Immunotherapy in Thymic Epithelial Tumors -- 'Risky Business'?

Roxanne Nelson, BSN, RN

July 10, 2018

Immunotherapy with the checkpoint inhibitor pembrolizumab (Keytruda, Merck) has demonstrated encouraging antitumor activity and a durable response in patients with advanced thymic epithelial tumors, according to new findings.

In a phase 2 trial that included 33 patients with both thymic carcinoma and thymoma, seven patients achieved a partial response, and 19 had stable disease.

The study was published online June 15 in the Journal of Clinical Oncology.

Thymic epithelial tumors are classified as either thymoma or thymic carcinoma. They are rare in adults, and complete surgical resection is the only potentially curative option. Palliative chemotherapy is indicated in the metastatic setting. These tumors are known to be sensitive to platinum-based regimens as first-line therapy. Options are limited following the failure of platinum-based chemotherapy, the authors note.

However, an expert considers the use of pembrolizumab and other checkpoint inhibitors to be "risky business" in patients with thymic epithelial neoplasms.

In an accompanying podcast, Jonathan W. Riess, MD, assistant professor of medicine at the University of California, Davis, pointed out that there was a high rate of severe immune-related adverse events, which has to be taken into account when considering use of these agents.

Substantial and severe immune-related adverse events were observed. Dr Jonathan Reiss

The study met its primary endpoint regarding prerequisite number of responses, "but substantial and severe immune-related adverse events were observed," he noted. "Five of seven patients with thymoma — that's 74.1% — had grade 3 or 4 immune-related adverse events, such as hepatitis, myocarditis, and colitis."

Owing to the high rate of these events, the study was modified to exclude patients with thymoma and any autoimmune diseases, Riess explained.

The rate of immune-related adverse events was lower in patients with thymic carcinoma (4 of 26 patients; 15.4%), he noted.

"In my opinion, I would not recommend treatment with programmed cell death [PD-1] or PDL-1 [programmed death ligand–1] checkpoint inhibitors in patients with thymoma," he said. "I think the rate of immune-related toxicity is too great to warrant treating thymoma patients with PD-1 or PDL-1 immune checkpoint blockade."

I think the rate of immune-related toxicity is too great to warrant treating thymoma patients. Dr Jonathan Reiss

For thymic carcinoma, Riess feels that these immunotherapies can be considered in patients who have no history of autoimmune diseases, who have experienced disease progression on prior treatments, and who have high PD1 expression. He advises having extensive discussion with patients about the risks, and that patients be closely monitored for toxicity.

Antitumor Activity Observed

The new study was led by Jinhyun Cho, MD, from Inha University School of Medicine, Incheon, Republic of Korea, who decided to explore the use of anti-PD-1/PD-L1 agents after finding that thymic epithelial tumors frequently show PDL-1 expression (in 70% of patients).

The phase 2 study involved 33 patients with advanced thymic epithelial tumors who experienced disease progression after at least one line of systemic treatment with platinum-based chemotherapy.

Within this cohort, 26 patients had thymic carcinoma, and seven had thymoma; 19 patients (57.3%) had received at least two prior lines of systemic chemotherapy, including platinum-based regimens. All patients received at least one dose of pembrolizumab. The median duration of follow-up was 14.9 months.

Among the seven patients with thymoma, two patients (28.6%) achieved a partial response, and five (71.6%) had stable disease, for an overall response rate (ORR) of 28.6% (95% confidence interval, 8.2% to 64.1%). The disease control rate in this subgroup was 100%; the median duration of response was not reached.

In the group of 26 patients with thymic carcinoma, five (19.2%) achieved a partial response, and 14 (53.8%) had stable disease (including one patient who had an unconfirmed partial response), for an ORR of 19.2% and a disease control rate of 73.1%. The median duration of response was 9.7 months.

The median progression-free survival was 6.1 months for both groups. The median overall survival was 14.5 months for the thymic carcinoma group; it was not reached for patients with thymoma. One thymoma patient and five thymic carcinoma patients were still receiving pembrolizumab treatment at the time of data cutoff (January 18, 2018).

The majority of patients (n = 28; 84.8%) experienced disease progression, and 17 (51.5%) died; 16 (48.5%) patients died from disease progression, and one died from systemic cytomegalovirus infection.

High Rate of Immune-Related Events

There was a high rate of immune-related adverse events, especially among the thymoma patients. Grade 3/4 events were reported in five (71.4%) thymoma patients; these events included myocarditis (n = 3; 42.9%), hepatitis (n = 2; 28.6%), thyroiditis (n = 1; 14.3%), colitis (n = 1; 14.3%), conjunctivitis (n = 1; 14.3%), and nephritis (n = 1; 14.3%).

Among patients with thymic carcinoma, four (15.4%) reported grade 3 or 4 events; these included hepatitis (n = 2; 7.7%), myasthenia gravis (n = 2; 7.7%), and subacute myoclonus (n = 1; 3.8%). In addition, three patients who had a prior previous history of autoimmune syndrome developed severe immune-related events during treatment. Eight patients discontinued pembrolizumab treatment because of toxicity.

Tumor samples were evaluated for PD-L1 expression. Five of 14 patients (35.7%) whose tumor expressed high PD-L1 achieved a partial response. There were no responses among patients with low PD-L1 expression (P = .034). There were no significant differences in the development of severe adverse events with respect to PD-L1 status (cutoff value of 50%; hazard ratio, 3.0; P = .242).

The authors conclude that pembrolizumab showed "encouraging antitumor activity in patients with refractory or relapsed thymic epithelial tumors." But they agree with Riess that, given the relatively high incidence of immune-related adverse events, especially in patients with thymoma, "treatment with an immune checkpoint inhibitor should be avoided in patients with thymoma.

"Early detection and management of immune-related adverse events is also critical in pembrolizumab treatment adherence and retention of patients with thymic carcinoma," they add.

The study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, which is funded by the Ministry of Health and Welfare, Republic of Korea. Several coauthors have disclosed relationships with industry, including Merck, the manufacturer of pembrolizumab.

J Clin Oncol. Published online June 15, 2018. Abstract

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