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An investigational PD-1 inhibitor combined with chemotherapy showed impressive activity in treatment-naive patients with advanced extranodal natural killer/T-cell lymphoma (ENKTL), according to results from a small Chinese single-arm phase II trial.

At a median follow-up of 21 months, 29 of 34 patients (85%) treated with sintilimab and P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) achieved a complete response, which surpassed the prespecified complete response rate of 62% and met the primary endpoint of the study, reported Wen-Long Zhong, MD, of the Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues.

Furthermore, the combination induced partial responses in the other five patients enrolled in the trial. Thus, "all patients showed objective response to the combination therapy, which is unprecedented for this tumor type," the authors wrote in .

"To the best of our knowledge, this is the first phase II trial on the activity and safety of anti-PD-1 antibody plus chemotherapy in treatment-naive patients with advanced ENKTL," they noted.

ENKTL is a rare and aggressive non-Hodgkin lymphoma more frequently seen in populations from Asia and South America, and less frequently in the U.S. and Europe, where it represents 0.2%-0.4% of all newly diagnosed non-Hodgkin lymphomas. Regimens containing L-asparaginase or pegaspargase are considered the standard first-line therapy for advanced ENKTL, but these patients have a poor prognosis, with a median overall survival (OS) of approximately 24 months.

P-GEMOX is among the preferred regimens for advanced ENKTL in National Comprehensive Cancer Network , alongside modified SMILE (steroid [dexamethasone], methotrexate, ifosfamide, pegaspargase, and etoposide) and DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase). PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) are preferred options in the relapsed/refractory setting.

"There remains an unmet medical need for more effective therapeutic options to improve clinical outcomes in this population," Zhong and team wrote. Thus, in this trial they wanted to assess the role of first-line sintilimab -- a PD-1 inhibitor approved in China for multiple indications, but not yet approved in the U.S. -- in combination with chemotherapy in advanced ENKTL.

"The high [overall response rate] in this trial, when considered within the generally unsatisfactory findings with chemotherapy in the literature, has provided rationale to conduct phase III trials of sintilimab plus P-GEMOX in patients with advanced ENKTL," they noted.

Median progression-free survival (PFS), disease-free survival (DFS), and OS were not reached. The 12-month PFS, DFS, and OS rates were 79%, 89%, and 100%, respectively, while the 24-month rates were 64%, 72%, and 91%. The 36-month OS rate was 76%.

In a , Shu-Nan Qi, MD, and Ye-Xiong Li, MD, both of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, said that while the study "provides a promising systemic treatment choice for patients with advanced-stage ENKTL," it had limitations, including a small sample size and a short follow-up period.

They said that 24-month PFS is a reliable predictor of 5-year overall survival in ENKTL, but more than half of the patients in this study were followed for less than 2 years, "leading to incomplete assessments of pivotal landmark survival."

"Whether the improvement in response could transfer to long-term survival benefit and a survival plateau could be attained remains unclear," they wrote.

The included 34 patients; median age was 39 years, and 74% were men. The median duration of treatment was 16 months, with 32 patients completing the planned six cycles of induction chemotherapy, and two discontinuing treatment due to disease progression. Patients received a median of 13 cycles of sintilimab maintenance therapy.

The patients were followed for a median duration of 21 months. At data cutoff, 10 patients had experienced disease progression, and three had died -- one due to hemophagocytic syndrome, one to disease progression, and one to unknown cause -- none of which were considered treatment related.

The most common grade 3/4 treatment-related adverse events were neutropenia (50% of patients), anemia (29%), and hypertriglyceridemia (29%). Hypothyroidism was the most frequent immune-related adverse event (53%), and included grade 3 hypothyroidism in one patient who required treatment termination. No severe adverse events occurred.

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