Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial

Lü, Shun; Wu, Lin; Hong, Jian; Cheng, Ying; Wang, Qiming; Fang, Jian; Wang, Ziping; Hu, Yanping; Liang, Huang; Sun, Meili; Miao, Liyun; Ding, Cuimin; Cui, Jiuwei; Wang, Ke; Li, Baolan; Li, Xingya; Ye, Feng; Liu, Anwen; Pan, Yueyin; Cang, Shundong; Zhou, Hui; Sun, Xiaofeng; Yang, Huan; Wang, Shuyan; Zhang, Wen; He, Yong

doi:10.1016/s2213-2600(23)00135-2

Cited by 60 publications

(24 citation statements)

References 19 publications

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“…However, pemetrexed based platinum combination has been widely used not only in clinical practice but also in clinical trials. 10,11,22 Finally, the absence of OS benefit is observed in the current analysis, which needs longer follow-up.…”

Section: Discussionmentioning

confidence: 62%

“…In China, a recent phase III study of sintilimab plus IBI305 (bevacizumab biosimilar) plus pemetrexed/cisplatin versus sintilimab plus chemotherapy versus chemotherapy alone (ORIENT-31 study) demonstrated significant improvement in PFS with a four-drug regimen. 21,22 In contrast to our study, the OREINT-31 study used pemetrexed plus cisplatin as cytotoxic chemotherapy. It remains unclear whether the different chemotherapeutic regimens have a significant impact on clinical efficacy.…”

Section: Discussionmentioning

confidence: 81%

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Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Rearranged or Translocated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)

Park,

Kim,

Han

et al. 2024

JCO

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PURPOSE In the treatment of non-small cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody following tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase 3 study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel and carboplatin (ABCP) in EGFR or ALK-mutated NSCLC that progressed prior to TKI therapy. METHODS We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC arm) followed by pemetrexed maintenance. The primary endpoint was progression-free survival (PFS). RESULTS A total of 228 patients with activating EGFR mutation (n=215) or ALK translocation (n=13) were enrolled from 16 sites in the Republic of Korea and randomized at 2:1 ratio to either ABCP (n=154) or PC arm (n=74). The median follow-up duration was 26.1 months (95%CI 24.7-28.2). Objective response rates (69.5% vs 41.9%, P <0.001) and median PFS (8.48 vs. 5.62 months, hazard ratio [HR] 0.62 [0.45-0.86], P=0.004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10% and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 vs. 20.27 months, HR 1.01 [0.69-1.46], P=0.975). The safety profile of the ABCP arm was comparable to that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared to the PC arm. CONCLUSION This study is the first randomized phase 3 study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in EGFR or ALK mutated NSCLC who have progressed on relevant targeted therapy.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 81%

Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Rearranged or Translocated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)

Park,

Kim,

Han

et al. 2024

JCO

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“…Eight additional RCTs were identified in the latest literature search that spanned from February 6 to October 30, 2023. 14-21 The randomized trials compared different therapies. Results from these studies either necessitated some modifications to the recommendations, or the quality of evidence rating in some recommendations.…”

Section: Resultsmentioning

confidence: 99%

“…Three prospective phase III studies have compared PD-1 inhibitors (nivolumab, pembrolizumab, or sintilimab) plus platinum doublet chemotherapy to platinum doublet alone in patients with disease progression on prior EGFR TKI. 14,78,79 Two studies yielded no improvement in PFS, while sintilimab plus chemotherapy improved PFS compared to chemotherapy (PFS HR, 0.72 [95% CI, 0.55 to 0.94]), although the absolute gain in PFS was small (median 5.5 v 4.3 months). 14 None of the three studies demonstrated an improvement in OS with the addition of PD-1 inhibition to chemotherapy.…”

Section: Recommendationsmentioning

confidence: 99%

“…14,78,79 Two studies yielded no improvement in PFS, while sintilimab plus chemotherapy improved PFS compared to chemotherapy (PFS HR, 0.72 [95% CI, 0.55 to 0.94]), although the absolute gain in PFS was small (median 5.5 v 4.3 months). 14 None of the three studies demonstrated an improvement in OS with the addition of PD-1 inhibition to chemotherapy. Two phase III trials in patients with advanced nonsquamous NSCLC, including patients post EGFR TKI, have examined the impact of adding atezolizumab to bevacizumab + carboplatin + paclitaxel.…”

Section: Recommendationsmentioning

confidence: 99%

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Therapy for Stage IV Non–Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3

Jaiyesimi,

Leighl,

Ismaila

et al. 2024

JCO

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Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See complete disclaimer in Appendix 1 and Appendix 2 for more. Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline . PURPOSE To provide evidence-based recommendations for patients with stage IV non–small cell lung cancer with driver alterations. METHODS This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized clinical trials (RCTs), with the latest time frame spanning February to October 2023. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened. The literature search included systematic reviews, meta-analyses, and randomized controlled trials. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Eight new RCTs were identified in the latest search of the literature to date. RECOMMENDATIONS Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients based on targetable driver alterations. Additional information is available at www.asco.org/living-guidelines .

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Ivonescimab Plus Chemotherapy in Non–Small Cell Lung Cancer With EGFR Variant

Fang,

Zhao,

Luo

et al. 2024

JAMA

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ImportanceFor patients with non–small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited.ObjectiveTo compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non–small cell lung cancer with the epidermal growth factor receptor (EGFR) variant.Design, Setting, and ParticipantsDouble-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled.InterventionsParticipants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed.Main Outcomes and MeasuresThe primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported.ResultsAmong 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P &lt; .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor–related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group.ConclusionsIvonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non–small cell lung cancer.Trial RegistrationClinicalTrials.gov Identifier: NCT05184712

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Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial

Cited by 60 publications

References 19 publications

Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Rearranged or Translocated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)

Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Rearranged or Translocated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)

Therapy for Stage IV Non–Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3

Ivonescimab Plus Chemotherapy in Non–Small Cell Lung Cancer With EGFR Variant

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