Anti–PD-1 therapies may emerge as first-line SoC for R/M NPC

Adding the anti–PD-1 monoclonal antibodies toripalimab or camrelizumab to first-line standard of care (SoC) with gemcitabine and cisplatin (GC) significantly improves progression-free survival (PFS) vs GC alone in patients with recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC), two phase III trials have shown. These results, reported at the 2021 American Society of Clinical Oncology Annual Meeting (ASCO 2021), may position toripalimab or camrelizumab in combination with GC as a new first-line SoC in this patient population.

Toripalimab + chemo: PFS, ORR & DoR benefits

Toripalimab, a humanized immunoglobulin G4κ (IgG4κ) PD-1 monoclonal antibody approved in China in February 2021 for third-line treatment of R/M NPC, was previously shown to provide durable clinical response (objective response rate [ORR], 20.5 percent; median duration of response [DoR], 12.8 months) with a manageable safety profile in patients with R/M NPC who had failed ≥2 lines of chemotherapy in the phase II POLARIS-02 trial. [J Clin Oncol 2021;39:704-712] This approval was followed by filing of a biologics license application for treatment of R/M NPC with the US FDA in March 2021, after the US FDA granted a breakthrough therapy designation in September 2020 for use of toripalimab in this patient population.

The phase III JUPITER-02 trial was one of the first NPC studies to evaluate an anti–PD-1 therapy in combination with first-line chemotherapy. Conducted in NPC-endemic regions including China, Taiwan and Singapore, the trial included 289 patients with primary metastatic NPC or recurrent NPC after curative-intent therapy, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1. The patients were randomized to receive first-line treatment with toripalimab 240 mg (n=146; median age, 46 years; male, 85 percent; Asian, 100 percent; prior radiation therapy [RT], 58 percent; PD-L1–positive, 75 percent) or placebo (n=143; median age, 51 years; male, 81 percent; Asian, 100 percent; prior RT, 61 percent; PD-L1–positive, 76 percent) on day 1, in combination with gemcitabine 1,000 mg/m² on days 1 and 8 and cisplatin 80 mg/m² on day 1, Q3W, for up to six cycles, followed by maintenance toripalimab or placebo Q3W in the respective arms. [Xu RH, et al, ASCO 2021, abstract LBA2]

“At the interim analysis, toripalimab plus GC demonstrated a significant improvement in the primary endpoint of PFS by blinded independent review committee [BIRC] assessment vs placebo plus GC. Median PFS was 11.7 months in the toripalimab/GC arm vs 8.0 months in the placebo/GC arm, with a stratified hazard ratio [HR] of 0.52 [95 percent confidence interval (CI), 0.36 to 0.74; p=0.0003], while 1-year PFS rate was 49.4 percent vs 27.9 percent,” reported investigator Professor Rui-Hua Xu of Sun Yat-Sen University Cancer Center, Guangzhou, China. “This led the BIRC to recommend unblinding of the trial.”

“PFS improvement was observed with the toripalimab/GC combination vs placebo/GC across all key subgroups analyzed, including in patients with PD-L1–positive tumours [n=218; HR, 0.59; 95 percent CI, 0.388 to 0.893] and those with PD-L1–negative tumours [n=45; HR, 0.35; 95 percent CI, 0.153 to 0.808] at baseline,” said Xu.

Overall survival (OS) results, although still immature, showed a stratified HR of 0.603 (95 percent CI, 0.364 to 0.997; p=0.0462), with 1-year and 2-year OS rates of 91.6 percent vs 87.1 percent and 77.8 percent vs 63.3 percent, respectively, for toripalimab/GC vs placebo/GC.

Adding toripalimab to GC also significantly improved ORR (77.4 percent vs 66.4 percent; p=0.0335) and median DoR (10.0 months vs 5.7 months; HR, 0.50; 95 percent CI, 0.33 to 0.78; p=0.0014) vs GC alone.

In JUPITER-02, the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was similar between the toripalimab/GC and placebo/GC arms (89 percent vs 89.5 percent), while immune-related AEs were more common with toripalimab/GC (any grade, 39.7 percent vs 18.9 percent; grade ≥3, 7.5 percent vs 0.7 percent).

