Frontline Sintilimab Triplet Improves PFS for Advanced Nonsquamous NSCLC

Sintilimab (Tyvyt) in combination with platinum and pemetrexed chemotherapy as frontline treatment of patients with locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) improved survival and responses with durable responses observed, according to findings from the ORIENT-11 trial.¹

Li Zhang, MD, of the Department of Medical Oncology at Sun Yat-Sen University Cancer Center in China, presented the interim results of the phase 3 study in a presentation during the WCLC 2020 Virtual Presidential Symposium.

“The addition of sintilimab to pemetrexed and platinum significantly improved PFS compared to the placebo combination,” Zhang said when presenting the results. “The benefit was seen across key clinical subgroups.”

Sintilimab is a investigational fully human IgG4 monoclonal antibody directed against PD-1. In a prior phase 1b trial of the combination, sintilimab plus chemotherapy demonstrated a tolerable safety profile and promising efficacy as frontline treatment of patients with advanced or metastatic NSCLC.² In nonsquamous patients, the objective response rate (ORR) was 68.4% (95% CI, 43.4%-87.4%) and in squamous patients the ORR was 64.7% (95% CI, 38.3%-85.8%). The median progression-free survival (PFS) was 11.4 months and 6.5 months for nonsquamous and squamous patients, respectively.

ORIENT-11 (NCT03607539) is a randomized, double-blind phase 3 trial that explored the safety and efficacy of sintilimab in combination with pemetrexed and platinum chemotherapy as treatment of patients with treatment-naïve nonsquamous NSCLC.

The study enrolled 397 patients with previously untreated nonsquamous stage IIIB/C NSCLC who were ineligible for surgery or local therapy, had no EGFR or ALK genetic alterations, and an ECOG performance status of 0 or 1. Patients were randomized 2:1 to either sintilimab and chemotherapy or chemotherapy and placebo and were stratified by gender, platinum, and PD-L1 expression.

In the investigational arm, patients received 200 mg sintilimab plus 500 mg/m2 pemetrexed and 75 mg/m2 cisplatin or AUC 5 carboplatin every 3 weeks for a total of 4 cycles. This was followed by sintilimab 200 mg and pemetrexed 500 mg/m2 administered every 3 weeks for up to 2 years. In the control arm, placebo was also administered for up to 2 years with pemetrexed, at which point crossover to the sintilimab arm was allowed.

The primary end point was PFS by independent radiologic review committee (IRRC) and secondary end points included overall survival (OS), ORR, duration of response (DOR), time to response, and safety.

The study had 90% power to detect a hazard ratio for PFS of 0.65 at a one-sided alpha of 0.025. Protocol allowed for 1 interim analysis to be completed when 70% of the required PFS events had occurred. This interim analysis took place after 198 events had occurred with a median follow-up of 8.9 months (range, 0.6-14.8).

Of the 397 patients enrolled, 266 were randomized to the sintilimab arm, of which 56.8% of patients in this arm are still receiving treatment. A total of 131 patients were randomized to the placebo arm, of which 35.1% of patients are ongoing and 31.3% crossed over to receive sintilimab.

Baseline characteristics were comparable between the 2 arms. The median age of patients was 61 in both arms (range, 30-75), and about three-quarters of patients were male and had an ECOG performance status of 1. The majority of patients in both arms had stage IV disease, were current or former smokers, had PD-L1 expression in terms of a tumor proportion score (TPS) ≥1%, and received carboplatin.

The median PFS in the sintilimab arm was 8.9 months (95% CI, 7.1-11.3) compared with 5.0 months (95% CI, 4.8-6.2) with placebo (HR, 0.482; 95% CI, 0.362-0.643; P <.00001). PFS findings consistently favored the sintilimab combination across all subgroups.

By PD-L1 subgroups, the median PFS in the group of patients with TPS <1% was 7.3 months with the addition of sintilimab versus 5.1 months without (HR, 0.664; 95% CI, 0.406-1.086). In the TPS 1%-49% group, the median PFS was 7.1 versus 4.8 months with and without sintilimab, respectively (HR, 0.503; 95% CI, 0.276-0.918), and in patients with TPS ≥50%, the median PFS was not reached with sintilimab versus 5.0 months without (HR, 0.310; 95% CI, 0.197-0.489).

The median OS was not reached In either arm (HR, 0.609; 95% CI, 0.400-0.926; P = .01921). At 6 months, the OS rate was 89.6% in the sintilimab combination arm compared with 80.4% in the chemotherapy-alone arm.

By IRRC, the ORR in the sintilimab-plus-chemotherapy arm was 51.9%, with a complete response observed in 1 patient, compared with 29.8% in the placebo-plus-chemotherapy arm, resulting in a delta of 21.6 percentage points (95% CI, 11.6%-31.1%). The disease control rate was 86.8% with the sintilimab combination and 75.6% with the chemotherapy doublet.

Median DOR was not reached in the sintilimab triplet arm compared with 5.5 months in the chemotherapy-alone arm. The median time to response was 1.5 months versus 2.6 months in the investigational and control arms, respectively.

In the investigational arm, 88.3% of patients were able to complete all 4 cycles of platinum treatment compared with 83.2% in the control arm.

Adverse events (AEs) were reported in all patients except 1. Grade 3 to 5 AEs were observed in 61.7% of patients treated with the sintilimab combination compared with 58.8% of patients who received placebo. Serious AEs were reported in 28.2% versus 29.8% of patients who received sintilimab versus chemotherapy alone, respectively.

The most common events were anemia, decreased neutrophil counts, decreased white blood cell counts, decreased platelet counts, increased aspartate aminotransferase (AST) levels, increased alanine aminotransferase (ALT) levels, nausea, decreased appetite, asthenia, vomiting, constipation, and pyrexia. Zhang noted that the most common events were all chemotherapy related and the rates were similar between the 2 arms.

AEs led to death in 6 patients in the investigational arm (2.3%) compared with 9 (6.9%) in the control arm. Treatment discontinuation due to AEs was reported in 16 patients (6.0%) versus 11 patients (8.4%) in the sintilimab combination and chemotherapy arms, respectively.

Immune-related AEs (irAEs) were reported in 43.2% of patients who received sintilimab compared with 36.6% who received placebo and 5.6% and 6.1% of these events, respectively, were grade 3 to 5.

The most common irAEs were hypothyroidism, rash, increased AST and ALT levels, increased blood TSH, hyperthyroidism, diarrhea, immune-mediated pneumonitis, decreased blood TSH, increased amylase levels, pruritis, and increased free thyroxine. Of note, the rate of increased amylase was significantly increased in the placebo arm compared with the sintilimab group.

The phase 3 ORIENT-12 trial is ongoing exploring the combination of sintilimab and chemotherapy in patients with previously untreated metastatic squamous NSCLC (NCT03629925).

_References:

_{1. Zhang L, Yang Y, Wang Z, et al. ORIENT-11: sintilimab + pemetrexed + platinum as first-line therapy for locally advanced or metastatic non-squamous NSCLC. Presented at: WCLC 2020 Virtual Presidential Symposium; August 8, 2020.}

_{2. Xu N, Ying K, Wang Z, et al. Phase Ib study of sintilimab in combination with chemotherapy for 1L advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl 15):e20546. doi:10.1200/JCO.2019.37.15_suppl.e20546}