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The addition of sintilimab to standard chemotherapy comprised of gemcitabine and platinum significantly improved progression-free survival with acceptable safety in previously untreated patients with advanced or metastatic squamous non–small cell lung cancer.
The addition of sintilimab to standard chemotherapy comprised of gemcitabine and platinum significantly improved progression-free survival with acceptable safety in previously untreated patients with advanced or metastatic squamous non–small cell lung cancer (NSCLC), according to data from the phase 3 ORIENT-12 trial (NCT03629925) recently published in the Journal of Thoracic Oncology.1
At a median follow-up of 12.9 months, the anti–PD-1 antibody plus chemotherapy yielded an resulted in a median PFS of 5.5 months (95% CI, 4.9-6.8) per independent radiographic review committee (IRRC) assessment vs 4.9 months (95% CI, 4.8-5.0) in the chemotherapy-alone arm (HR 0.536; 95 % CI, 0.422-0.681]; P < .00001). At 12 months, the PFS rates in the investigative and control arms were 22.3% (95% CI, 16.0%-29.4%) and 3.1% (95% CI, 1.2-6.7).
Notably, across most of the patient subsets examined, and all the subgroups of PD-L1 tumor proportion score (TPS), PFS benefit favored the sintilimab arm over the chemotherapy-alone arm.
“In this study, the risk of disease progression or death was reduced by 37.9 % at interim analysis and by 46.4 % at updated analysis,” Caicun Zhou, MD, PhD, lead study author and director of the Department of Oncology at Shanghai Pulmonary Hospital in Shanghai, China, stated in a press release.2
Gemcitabine plus platinum represents a standard treatment regimen for patients with squamous NSCLC and it is frequently utilized in Asia. Results from the ECOG 1594 study showed that this regimen improved PFS vs cisplatin plus paclitaxel.3 Notably, gemcitabine has been found to eliminate immunosuppressive cells in vitro, which makes it amenable for combination with an immunotherapy.4 Additionally, data from a phase 1b study has shown that when gemcitabine/paclitaxel was combined with nivolumab (Opdivo), it resulted in a median overall survival (OS) of 11.6 months, with an objective response rate (ORR) of 33%.5
Sintilimab, a potent selective anti–PD-1 antibody, has been shown to have a different binding epitope than that of nivolumab or pembrolizumab (Keytruda). As such, the agent has a greater binding affinity for PD-1. Sintilimab plus gemcitabine/cisplatin demonstrated preliminary safety and efficacy when used as a first-line treatment in patients with squamous NSCLC, according to findings from a phase 1b trial (NCT02937116).6 As such, investigators sought to further examine the agent in combination with gemcitabine/platinum chemotherapy as a frontline approach in this patient population.
The randomized, double-blind, phase 3 ORIENT-12 study enrolled 357 patients with locally advanced or metastatic squamous NSCC who did not harbor EGFR-sensitive mutations or ALK rearrangements.
To be eligible for enrollment, patients needed to be between 18 and 75 years of age, have stage IIIB/IIIC or stage IV squamous disease, and at least 1 measurable lesion per RECIST v1.1 criteria. Moreover, patients needed to have an ECOG performance status of 0 or 1, as well as acceptable hepatic, renal, hematological, and coagulation function. They could not have previously received systemic treatment for advanced and metastatic disease.
Those who had EGFR-sensitive mutations, ALK rearrangements, symptomatic central nervous system metastases, active hepatitis B or hepatitis C virus infection, or who had previously received immune checkpoint blockade treatment were excluded.
Participants were randomized 1:1 to either the sintilimab arm (n = 179) or the placebo arm (n = 178). Those in the sintilimab arm received the agent at a dose of 200 mg intravenously (IV) on day 1 every 3 weeks and patients in both cohorts received IV gemcitabine at 1.0 g/m2 on days 1 and 8 every 3 weeks, and either IV cisplatin at 75 mg/m2 on day 1 every 3 weeks or IV carboplatin at area under the concentration–time curve 5 mg/mL/min on day 1 every 3 weeks for 4 or 6 cycles per investigator decision.