“The most common TEAEs were haematological events in both arms, which were attributable to the CG regimen. The most common immune-related AE was hypothyroidism [any grade, 30.8 percent vs 16.8 percent for toripalimab/GC vs placebo/GC; grade ≥3, 0 in both arms],” said Xu. “The safety profile of toripalimab plus GC was manageable and similar to that of GC alone, with no new safety signals identified.”

“Our findings suggest that toripalimab plus GC may represent a new first-line SoC for patients with R/M NPC,” Xu concluded.

“Treatment advances for late-stage NPC have lagged behind those for other cancers. Findings of the JUPITER-02 study offer new hope for these patients, and may represent a paradigm shift in their care,” said Dr Julie Gralow, ASCO Chief Medical Officer and Executive Vice President, who was not affiliated with the study.

Camrelizumab + chemo: Improved PFS & DoR

Camrelizumab, a humanized IgG4κ PD-1 monoclonal antibody, has previously shown promising anticancer activity and a manageable toxicity profile when used in combination with GC as first-line therapy for R/M NPC in a phase I trial. [Lancet Oncol 2018;19:1338-1350] In the phase III multicentre CAPTAIN-1st trial, camrelizumab plus GC demonstrated a significant improvement in PFS vs placebo plus GC in first-line treatment of R/M NPC. [Zhang L, et al, ASCO 2021, abstract 6000; Lancet Oncol 2021;doi:10.1016/S1470-2045(21)00302-8]

The CAPTAIN-1st trial included 263 patients with an ECOG PS of 0–1, who were randomized to receive camrelizumab 200 mg (n=134; median age, 52 years; male, 84 percent; prior concurrent chemoradiotherapy [CRT], 64 percent) or placebo (n=129; median age, 49 years; male, 81 percent; prior concurrent CRT, 64 percent) on day 1, in combination with gemcitabine 1,000 mg/m² on days 1 and 8 and cisplatin 80 mg/m² on day 1, Q3W, for 4–6 cycles, followed by maintenance camrelizumab or placebo Q3W in the respective arms.

“The primary endpoint of PFS by independent review committee assessment was significantly improved in the camrelizumab/GC vs placebo/GC arm. Median PFS was 10.8 months vs 6.9 months [HR, 0.51; 95 percent CI, 0.37 to 0.69; p<0.0001], while 12-month and 18-month PFS rates were 45.8 percent vs 20.5 percent and 34.8 percent vs 12.7 percent, respectively,” reported investigator Dr Li Zhang of Sun Yat-Sen University Cancer Center, Guangzhou, China. “A consistent PFS benefit of camrelizumab/GC was observed across all subgroups analyzed.” [Zhang L, et al, ASCO 2021, abstract 6000]

While ORR was similar between the camrelizumab/GC and placebo/GC arms (88.1 percent vs 80.6 percent; p=0.1063), median DoR was significantly longer with camrelizumab/GC vs placebo/GC (9.9 months vs 5.7 months; HR, 0.48; 95 percent CI, 0.34 to 0.68; <0.0001).

“OS was immature in both groups, but a trend of benefit was observed with camrelizumab/GC vs placebo/GC [median, not reached vs 22.6 months; HR, 0.67; 95 percent CI, 0.41 to 1.11; p=0.0576],” said Zhang.

“The safety profile of camrelizumab plus GC was manageable, with no new signals identified,” he continued. “The most common treatment-related AEs [TRAEs] were leukemia, neutropenia, anaemia, and thrombocytopenia, with comparable frequency and grade between the two arms. Reactive capillary endothelial proliferation and hypothyroidism were the most common immune-related AEs, which were mostly grade 1 or 2 and were more common with camrelizumab/GC vs placebo/GC.”

Grade ≥3 TRAEs were reported in 93 percent vs 90 percent of patients in the camrelizumab/GC vs placebo/GC arm. TRAEs led to treatment discontinuation in 9 percent vs 5 percent and to death in 4 percent vs <1 percent of patients, respectively.

“These results suggest that first-line treatment with camrelizumab plus GC could be a new SoC for patients with R/M NPC,” the investigators concluded.