Sintilimab plus pemetrexed, chemotherapy extends PFS in non-small cell lung cancer subset
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The addition of sintilimab to pemetrexed and platinum chemotherapy conferred a significant PFS benefit for a subset of patients with nonsquamous non-small cell lung cancer, according to results of an interim analysis of the ORIENT-11 study.
Researchers observed the benefit specifically among patients with locally advanced or metastatic disease and no EGFR or ALK mutations.
Li Zhang, MD, researcher at Sun Yat-sen University Cancer Center in China, presented the results during the International Association for the Study of Lung Cancer World Conference on Lung Cancer Virtual Presidential Symposium. The findings were published simultaneously in Journal of Thoracic Oncology.
“Sintilimab [Tyvyt; Eli Lilly & Co., Innovent Biologics] is a fully human IgG4 monoclonal antibody that blocks the binding of PD-1 to PD-L1 or PD-L2, with high affinity to human PD-1 and high PD-1 receptor occupancy,” Zhang said during the presentation. “Previously, sintilimab in combination with pemetrexed and a platinum-based chemotherapy had shown promising activity for nonsquamous non-small cell lung cancer in a phase 1b study. Based upon these data, we sought to evaluate the efficacy and safety of sintilimab in combination with pemetrexed and platinum-based chemotherapy in a randomized phase 3 study.”
The ORIENT-11 study included 397 patients with previously untreated locally advanced or metastatic nonsquamous NSCLC without EGFR or ALK mutations and an ECOG performance status of 0 or 1.
Researchers randomly assigned patients 2:1 to 200 mg sintilimab (n = 266; median age, 61 years; 76.7% men) or placebo (n = 131; median age, 61 years; 75.6% men) plus 500 mg/m2 pemetrexed and either 75 mg/m2 cisplatin or carboplatin area under the curve 5 every 3 weeks for four cycles. Patients then received maintenance therapy with either sintilimab or placebo with pemetrexed. Treatment continued until disease progression, and participants in the placebo group could cross over to sintilimab.
PFS served as the primary endpoint. Secondary endpoints included OS, overall response rate, time to response, duration of response and safety. Researchers had planned to conduct an interim analysis when 70% of PFS events occurred. Data cutoff was Nov. 15, 2019.
At a median follow-up of 8.9 months (range, 0.6-14.8), 198 PFS events or deaths had occurred. Overall, 85.3% (n = 227) of patients assigned the sintilimab combination and 80.2% (n = 105) assigned the placebo combination completed all four cycles of induction treatment and received maintenance therapy.
Median treatment duration was 7.1 months in the sintilimab group vs. 5.5 months in the placebo group. The effective crossover rate in the placebo group was 35.9%. Overall, 31.2% (n = 83) of patients in the sintilimab group and 35.1% (n = 46) in the placebo group continued study treatment beyond first disease progression.
Results showed median PFS of 8.9 months with the sintilimab combination vs. 5 months with the placebo combination (HR = 0.48; 95% CI, 0.36-0.64). Researchers reported 6-month PFS rates of 68.3% (95% CI, 62-73.8) for the sintilimab group vs. 42% (95% CI, 32.8-50.9) for the placebo group.
The HR for patients with brain metastases in the sintilimab vs. placebo group was 0.57 (95% CI, 0.28-1.18) compared with an HR of 0.46 (95% CI, 0.34-0.64) for those without brain metastases.
Sintilimab also demonstrated a PFS benefit among patients who never smoked (HR = 0.55; 95% CI, 0.33-0.92), as well as among those in all subgroups based on PD-L1 tumor proportion score (see Table).
Median OS was not reached in either treatment group, but researchers observed a trend toward improvement in the sintilimab group (HR = 0.6; 95% CI, 0.4-0.92).
The confirmed ORR was 51.9% (95% CI, 45.7-58) with the sintilimab combination vs. 29.8% (95% CI, 22.1-38.4) with the placebo combination (P = .00003), and the time to treatment response was shorter with the sintilimab combination (1.5 months vs. 2.6 months). Median duration of response was not reached with sintilimab vs. 5.5 months with placebo.
Grade 3 or higher adverse events occurred more often with the sintilimab combination (61.7% vs. 58.8%). The most common of these included decreased neutrophil count (36.5% vs. 30.5%), anemia (15% vs. 19.1%) and decreased white blood cell count (14.7% vs. 15.3%).
“Sintilimab plus chemotherapy significantly improved PFS and led to a nominally significant improvement in OS, with a manageable safety profile and no new safety signals,” Zhang said.
Future research will focus on biomarker exploration in this setting, Zhang added.
References
- Yang Y, et al. J Thor Onc. 2020;doi:10.1016/j.jtho.2020.07.014.
- Zhang L, et al. Abstract LBA 7. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer Virtual Presidential Symposium; Aug. 8, 2020.
Perspective
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Howard (Jack) West, MD
The phase 3 ORIENT-11 trial will not change practice, at least outside of China, where the trial was conducted. Although the addition of the immunotherapy sintilimab to standard doublet chemotherapy improved PFS compared with chemotherapy alone as first-line treatment for advanced nonsquamous NSCLC, the latter is now an obviated standard of care that has been replaced by chemotherapy and immunotherapy or immunotherapy alone for select patients. Multiple prior trials have demonstrated superiority to chemotherapy alone in this population during the past 2 or more years, including significant improvement in OS, which has not been demonstrated in ORIENT-11.
This trial is now too little, too late — a lateral move, at best, against the current standards of care that have handily beaten the obviated prior standard of care tested in this trial. Just as you do not bring a knife to a gunfight, you do not bring a PFS benefit to an OS fight.
Perspective
Back to TopMisako Nagasaka, MD
The benefit observed in PFS in the sintilimab combination arm is certainly encouraging, but we have seen studies with PFS improvement that did not translate in OS improvement. Longer follow-up will allow for events to mature and we will ultimately see if there will be a significant OS benefit.
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Zhang L, et al. Abstract LBA 1. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer Virtual Presidential Symposium; Aug. 8, 2020.
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