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Immunotherapy in non-metastatic non-small cell lung cancer: Can the benefits of stage IV therapy be translated into earlier stages?

ABSTRACT: Over the last decade, several steps forward in the treatment of patients with stage IV non-small cell lung cancer (NCSLC) were made. Examples are the use of pemetrexed, pemetrexed maintenance therapy, or bevacizumab for patients with nonsquamous NSCLC. A big leap forward was the use of tyrosine kinase inhibitors in patients selected on the basis of an activating oncogene, such as epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) translocations. However, all of these achievements could not be translated into survival benefits when studied in randomized controlled trials in patients with nonmetastatic NSCLC. Aside from chemotherapy and targeted therapy, immunotherapy has become the third pillar in the treatment armamentarium of advanced NSCLC. Antigen-specific immunotherapy (cancer vaccination) has been disappointing in large phase III clinical trials in stages I-III NSCLC. Based on the recent breakthroughs with immune checkpoint inhibitor immunotherapy in metastatic NSCLC, much hope currently rests on the use of this approach in patients with stage I-III NSCLC as well. Here we give a brief overview of how most new therapeutic approaches for advanced NSCLC failed in other stages, and then elaborate on the role of immunotherapy in patients with stage I-III NSCLC.

SUBMITTER: Deslypere G

PROVIDER: S-EPMC5949924 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Immunotherapy in non-metastatic non-small cell lung cancer: Can the benefits of stage IV therapy be translated into earlier stages?

Deslypere Griet G Gullentops Dorothée D Wauters Els E Vansteenkiste Johan J

Therapeutic advances in medical oncology 20180504

Over the last decade, several steps forward in the treatment of patients with stage IV non-small cell lung cancer (NCSLC) were made. Examples are the use of pemetrexed, pemetrexed maintenance therapy, or bevacizumab for patients with nonsquamous NSCLC. A big leap forward was the use of tyrosine kinase inhibitors in patients selected on the basis of an activating oncogene, such as epidermal growth factor receptor (<i>EGFR</i>) activating mutations or anaplastic lymphoma kinase (<i>ALK</i>) transl ...[more]

PMID: 29774061

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Project description:Background: Immune checkpoint inhibitors (ICIs) have dramatically expanded the therapeutic landscape of non-small-cell lung cancer (NSCLC). In a previous study, gender, smoking history, and PD-L1 status were found to influence the efficacy of single-agent ICI in NSCLC. This meta-analysis evaluated the clinical and molecular factors that could predict a benefit from adding ICIs to first-line chemotherapy in metastatic NSCLC. Patients and Methods: The pooled hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) among the selected subgroups were analyzed using the random effects model. The correlation between PD-L1 expression and outcome was analyzed by meta-regression. Results: Seven phase III randomized controlled trials comparing chemo-immunotherapy (CIT) with chemotherapy in untreated stage 4 NSCLC were included. CIT evenly improved PFS irrespective of age, gender, histology, smoking history, and performance status. Among patients with baseline hepatic metastasis treated with Atezolizumab-containing CIT, PFS improvement was only detected with the addition of Bevacizumab. Whereas patients with EGFR/ALK-driven cancer exhibited greater PFS with the addition of ICI to a Bevacizumab (BEV)-based regimen, the derived benefit was no longer statistically significant among those treated with non-BEV-based regimens. Although the superior PFS conferred by CIT was noticeable across all PD-L1 expression subgroups, this benefit correlated with PD-L1 level and was more pronounced in the "PD-L1 high" cohort. Except for patients harboring EGFR/ALK aberrations or squamous histology, CIT consistently improved OS across the other selected subgroups. Conclusions: The survival advantage associated with first-line CIT in metastatic NSCLC was observed in different patient populations, including those for which single-agent ICI has marginal therapeutic benefit. Our findings support the role of chemotherapy with or without VEGF blockade as enhancers of ICI activity in NSCLC.

