Takashi Seto, MD
Researchers from Japan recommended against further development of nivolumab (Opdivo) for patients with previously treated unresectable or recurrent thymic carcinoma based on their findings from the phase II PRIMER study, presented at the 2018 European Lung Cancer Conference.
“Thymic carcinoma carries a poor prognosis,” said Takashi Seto, MD, Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan. “Treatment options are limited, especially after relapse.”
Therefore, Seto and colleagues conducted the open-label, 2-stage, multicenter, single-arm, phase II PRIMER study--funded by the Japan Agency for Medical Research and Development—designed to evaluate nivolumab in 15 patients with unresectable or recurrent thymic cancer. Nivolumab was administered at 3 mg/kg IV every 2 weeks for a median 8 cycles (range, 3-29).
Response rate (RR) served as the primary endpoint, while secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety.
All patients were Japanese (male, 12 patients) with a median age of 55 years (range, 34-70). Squamous histology was confirmed in 13 patients, 11 patients were ECOG-PS 1, and all had measurable disease that had progressed after at least 1 previous platinum-based chemotherapy or radiotherapy treatment. Half of patients were ex-smokers and one was current. None of the patients had a history of autoimmune disease.
PRIMER had a planned sample size of 15 patients for the first stage and was to proceed to a second stage of enrolling an additional 15 patients with a threshold RR of 5%, an expected RR of 20%, one-sided alpha of 5%, and power of 80%
At the primary analysis, carried out after a median follow-up of 3.8 months (range, 1.4-2.0), RR by central review was 0% (95% CI, 0–21.8) and the study was not taken forward.
“Because the early termination criteria at the first stage of less than one responder was fulfilled, patient accrual was terminated,” Seto said.
Median PFS was 3.8 months (95% CI; 1.9–5.6), and the 12-month PFS rate was 13.3% (95% CI; 2.2–34.6). Four patients had progressive disease. However, Seto noted that 11 patients achieved stable disease with nivolumab, which lasted for 24 or more weeks in 5 patients, providing a DCR of 73.3% (95% CI, 44.9-92.2). Two patients remain on nivolumab therapy.
No patient discontinued treatment due to an adverse event (AE). Two patients experienced a serious treatment-related AE, which included grade 3 AST increase and grade 2 adrenal insufficiency.
“Despite the small number of patients, our results did not show tumor shrinkage with nivolumab (which) suggests further development of nivolumab is not recommended in previously treated unresectable or recurrent thymic carcinoma,” Seto said.
Session chair Maurice Perol, MD, Centre Léon Bérard in Lyon, France, questioned whether 12 weeks was too short for an evaluation of a primary endpoint. He further asked whether Seto thought, in light of the results from the PRIMER study, the European Organisation for Research and treatment of Cancer (EORTC) should continue with its planned NIVOTHYM trial of nivolumab for the treatment of patiens with type B3 thymoma and thymic carcinoma.
“Thymoma is easier to treat than thymic carcinoma,” Seto replied, and further responded that the planned trial should provide interesting results, especially in non-Japanese patients.
Invited discussant, Nicolas Girad, MD, Institut du Thorax Curie Montsouris in Paris, France, and an investigator on the EORTC trial, explained that current treatment consists primarily of cisplatin, doxorubicin, and cyclophosphamide (CAP). He added that data from RYTHMIC, a French thymic carcinoma network, showed this treatment option yields a 36% partial response rate, 36% stable disease rate, and 28% disease progression rate.
He rationalized that researchers should pursue immunotherapy as a treatment option for this population because these tumors frequently show high PD-L1 expression. In addition, patients with thymic carcinoma who have been treated with pembrolizumab in a phase II study demonstrated a RR of 23%, with 3% of patients who experienced a complete response and 20% with partial responses. Treatment also yielded a median duration of response of 22 months and median PFS of 4.2 months.
The NIVOTHYM study is currently accruing patients with relapsed and/or advanced thymoma B3 and thymic carcinoma who are not candidates for curative-intent radical treatment who have undergone at least 1 previous line of platinum-based chemotherapy for advanced disease, Girad added.
<<< 2018 European Lung Cancer Congress
- Giaconne G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncology. 2018;19(3):347-355. doi:10.1016/S1470-2045(18)30062-7.
- Seto T, Katsuya Y, Horinouchi H, et al. Primary result of an investigator-initiated phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study (NCCH1505). Abstract 112O. Presented at: the 2018 European Lung Cancer Conference; April 11-14; Geneva, Switzerland.