Patients who did not experience disease progression after treatment would continue to receive sintilimab or placebo monotherapy as maintenance treatment every 3 weeks until progression, unacceptable toxicity, or withdrawal.
The primary end point of the study was PFS, per IRRC assessment, and secondary end points included OS, ORR, time to response (TTR), disease control rate (DCR), and duration of response (DOR).7
Among the 357 patients treated on the study, the median age was 63 years, and a majority were male (91.6%) and had an ECOG performance status of 1 (85.4%). Moreover, most patients were former smokers (56.0%) and had stage IV disease at the time of enrollment (76.8%). Most patients received carboplatin as their platinum agent (62.2%), and very few had received prior treatment with radiotherapy (3.4%), or neoadjuvant or adjuvant chemotherapy (5.9%).
In the sintilimab and placebo arms, 151 patients (84.4 %) and 138 patients (77.5 %), respectively, completed at least 4 cycles of platinum treatment. The mean duration of treatment for the 2 arms was 5.9 ± 2.8 months and 5.0 ± 2.4 months, respectively. By March 25, 2020, 138 patients in the sintilimab cohort (77.1 %) and 169 patients in the placebo cohort (94.9 %) had discontinued treatment, mostly because of disease progression.
When the trial was unblinded, and crossover from placebo to sintilimab was permitted, 87 patients in the placebo arm (48.9 %) crossed over to receive sintilimab monotherapy following radiographic disease progression.
At a median follow-up of 8 months, an IRRC-assessed PFS event was reported in 99 patients in the sintilimab arm (55.3 %), and 128 patients in the placebo arm (71.9 %). The median PFS with the sintilimab regimen per investigator assessment was 5.9 months (95 % CI, 5.0-6.9) vs 4.9 months (95 % CI 4.8-5.0) with chemotherapy alone (HR 0.575; 95 % CI, 0.435-0.761; P = .00009).
At the time of the interim analysis, which had a data cutoff of October 15, 2019, the median OS had not yet been reached, although benefit trended toward the sintilimab arm vs the placebo arm (HR 0.567; 95 % CI, 0.353-0.909; P = .01701). The 6-month OS rate with sintilimab was 91.8% (95 % CI, 86.2-95.2) vs 80.6% (95 % CI, 73.6-85.9) with placebo.
Additional data showed that the confirmed ORR per IRRC assessment with sintilimab was 44.7% (95 % CI 37.3%-52.3%) vs 35.4% (95 % CI, 28.4-42.9) with chemotherapy alone. The median DOR in the investigative and control arms was 6.1 months (95 % CI, 4.7-9.6) and 5.1 months (95 % CI, 3.7-5.5), respectively, and the median TTR was 1.4 months (range, 1.2-11.1) and 1.4 months (range, 1.2-2.9), respectively.
In terms of safety, treatment-emergent adverse effects (TEAEs) of any grade occurred in all patients; TEAEs that were grade 3 or higher were reported in 155 patients in the sintilimab arm (86.6%) and 148 patients in the placebo arm (83.1%). Moreover, 26 patients in the sintilimab arm (14.5%) discontinued treatment due to a TEAE vs 29 patients (16.3%) in the placebo arm.
The most common TEAEs of any grade reported in the sintilimab and placebo arms included anemia (93.3% vs 90.4%, respectively), decreased white blood cell count (88.8% vs 86.0%), decreased neutrophil count (83.2% vs 82.0%), and decreased platelet count (72.6% vs 70.2%). The most frequently experienced grade 3 or higher TEAEs comprised decreased neutrophil count (48.6% vs 47.8%), decreased platelet count (45.3% vs 42.7%), decreased white blood cell count (36.3% vs 36.5%), and anemia (33.5% vs 32.0%).
“In conclusion, the ORIENT-12 study demonstrated that the addition of sintilimab to standard chemotherapy with gemcitabine and platinum could significantly prolong the PFS in patients with previously untreated advanced or metastatic squamous NSCLC, with manageable safety profiles,” the study authors wrote. “The results from ORIENT-12 could provide a new option for combination therapy in this patient population.”