimal data in those that develop significant toxicity with prior ipilimumab,”

The researchers identified 119 patients with advanced melanoma — 52 (median age, 71 years) of whom had pre-existing autoimmune disorders and 67 (median age, 63 years) of whom had major immune-related adverse events that occurred with prior ipilimumab — who were treated with anti–PD-1 antibodies across 13 treatment centers to determine safety and efficacy outcomes.

Pre-existing a utoimmune disorders

Of the patients with pre-existing autoimmune disorders, 58% had received prior ipilimumab and 44% received first-line anti–PD-1 therapy.

At the start of anti–PD-1 therapy, these patients demonstrated active symptoms of autoimmunity — which included rheumatologic conditions (n = 11), psoriasis (n = 3) and severe asthma (n = 1).

Twenty patients with pre-existing autoimmune disease had a flare of an underlying autoimmune disorder a median of 38 days after the first dose of anti–PD-1 antibody. This occurred more often in patients with active symptoms (60%) than in patients with clinically inactive disease (30%).

Flares occurred in 14 patients with rheumatologic disorders, three patients with psoriasis, two patients with immune thrombocytopenic purpura and one patient with Graves’ disease; flares did not occur in any patients with gastrointestinal, neurological or respiratory disorders.

Eight patients temporarily interrupted therapy and two patients discontinued treatment due to a flare of autoimmune disorders.

Fifteen conventional immune-related adverse events occurred, of which five cases were grade 3. Four patients discontinued anti–PD-1 therapy.

Patients with pre-existing autoimmune disease demonstrated a response rate of 33% and a median PFS of 6.2 months (95% CI, 4.2-8.2).

Response rates were similar in those who had autoimmune disease flares (35%) and those who did not (31%).

Median duration of response (range, 2.7-24.6 months) and median OS were not reached in these patients.

Previous severe toxicity

In the group of patients who had experienced a severe adverse event with prior ipilimumab, severe toxicity had included colitis (63%), hepatitis (5%) and hypophysitis (18%). Severe toxicity had resolved in all but one patients at the time of anti–PD-1 therapy initiation.

Two patients had a recurrence of the same ipilimumab immune-related adverse event, whereas 23 patients developed new immune-related adverse events. Eight patients discontinued treatment after they developed pneumonitis, hepatitis, colitis and myasthenia gravis.

There were no treatment-related deaths.

In this cohort, response rate was 40% and median PFS was 7.2 months (95% CI, 3.1-11.3).

Median duration of response (range, 2.6-31.2 months) and median OS were not reached.

The researchers acknowledged the study was limited by its inherent selection bias in both cohorts, the lack of strict classification of activity and severity of autoimmunity and the short duration of follow-up. Also, data on the interval between the last dose of ipilimumab and anti–PD-1 treatment were not available.

“Clinicians may consider anti–PD-1 antibodies for appropriately selected patients with pre-existing autoimmune disease or prior severe immune-related adverse events with ipilimumab, provided there is close monitoring and adherence to standard immune-related adverse event treatment algorithms, and in discussion with experts in major immunotherapy centers,” the researchers wrote. – by Kristie L. Kahl

Disclosures: Menzies reports advisory roles with Chugai and Merck Sharp & Dohme, and honoraria from Bristol-Myers Squibb and Novartis. Please see the full study for a list of all other researchers’ relevant financial disclosures.