Sintilimab/Pemetrexed Regimen Significantly Improves PFS in Advanced NSCLC

Sintilimab injection plus pemetrexed and platinum-based therapy led to a statistically significant improvement in progression-free survival (PFS) compared with chemotherapy alone as a first-line treatment for patients with locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC), according to results of the phase 3 ORIENT-11 trial that were presented during the 2020 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer Virtual Presidential Symposium.¹

At a median follow-up of 8.9 months, results showed that the median PFS by an independent radiologic review committee (IRRC) was 8.9 months (95% CI, 7.1-11.3) in the sintilimab arm compared with 5.0 months (95% CI, 4.8-6.2) in the chemotherapy-alone arm, translating to an estimated 52% reduction in the risk of disease progression or death (HR, 0.482; 95% CI, 0.362-0.643; P <.00001).

“The addition of sintilimab to pemetrexed and platinum significantly improved PFS compared to placebo,” lead study author Li Zhang, MD, head of the Department of Internal Medicine, Sun Yat-sen University Cancer Center, said in a presentation during the meeting. “The benefit was seen across key clinical subgroups, and [objective response rate] was also improved, with durable responses.”

Sintilimab is a fully human IgG4 monoclonal antibody that blocks the binding of PD-1 to PD-L1/PD-L2, along with high affinity to human PD-1 and high PD-1 receptor occupancy, Zhang explained. Previously, phase 1b data with sintilimab in combination with pemetrexed and platinum-based therapy demonstrated clinical activity and a tolerable safety profile in patients with treatment-naïve, nonsquamous NSCLC.²

In the Chinese, double-blind, randomized, phase 3 ORIENT-11 study, investigators sought to evaluate the efficacy and safety of sintilimab in combination with pemetrexed and platinum-based therapy as first-line treatment in 397 patients with nonsquamous NSCLC. Patients were randomized 2:1 to receive sintilimab at 200 mg (n = 266) or placebo (n = 131) plus pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 or carboplatin area under the curve (AUC)5, every 3 weeks for 4 cycles. In the experimental arm, sintilimab was then given at 200 mg every 3 weeks for up to 2 years plus pemetrexed at 500 mg/m2 every 3 weeks. In the placebo arm, patients then received placebo every 3 weeks for up to 24 months plus pemetrexed at the 500 mg/m2 every-3-week dosing schedule. After this point, patients on placebo were permitted to cross over and receive sintilimab at 200 mg every 3 weeks for up to 24 months.

To be eligible for enrollment, patients must have had stage IIIB/C or IV disease that was ineligible for surgery or local therapy, an ECOG performance status of 0 or 1, and a provision of tumor sample for PD-L1 assessment. Patients were stratified by gender, type of platinum therapy (cisplatin vs carboplatin) and PD-L1 expression level (tumor proportion score [TPS] less than 1% vs 1% or higher).

The primary end point was PFS via IRRC; secondary end points were overall survival (OS), response rate, duration of response, time to response, and safety. Efficacy was analyzed in the intent-to-treat population, and safety data comprised all patients who received 1 dose or more of the study treatment.

The study had 90% power to detect a hazard ratio for PFS of 0.65 at one-sided alpha of .025. The protocol specified 1 interim analysis, which is planned to perform when 70% of PFS events were achieved, prior to the final analysis. The data cutoff date was November 15, 2019.

The median age was 61 years (range, 32.5-75), three-fourths of patients were male (76.2%), and 72.7% of patients had an ECOG performance status of 1. The majority of patients (90.3%) had stage IV disease, and approximately 15% had brain metastases.

More patients were treated with carboplatin (74.1%) than cisplatin, and more than half of patients (65.4%) were current or former smokers. A total 67.2% of patients had a PD-L1 TPS of 1% or higher.

At a median follow-up of 8.0 months (range, 0.6-14.8), 198 PFS events were reported. Thirty-five patients (31.3%) on the placebo arm crossed over to receive sintilimab. Results showed that the PFS benefit with sintilimab was reported across key subgroups via IRRC, including age, performance status, platinum-based therapy, smoking status, and presence of brain metastases.