Project description:BackgroundHistorically, older patients with advanced lung cancer have often received no systemic treatment. Immunotherapy has improved outcomes in clinical trials, but its dissemination and implementation at the population level is not well-understood.MethodsA retrospective cohort study of patients with stage IV non-small cell lung cancer (NSCLC) diagnosed age 66 or older from 2012 to 2015 was conducted using SEER-Medicare. Treatment patterns within one year of diagnosis were ascertained. Outcomes included delivery of (a) any systemic therapy; (b) any second-line infusional therapy, following first-line infusional therapy; and (c) any second-line immunotherapy, following first-line infusional therapy. Trends in care patterns associated with second-line immunotherapy approvals in 2015 were assessed using generalized additive models. Sociodemographic and clinical predictors of treatment were explored using logistic regression.ResultsAmong 10 303 patients, 5173 (50.2%) received first-line systemic therapy, with little change between the years 2012 (47.5%) and 2015 (50.3%). Among 3943 patients completing first-line infusional therapy, the proportion starting second-line infusional treatment remained stable from 2012 (30.5%) through 2014 (32.9%), before increasing in 2015 (42.4%) concurrent with second-line immunotherapy approvals. Factors associated with decreased utilization of any therapy included age, black race, Medicaid eligibility, residence in a high-poverty area, nonadenocarcinoma histology, and comorbidity; factors associated with increased utilization of any therapy included Asian race and Hispanic ethnicity. Among patients who received first-line infusional therapy, factors associated with decreased utilization of second-line infusional therapy included age, Medicaid eligibility, nonadenocarcinoma histology, and comorbidity; Asian race was associated with increased utilization of second-line infusional therapy.ConclusionUnited States Food and Drug Administration (FDA) approvals of immunotherapy for the second-line treatment of advanced NSCLC in 2015 were associated with increased rates of any second-line treatment, but disparities based on social determinants of health persisted.

Project description:ObjectiveTo analyze the relationship between tumor size and metastatic site in stage IV NSCLC patients.MethodsA total of 40,196 stage IV NSCLC patients from 2010 to 2015 were screened by SEER database. Chi-square test was used to compare the characteristics of clinical variables. At the same time, multivariate Logistic regression analysis was used to evaluate the relationship between tumor size and organ metastasis.ResultsRegardless of tumor size, the proportion of bone metastasis and lung metastasis was higher and similar in patients with squamous cell carcinoma, while in patients with adenocarcinoma, bone metastasis accounted for the highest proportion. We found that whether the metastatic site was bone, brain, liver or lung, the proportion of patients with a tumor size of 3-7 cm was the highest. Multivariate regression analysis demonstrated that patients with a tumor size of 3-7 cm and a tumor size ≥7 cm were more likely to develop brain metastasis and lung metastasis compared with patients with a tumor size ≤3 cm (all P < 0.001), which meant the larger the tumor, the greater the risk of brain or lung metastasis. At the same time, the results indicated that patients with a tumor size of 3-7 cm had a tendency to develop liver metastasis (P = 0.004), while the statistical significance was not found for patients with a tumor size ≥7 cm (P = 0.524). The results also revealed that patients with a tumor size of 3-7cm had no significant difference to develop bone metastasis (P = 0.116), while the statistical significance was found for patients with a tumor size ≥7 cm (P < 0.001).ConclusionsThere was statistical significance between tumor size and metastatic site in patients with stage IV NSCLC. For brain or lung metastasis, the larger the tumor, the higher the risk of brain or lung metastasis. For liver metastasis, patients with a tumor size of 3-7 cm were more prone to develop liver metastasis. For bone metastasis, patients with a tumor size ≥7 cm were more likely to have bone metastasis.

Project description:BackgroundNivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC.MethodsWe randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more.ResultsAmong the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.ConclusionsNivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).

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Immunotherapy in non-metastatic non-small cell lung cancer: Can the benefits of stage IV therapy be translated into earlier stages?

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Immunotherapy in non-metastatic non-small cell lung cancer: Can the benefits of stage IV therapy be translated into earlier stages?

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