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Correlation between B7-H4 and Survival of Non-Small-Cell Lung Cancer Patients Treated with Nivolumab.

ABSTRACT: Reliable predictors of benefit from immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are still limited. We aimed to evaluate the association between the expression of selected molecules involved in immune response and clinical outcomes in NSCLC patients receiving nivolumab. In our study, the outcomes of 46 NSCLC patients treated with nivolumab in second or subsequent lines (Nivolumab Cohort) were compared with the expression of PD-L1, PD-L2, PD-1, B7-H3, and B7-H4 assessed by immunohistochemistry (IHC). Samples from 17 patients (37.0%) in the Nivolumab Cohort were positive for B7-H4 expression. At univariate analyses, only B7-H4 expression was associated with significantly decreased progression-free survival (PFS; 1.7 vs. 2.0 months; p = 0.026) and with a disadvantage in terms of overall survival (OS) close to statistical significance (4.4 vs. 9.8 months; p = 0.064). At multivariate analyses, B7-H4 expression was significantly associated with decreased PFS (hazard ratio (HR) = 2.28; p = 0.021) and OS (HR = 2.38; p = 0.022). Subsequently, B7-H4 expression was compared with clinical outcomes of 27 NSCLC patients receiving platinum-based chemotherapy (Chemotherapy Cohort), but no significant association was observed. Our results suggest a negative predictive role of B7-H4 in a population of NSCLC treated with immune checkpoint inhibitors, which deserves further research.

SUBMITTER: Genova C

PROVIDER: S-EPMC6832616 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Correlation between B7-H4 and Survival of Non-Small-Cell Lung Cancer Patients Treated with Nivolumab.

Genova Carlo C Boccardo Simona S Mora Marco M Rijavec Erika E Biello Federica F Rossi Giovanni G Tagliamento Marco M Dal Bello Maria Giovanna MG Coco Simona S Alama Angela A Vanni Irene I Barletta Giulia G Bianchi Rita R Maggioni Claudia C Bruzzi Paolo P Grossi Francesco F

Journal of clinical medicine 20191001 10

Reliable predictors of benefit from immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are still limited. We aimed to evaluate the association between the expression of selected molecules involved in immune response and clinical outcomes in NSCLC patients receiving nivolumab. In our study, the outcomes of 46 NSCLC patients treated with nivolumab in second or subsequent lines (Nivolumab Cohort) were compared with the expression of PD-L1, PD-L2, PD-1, B7-H3, and B7-H4 assessed by i ...[more]

PMID: 31581482

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Project description:BACKGROUND:Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival. METHODS:We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab. FINDINGS:Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11-17) for all patients (n=664), 19% (15-24) for those with at least 1% PD-L1 expression, and 11% (7-16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11-18) in patients treated with nivolumab, compared with 5% (3-7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12-0·27) for nivolumab and 0·43 (0·29-0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37-0·71) for nivolumab and 0·80 (0·61-1·04) for docetaxel. Long-term data did not show any new safety signals. INTERPRETATION:Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage. FUNDING:Bristol-Myers Squibb.

Project description:Importance:Nivolumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now the standard-of-care therapies in non-small cell lung cancer (NSCLC). Although EGFR-TKIs are well understood and have well-defined safety profiles, our experience with immune checkpoint inhibitors is still growing, particularly regarding the use of combinations of different classes of antitumor agents, including both the concomitant and sequential use of such agents. Objective:To determine whether nivolumab increases EGFR-TKI-associated interstitial pneumonitis (IP). Design, Setting, and Participants:A database study of 20 516 participants with NSCLC in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, performed between April 2015 and March 2017. Main Outcomes and Measures:We compared the incidence of EGFR-TKI-associated IP in patients receiving and not receiving nivolumab treatment. Results:The mean (SD) age of participants treated with EGFR-TKI, with and without nivolumab, was 64.4 (15.5) and 68.9 (11.8) years, respectively, and the proportion of men was 40.0% and 53.8%, respectively. Of the 20 516 participants with NSCLC, 985 cases (4.80%; 95% CI, 4.51-5.10) developed IP. Of 5777 patients treated with EGFR-TKI, 265 developed IP (4.59%; 95% CI, 4.06-5.16). Of 70 patients treated with both EGFR-TKI and nivolumab, 18 developed IP (25.7%; 95% CI, 16.0-37.6). The adjusted odds ratio for an interaction between EGFR-TKI and nivolumab was 4.31 (95% CI, 2.37-7.86; P < .001), suggesting the existence of an interaction. When we further stratified the patients by treatment with and without nivolumab, the odds ratio of EGFR-TKI-associated IP in cases with and without nivolumab treatment was 5.09 (95% CI, 2.87-9.03) and 1.22 (95% CI, 1.00-1.47), respectively. Conclusions and Relevance:We found a higher proportion of reports of IP for nivolumab in combination with EGFR-TKI vs treatment with either drug alone. Owing to the limitations of this study, the results warrant further confirmation. However, careful consideration should be given to the possibility of an increased risk of IP when EGFR-TKI is administered in combination with nivolumab, including concomitant and sequential use, and careful monitoring for IP is recommended.

