Comparison of Chemotherapy With PD-1/L1 or CTLA-4 Inhibitors Alone Or In Combination In Advanced Or Metastatic Non-Small Cell Lung Cancer: A Meta- Analysis

Abstract Background: In spite of the wide use of immune-checkpoint inhibitors (ICIs) in advanced or metastatic non-small cell lung cancer (NSCLC), whether ICIs or conventional chemotherapy is more effective still remains controversial. This study was conducted to evaluate the efficacy of giving patients programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), or cytotoxic T-lymphocyte protein 4 (CTLA-4) alone or in their combination (PD-1/L1 + CTLA-4) versus simply applying chemotherapy in patients with advanced or metastatic NSCLC.Methods: This meta-analysis was conducted from PubMed, Web of Science, Medline, Embase, and the Cochrane Library up to March 2021 to identify relevant randomized controlled trials (RCTs). Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoint was adverse events (AEs). Results: The search process has identified 13 studies containing 7918 patients with advanced or metastatic NSCLC. The benefit of PD-1/L1 or CTLA-4 inhibitors alone or in combination compared with chemotherapy for advanced or metastatic NSCLC was elucidated in both overall survival (OS) [HR=0.75, 95%CI (0.70-0.80), P<0.001] and progression-free survival (PFS) [HR=0.83, 95%CI (0.73-0.95), P<0.001]. Sex is another vital factor that affects the efficacy of ICIs. Male [HR=0.71, 95%CI (0.63-0.81)] benefits more from ICIs than the female [HR 0.80, 95%CI (0.68-0.94)] in OS. Besides, ICIs were associated with fewer AEs compared to chemotherapy.Conclusion: PD-1/L1 or CTLA-4 inhibitors alone or in combination, with fewer AEs, was associated with significant improvements in terms of OS and PFS than chemotherapy in treatment of advanced or metastatic NSCLC.

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PIOS (Patras Immunotherapy Score) Score Is Associated with Best Overall Response, Progression-Free Survival, and Post-Immunotherapy Overall Survival in Patients with Advanced Non-Small-Cell Lung Cancer (NSCLC) Treated with Anti-Program Cell Death-1 (PD-1) Inhibitors

Cancers ◽

10.3390/cancers12051257 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1257

Author(s):

Foteinos-Ioannis Dimitrakopoulos ◽

Achilleas Nikolakopoulos ◽

Anastasia Kottorou ◽

Fotini Kalofonou ◽

Elias Liolis ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Cell Death ◽

Prognostic Value ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Free Survival ◽

Nsclc Patients ◽

Program Cell Death

Immunotherapy with immune checkpoint inhibitors (ICIs) has changed the therapeutic management of advanced non-small cell lung cancer (aNSCLC) over the last decade. However, there is an unmet need for clinically useful biomarkers in this patient subgroup. The aim of this study was to combine baseline clinical characteristics of aNSCLC patients, in the form of a scoring system, and to investigate its predictive and prognostic value in NSCLC patients treated with ICIs. A total of 112 patients with advanced (stages IIIA to IV) NSCLC, treated with nivolumab or pembrolizumab, were enrolled in this study. Patras Immunotherapy Score (PIOS) was developed based on four of the studied parameters (performance status (PS), body mass index (BMI), age, and lines of treatment (LOT), which were incorporated into our formula (PS × BMI/ LOT × age). PIOS score was strongly associated with best overall responses (BOR), with those patients having benefit/good response (stable disease (SD) or partial (PR) or complete response (CR), achieving a higher score compared to patients who developed progressive disease (PD) (p < 0.001). Furthermore, PIOS score was associated with progression-free survival (PFS), since high-score patients had longer PFS (p < 0.001, hazard ratio (HR) = 0.469). Moreover, PIOS was associated with post-immunotherapy overall survival (OS), with high-score patients having improved OS (log-rank p = 0.019). This study suggests that a combination of baseline parameters, which give rise to PIOS score, may predict the best response of NSCLC patients treated with anti-program cell death -1 (PD-1) monotherapy as well as it may have a potent prognostic value for PFS and post immunotherapy OS.

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Real-world effectiveness of nivolumab in patients with non-small-cell lung cancer: a systematic review and meta-analysis

Future Oncology ◽

10.2217/fon-2020-0248 ◽

2020 ◽

Vol 16 (27) ◽

pp. 2045-2058 ◽

Cited By ~ 1

Author(s):

Yong-Jin Kim ◽

Mark Oremus ◽

Helen H Chen ◽

Thomas McFarlane ◽

Devanshi Shah ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Real World ◽

Meta Analysis ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Free Survival

Background: The effectiveness of immunotherapies for non-small-cell lung cancer under real-world clinical settings remains uncertain. Materials & methods: Systematic searches of PubMed, EMBASE and Web of Science were conducted. Random-effects models were used to estimate pooled median overall survival and progression-free survival estimates. Results: 36 studies of nivolumab were included for narrative synthesis and 11 of these studies were included for meta-analysis. Age, sex, histology and prior lines of treatment did not affect survival outcomes, while Eastern Cooperative Oncology Group Performance Status and brain metastasis were inversely associated with survival. In the meta-analysis, nivolumab was associated with 9.6 months (95% CI: 8.4–10.9) of overall survival and 2.6 months (95% CI: 1.6–3.6) of progression-free survival. Conclusion: Very-low-certainty evidence suggested the real-world effectiveness of nivolumab was consistent with those observed in the clinical trials.