When stratified by PD-L1 TPS, the PFS benefit correlated with the level of PD-L1 expression. In those with TPS less than 1%, the median PFS was 7.3 months (95% CI, 6.2–not reached) with sintilimab and 5.1 months (95% CI, 4.6-7.8) with chemotherapy alone (HR, 0.664; 95% CI, 0.406-1.086). For those with PD-L1 TPS 1% to 49%, the median PFS was 7.1 months (95% CI, 6.2-9.2) and 4.8 months (95% CI, 2.5-8.0), respectively (HR, 0.503; 95% CI, 6.2-9.2). For patients with PD-L1 TPS 50% or higher, the median PFS was not reached (95% CI, 9.2–not reached [NR]) with sintilimab and 5.0 months (95% CI, 4.3-6.8) with chemotherapy alone (HR, 0.310; 95% CI, 0.197-0.489).

OS also favored the sintilimab arm, demonstrating an approximate 40% reduction in the risk of death versus pemetrexed/platinum alone, which was found to be nominally significant (HR, 0.609; 95% CI, 0.400-0.926; P = .01921). The 6-month OS rates were 89.6% and 80.4%, respectively.

The objective response rate (ORR) with the sintilimab regimen was 51.9%, which comprised a 1.1% complete response (CR) rate and a 50.8% partial response (PR) rate. The stable disease (SD) rate was 35.0% and the progressive disease (PD) rate was 10.2%. In the placebo arm, the ORR was 29.8%, which included a 0% CR rate and a 29.8% PR rate; the SD and PD rates were 45.8% and 19.1%, respectively. The disease control rate was 86.8% with sintilimab and 75.6% for placebo.

Moreover, the median duration of response was not reached (95% CI, 8.0–NR) in the sintilimab arm and 5.5 months (95% CI, 4.1-10.9) in the placebo arm. The time to response was shorter with sintilimab at 1.5 months versus 2.6 months with chemotherapy/placebo.

Regarding safety, the rates of adverse effects (AEs) were similar between arms. Grade 3 to 5 AEs occurred in 61.7% of patients on sintilimab versus 58.5% of those on placebo; serious AEs occurred in 28.2% and 29.8% of patients, respectively. AEs that led to death occurred in 6 (2.3%) patients on sintilimab and 9 (6.9%) patients on placebo; AEs that led to any treatment discontinuation occurred in 16 (6.0%) and 11 (8.4%) patients, respectively. Immune-related AEs (irAEs) occurred in 43.2% of patients on sintilimab and 36.6% of those on placebo, and grade 3 to 5 irAEs were reported in 5.6% and 6.1% of patients, respectively.

AEs that occurred in 20% or more of patients, in either arm, were anemia, decreased neutrophil count, decreased white blood cell count, decreased platelet count, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), nausea, decreased appetite, asthenia, vomiting, constipation, and pyrexia.

“In both arms, the most common AEs were anemia, neutropenia, and leukopenia, which is chemotherapy associated,” Zhang said. “Generally, the AE profiles were similar in the 2 arms.”

irAEs that occurred in 2% or more of patients on either treatment included hypothyroidism, rash, increased AST, increased ALT, increased blood thyroid-stimulating hormone (TSH), hyperthyroidism, diarrhea, immune-mediated pneumonitis, decreased blood TSH, increased amylase, pruritus, and increased free thyroxine.

Based on these findings, the National Medical Products Administration of China accepted a supplemental new drug application in April 2020 for sintilimab injection for use in combination with pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous NSCLC.³

In May 2020, results of the ORIENT-12 study showed that adding sintilimab injection to gemcitabine and platinum-based chemotherapy improved PFS as a frontline treatment in patients with advanced or metastatic squamous NSCLC, meeting the primary end point of the phase 3 Chinese ORIENT-12 trial.⁴

References

1. Zhang Li, 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: International Association for the Study of Lung Cancer 2020 Presidual Symposium; August 8, 2020; virtual. Abstract 1.
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; abstr e20546). doi: 10.1200/JCO.2019.37.15_suppl.e20546.
3. Innovent and Eli Lilly announce NMPA acceptance of a supplemental new drug application for sintilimab in combination with Alimta (pemetrexed) and platinum as first-line therapy in non-squamous NSCLC. https://prn.to/3ayqwJe. Published April 24, 2020. https://bit.ly/2FOrG6p. Accessed April 24, 2020.
4. Tyvyt (sintilimab injection) combined with Gemzar (gemcitabine for injection) and platinum chemotherapy met the predefined primary endpoint in the phase 3 ORIENT-12 study as first-line therapy in patients with locally advanced or metastatic squamous non-small cell lung cancer. Published May 6, 2020. https://prn.to/2WdVsKN. Accessed May 7, 2020.