The addition of tislelizumab to standard chemotherapy continues to show improvement in progression-free survival (PFS) compared with chemotherapy alone in patients with recurrent/metastatic nasopharyngeal cancer (NPC).
"Tislelizumab plus chemotherapy should be used in first-line therapy to deliver maximal clinical benefit to these patients," said lead principal investigator Li Zhang, MD, Professor at the Collaborative Innovation Center for Cancer Medicine at the State Key Laboratory of Oncology in South China and Sun Yat-sen University Cancer, presenting at the April 2022 ASCO Plenary Series session.
NPC accounts for about 133,000 new cancer cases and 80,000 deaths each year worldwide. The prognosis for patients with relapsed/refractory disease treated with first-line chemotherapy remains poor, highlighting the unmet medical need in this setting, Zhang noted.
The current standard treatment for recurrent or metastatic nasopharyngeal cancer is a combination of gemcitabine plus cisplatin. When this study began, tislelizumab had been approved in China for the treatment of other types of cancer, both alone and in combination with chemotherapy. It is a humanized anti-PD-1 monoclonal antibody, and its efficacy has been demonstrated in Phase II and III trials across multiple tumor types, including NPC.
In the Phase III, double-blind, placebo-controlled RATIONALE-309 study, 263 patients with recurrent/metastatic NPC were randomized to receive either tislelizumab plus gemcitabine/cisplatin or placebo plus gemcitabine/cisplatin. The study met its primary endpoint, as first-line tislelizumab plus chemotherapy significantly improved PFS, as assessed by an independent review committee, with an acceptable safety profile.
Updated Analysis
After a median follow-up of 15.5 months, tislelizumab plus chemotherapy continued to demonstrate greater PFS benefit versus placebo plus chemotherapy, as well as a favorable overall survival (OS) benefit. The PFS benefit observed was regardless of PD-L1 expression.
Results showed improvement of median PFS in the tislelizumab plus chemotherapy arm (9.6 months) compared to the placebo plus chemotherapy arm (7.4 months), with a 50 percent lower risk of disease progression. Median PFS after next line of treatment (PFS2) and OS were not yet reached for the tislelizumab plus chemotherapy arm. In the placebo plus chemotherapy arm, PFS2 was 13.9 months and OS was 23 months. The safety profile of tislelizumab plus chemotherapy was manageable in the interim analysis and consistent with previous reports, Zhang noted. No new safety signals were identified.
Sharon Spencer, MD, Professor and Chief of Medical Services at Heersink School of Medicine and an ASCO expert in nasopharyngeal cancer commented: "This study demonstrates that the addition of tislelizumab to chemotherapy extended survival for patients with recurrent or metastatic NPC and the combination provides another treatment option for patients affected by this disease."
Gene expression profiling identified three gene expression clusters as potential biomarkers for efficacy. The GEP analysis was performed using GEP signatures representing both immune and tumor cell characteristics. A greater PFS benefit was observed in patients with a "hot" tumor microenvironment. Dendritic cell activation was positively correlated with PFS benefit and may serve as a potential biomarker for predicting efficacy, Zhang noted.
"At the latest data cutoff, PFS remained consistent with the interim analysis and demonstrated a clinically meaningful improvement for tislelizumab plus chemotherapy versus placebo plus chemotherapy. A numerical OS benefit was observed in the tislelizumab plus chemotherapy arm. Final OS data are still immature. PFS2 was substantially improved for patients treated with tislelizumab plus chemotherapy versus placebo plus chemotherapy," Zhang stated. "This updated analysis of the RATIONALE-309 study indicates that tislelizumab plus chemotherapy may become a standard-of-care first-line therapy for patients with recurrent/metastasized NPC."
Robert Haddad, MD, Professor of Medicine at Harvard University, noted that "PFS2 in favor of the addition of a checkpoint inhibitor to chemotherapy is new, important information. It shows the importance of triple therapy in the context of this disease. The addition of a checkpoint inhibitor to gemcitabine/cisplatin improves PFS and shows trends for favorable OS in non-keratinizing and EBV-related NPC." National guidelines have been updated to reflect this substantial benefit.
Haddad highlighted two other randomized, placebo-controlled, Phase III trials of PD-1 inhibitors combined with gemcitabine/cisplatin. JUPITER-02 with toripalimab plus this chemotherapy combination and CAPTAIN-1st with camrelizumab plus gemcitabine/cisplatin found similar robust improvements in PFS, he noted.
"We now have three randomized, Phase III studies that show robust improvement in PFS. If we combine three drugs early on, we see significant improvement in PFS," Haddad said. "Gemcitabine/cisplatin plus PD-1 inhibition represents a reasonable approach for recurrent/metastatic NPC."
He noted that the next step is to move PD-1 inhibition to the upfront and curable setting as part of neoadjuvant and definitive therapy.
Mark L. Fuerst is a contributing writer.