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Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study

Journal of Clinical Oncology ◽

10.1200/jco.20.03579 ◽

2021 ◽

pp. JCO.20.03579 ◽

Cited By ~ 1

Author(s):

Michael Boyer ◽

Mehmet A. N. Şendur ◽

Delvys Rodríguez-Abreu ◽

Keunchil Park ◽

Dae Ho Lee ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Progression Free Survival ◽

Small Cell ◽

Phase Iii ◽

Small Cell Lung ◽

First Line ◽

Double Blind ◽

Free Survival ◽

Metastatic Nsclc

PURPOSE Pembrolizumab monotherapy is standard first-line therapy for metastatic non–small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population. METHODS In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234 ), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival. RESULTS Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo. CONCLUSION Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.

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Immunotherapy plus chemotherapy versus chemotherapy alone in metastatic non–small-cell lung cancer: A systematic review with meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20700 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20700-e20700

Author(s):

Andre Deeke Sasse ◽

Fernanda Proa Ferreira ◽

Adolfo Jose de Oliveira Scherr ◽

David Pinheiro Cunha ◽

Vivian Castro Antunes Vasconcelos ◽

...

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Free Survival ◽

Metastatic Nsclc

e20700 Background: Palliative systemic therapy is the primary approach for stage IV non-small cell lung cancer(NSCLC). For patients with NSCLC that lacks targetable mutations, immunotherapy alone or in combination with chemotherapy has become a promising alternative, focusing survival and quality of life. Our objectives were to review, summarize and compare the evidence of immunotherapy plus chemotherapy in first-line treatment in comparison with chemotherapy alone in patients with metastatic NSCLC in terms of effectiveness. Methods: A systematic review of randomized controlled trials (RCTs) was planned. PubMed, Embase and Lilacs were searched for trials evaluating metastatic NSCLC patients, comparing chemotherapy alone versus chemotherapy plus anti-PD1, anti-PDL1 or anti-CTLA-4 agents. Four investigators independently extracted characteristics and results of identified studies and performed standardized quality ratings. Meta-analyses for overall survival (OS), progression-free-survival (PFS), overall response rates (ORR) and toxicities were performed. Results: Six RCTs met the inclusion criteria. One trial with anti-PD-L1 (Atezolizumab), three trials with anti-PD-1 (Pembrolizumab) and two trials with anti-CTLA-4 (Ipilimumab) were included. Three trials included non-squamous carcinomas, two trials included squamous cell carcinoma and one trial included all NSCLC. The combination of anti-PD-1 or anti-PDL1 to chemotherapy improved OS (Hazard Ratio [HR] for death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; p < 0.0001). This combination also improved PFS (HR for progression or death, 0.57; 95% CI, 0.51 to 0.63; p < 0.00001) and ORR (Odds Ratio [OR], 2.55; 95% CI, 1.80 to 3.61; p < 0.00001). The combination of anti-CTLA-4 to chemotherapy slightly increased the PFS (HR 0.84; 95% CI, 0.73 to 0.96; p = 0.01), but not OS (HR 0.92; 95% CI, 0.80 to 1.05; p = 0.21) or ORR (OR 0.92; 95% CI, 0.71 to 1.19; p = 0.52). General and immune mediated adverse events were higher in all combination groups. Conclusions: In patients with previously untreated metastatic squamous and non-squamous NSCLC without EGFR or ALK mutations, the addition of anti-PD-1 or anti-PD-L1 to standard chemotherapy resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

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Therapy of Advanced Non–Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan

Journal of Clinical Oncology ◽

10.1200/jco.2016.72.1894 ◽

2017 ◽

Vol 35 (24) ◽

pp. 2790-2797 ◽

Cited By ~ 40

Author(s):

Rebecca Suk Heist ◽

Michael J. Guarino ◽

Gregory Masters ◽

W. Thomas Purcell ◽

Alexander N. Starodub ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

End Points ◽

Free Survival ◽

Metastatic Nsclc

Purpose Trop-2, expressed in most solid cancers, may be a target for antibody-drug conjugates (ADCs) in non–small-cell lung cancer (NSCLC). We studied sacituzumab govitecan (IMMU-132), a Trop-2 ADC, for the targeting of SN-38. Patients and Methods We evaluated IMMU-132 in a single-arm multicenter trial in patients with pretreated metastatic NSCLC who received either 8 or 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end points were safety and objective response rate (ORR). Progression-free survival and overall survival were secondary end points. Results Fifty-four patients were treated. In the response-assessable study population (n = 47), which had a median of three prior therapies (range, two to seven), the ORR was 19%; median response duration, 6.0 months (95% CI, 4.8 to 8.3 months); and clinical benefit rate (complete response + partial response + stable disease ≥ 4 months), 43%. ORR in the intention-to-treat (ITT) population was 17% (nine of 54). Responses occurred with a median onset of 3.8 months, including patients who had relapsed or progressed after immune checkpoint inhibitor therapy. Median ITT progression-free survival was 5.2 months (95% CI, 3.2 to 7.1 months) and median ITT overall survival, 9.5 months (95% CI, 5.9 to 16.7 months). Grade 3 or higher adverse events included neutropenia (28%), diarrhea (7%), nausea (7%), fatigue (6%), and febrile neutropenia (4%). One patient developed a transient immune response, despite patients receiving a median of 10 doses. More than 90% of 26 assessable archival tumor specimens were highly positive (2+, 3+) for Trop-2 by immunohistochemistry, which suggests that Trop-2 is not a predictive biomarker for response. Conclusion IMMU-132 was well-tolerated and induced durable responses in heavily pretreated patients with metastatic NSCLC. This ADC should be studied further in this disease and in other patients with Trop-2–expressing tumors.

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