Project description:ImportanceNivolumab, a monoclonal antibody that inhibits programmed cell death 1, is approved by the US Food and Drug Administration for treating advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and other malignancies. Data on long-term survival among patients receiving nivolumab are limited.ObjectivesTo analyze long-term overall survival (OS) among patients receiving nivolumab and identify clinical and laboratory measures associated with tumor regression and OS.Design, setting, and participantsThis was a secondary analysis of the phase 1 CA209-003 trial (with expansion cohorts), which was conducted at 13 US medical centers and included 270 patients with advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011. The analyses were either specified in the original protocol or included in subsequent protocol amendments that were implemented between 2008 and 2012. Statistical analysis was performed from October 30, 2008, to November 11, 2016.InterventionIn the CA209-003 trial, patients received nivolumab (0.1-10.0 mg/kg) every 2 weeks in 8-week cycles for up to 96 weeks, unless they developed progressive disease, achieved a complete response, experienced unacceptable toxic effects, or withdrew consent.Main outcomes and measuresSafety and activity of nivolumab; OS was a post hoc end point with a minimum follow-up of 58.3 months.ResultsOf 270 patients included in this analysis, 107 (39.6%) had melanoma (72 [67.3%] male; median age, 61 [range, 29-85] years), 34 (12.6%) had RCC (26 [76.5%] male; median age, 58 [range, 35-74] years), and 129 (47.8%) had NSCLC (79 [61.2%] male; median age, 65 [range, 38-85] years). Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC. In a multivariable analysis, the presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83; P = .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93; P = .04) was independently associated with reduced likelihood of survival at 5 years, whereas an Eastern Cooperative Oncology Group performance status of 0 (OR, 2.74; 95% CI, 1.43-5.27; P = .003) was independently associated with an increased likelihood of 5-year survival. Overall survival was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months; 95% CI, 13.8-26.9 months) or grade 3 or more (median, 20.3 months; 95% CI, 12.5-44.9 months) compared with those without treatment-related AEs (median, 5.8 months; 95% CI, 4.6-7.8 months) (P < .001 for both comparisons based on hazard ratios).Conclusions and relevanceNivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, RCC, or NSCLC. Characterizing factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development.Trial registrationClinicalTrials.gov identifier: NCT00730639.

Project description:ImportanceEvidence regarding real-world effectiveness of therapies for patients with advanced non-small cell lung cancer (NSCLC) whose tumors are resistant to platinum-based chemotherapy is lacking.ObjectiveTo compare the effectiveness of the immune checkpoint inhibitors atezolizumab (programmed cell death ligand 1 inhibitor) and nivolumab (programmed cell death 1 inhibitor) and the chemotherapy drug docetaxel in patients with advanced NSCLC resistant to platinum-based chemotherapy.Design, setting, and participantsThis comparative effectiveness study compared patients aged 18 years or older with advanced NSCLC who initiated atezolizumab, docetaxel, or nivolumab and who had previously been exposed to platinum-based chemotherapy using nationally representative real-world data from more than 280 US cancer clinics. Patients were followed-up from May 2011 to March 2020. Data analysis was performed between April and June 2021. Comparisons of interest were between atezolizumab vs docetaxel and atezolizumab vs nivolumab.ExposuresInitiation of atezolizumab, nivolumab, or docetaxel monotherapy.Main outcome and measuresThe main outcome was overall survival (OS).ResultsA total of 3336 patients (mean [SD] age, 67.1 [9.49] years; 1820 [54.6%] men and 1516 [45.4%] women) were assessed in the main analysis, including 206 patients receiving atezolizumab, 500 receiving docetaxel, and 2630 receiving nivolumab. Patients receiving atezolizumab were older than those treated with docetaxel (mean age [SD], 68.3 [9.4] years vs 65.6 [9.5] years), and were more likely to have been treated in an academic setting (39 patients [18.9%]) than those receiving docetaxel (49 patients [9.8%]) and nivolumab (128 patients [4.9%]). After adjustment for baseline characteristics, atezolizumab was associated with a significantly longer OS compared with docetaxel (adjusted hazard ratio [aHR], 0.79; 95% CI, 0.64-0.97). No significant difference in OS was observed between atezolizumab and nivolumab (aHR, 1.07; 95% CI, 0.89-1.28). These findings were consistent across all patient subgroups tested, and robust to plausible deviations from random missingness for Eastern Cooperative Oncology Group performance status in real-world data (eg, the tipping point for loss of a significantly beneficial effect for atezolizumab vs docetaxel was achieved if patients in the docetaxel group missing baseline Eastern Cooperative Oncology Group performance status had a mean performance status of 1.43 higher than expected).Conclusions and relevanceIn this comparative effectiveness study, atezolizumab was superior to docetaxel and matched nivolumab in prolonging OS in a real-world cohort of patients with advanced NSCLC who previously received platinum-based chemotherapy.

Dataset Information

Correlation between B7-H4 and Survival of Non-Small-Cell Lung Cancer Patients Treated with Nivolumab.

Publications

Correlation between B7-H4 and Survival of Non-Small-Cell Lung Cancer Patients Treated with Nivolumab.

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