Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02)

Abstract

PURPOSE As yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1) inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard chemotherapy. PATIENTS AND METHODS In this single-arm, multicenter phase II study, patients with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous infusion until confirmed disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). The secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS Among all 190 patients, the ORR was 20.5% with median DOR 12.8 months, median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were 27.1% and 19.4% in PD-L1+ and PD-L1− patients, respectively ( P = .31). Patients with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28 had significantly better ORR than those with <50% decrease, 48.3% versus 5.7% ( P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base in the cohort and had no predictive value for response. Whole-exome sequencing results from 174 patients revealed that the patients with genomic amplification in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab. CONCLUSION The POLARIS-02 study demonstrated a manageable safety profile and durable clinical response of toripalimab in patients with chemorefractory metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with favorable response.

Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape

“…1B). Consistent with previous studies, TP53 was the most significantly mutated gene (n = 10; q = 1.1 × 10 −6 ), followed by TRAF3, NFKBIA, AEBP1, and NLRC5; all of which have been reported to regulate NF-κB signaling 4,[8][9][10][11][12][13][14]17 . In addition, significant somatic aberrations detected in HLA-A and NLRC5 suggest impairment of antigen presentation while PTEN mutations may activate the PI3K pathway [8][9][10] .…”

“…Notably, a single recurrent mutation (chr2:10097565 C > T) was identified in four tumors from three patients (Supplementary figure 2). Despite reports from several genome sequencing studies conducted thus far, this represents the first recurrent mutation identified in the non-coding region of NPC genome [8][9][10][11][12][13][14] . Furthermore, this mutation results in a gain of a putative NFKB1/p50 binding sequence upstream of RRM2 which has been reported to be associated with NF-κB-signaling activation 18 .…”

“…Together, these recurrent SCNAs are consistent with the previous genome-wide studies and accurately defined NPC-associated genes including CD274 and the type I interferon genes 2,8,20 . Importantly, using microdissected tumor samples and WGS, we detected the highest frequencies of homozygous deletions of the critical tumor suppressor genes CDKN2A, TGFBR2, TRAF3, and potential synthetic lethal target MTAP amongst NPC genomic reports thus far [8][9][10][11][12][13][14] .…”

“…MTAP deletion is druggable in primary and recurrent NPC. Previous exome studies have shown that there are many potentially druggable targets scattered across the NPC genome 2,[8][9][10][11]13,14 . Our whole-genome study also revealed hotspot aberrations of common drug targets including PIK3CA, EGFR, BRAF, MET, and ERBB2, yet these appeared infrequently (totaling 2.9%, 2/70).…”

“…As an immediate background to the present study, wholeexome, genome, and targeted DNA-sequencing studies of primary and recurrent NPCs have revealed various somatic alterations that drive constitutive nuclear factor kappa B (NF-κB) signaling activation in up to 40% of cases [8][9][10][11][12][13][14] . Our previous work, in this context, isolating the malignant NPC cells from their abundant lymphocytic infiltrate by microdissection, used exome sequencing to identify two driver genes in the NF-κB pathway, TRAF3 and CYLD 8 .…”