Italian Nivolumab Expanded Access Program in Nonsquamous Non–Small Cell Lung Cancer Patients: Results in Never-Smokers and EGFR-Mutant Patients

Garassino, Marina Chiara; Gelibter, Alain; Grossi, Francesco; Chiari, Rita; Parra, Héctor Soto; Cascinu, Stefano; Cognetti, Francesco; Turci, D.; Blasi, Livio; Bengala, Carmelo; Mini, Enrico; Baldini, Editta; Quadrini, Silvia; Ceresoli, Giovanni Luca; Antonelli, Paola; Vasile, Enrico; Pinto, Carmine; Fasola, Gianpiero; Galetta, Domenico; Macerelli, Marianna; Giannarelli, Diana; Russo, Giuseppe Lo; Marinis, Filippo de

doi:10.1016/j.jtho.2018.04.025

Cited by 78 publications

(73 citation statements)

References 24 publications

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“…Several studies have shown that NSCLC patients who are smokers and have wild-type EGFR were able to benefit the most from anti-PD-1 therapy. [43][44][45][46][47] Therefore, anti-PD-1 therapy may be the most beneficial for patients with abundant macrophage infiltration. Our findings provide a new potential strategy for priority population selection for anti-PD-1/PD-L1 therapy.…”

Section: Discussionmentioning

confidence: 99%

<p>M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer</p>

Cao

Che

Qiu

et al. 2019

CMAR

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These authors contributed equally to this workBackground: Lung cancer is the leading cause of cancer-related death worldwide. Although the macrophages can affect the development of tumor, the contribution of macrophages to the prognosis of non-small-cell lung cancer (NSCLC) is still controversial. Moreover, anti-PD-1 therapy can redirect macrophages from an M2 to an M1 phenotype, suggesting that tumor PD-L1 may affect the prognostic role of macrophages. Therefore, in this study, we aimed to display a macrophage landscape to clarify the function of macrophages, considering the localization and polarization of the macrophages, and evaluate the effect of M2 macrophages and tumor PD-L1 in combination on the prognosis of NSCLC. Methods: We performed multiplex quantitative immunofluorescence staining of pan-cytokeratin (CK), CD68, CD163, PD-L1, and DAPI on one tissue specimen simultaneously from 137 NSCLC patients. Results: M2 macrophages, involved marginM2 (M2 macrophages in tumor stroma), and centralM2 (M2 macrophages infiltrating into tumor islets) increased as the tumor stage increased. More macrophages were found in lung squamous cell carcinoma (LUSC) patients, patients with wild-type EGFR, and smokers than in patients with lung adenocarcinoma (LUAD), patients with EGFR mutations, and non-smokers. Infiltration of centralM2 was an independent prognostic factor of poor overall survival (OS) and disease-free survival (DFS) for NSCLC patients (P<0.05), which was superior to total macrophages and total M2 macrophages. Moreover, patients with centralM2 less PD-L1 − tumors showed the best OS and DFS, while the patients with centralM2 more PD-L1 + tumors showed the worst OS and DFS, and the two groups with centralM2 less PD-L1 + and centralM2 more PD-L1 − were in the middle (P=0.002, 0.034, respectively). Conclusion: Tumor islet-infiltrating M2 macrophages influence the prognosis of NSCLC patients. The analysis of M2 macrophages and tumor PD-L1 in combination may enhance the accuracy of prognostic prediction. This study provides a new understanding of macrophages in the development of NSCLC through the analysis of macrophage landscape.

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Section: Discussionmentioning

confidence: 99%

<p>M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer</p>

Cao

Che

Qiu

et al. 2019

CMAR

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“…Results of the IMpower 150 trial (see Recommendation 5, first-line treatment of NSCLC without a druggable oncogene driver) [102], which included data on patients with EGFR or ALK genetic alterations, support the use of a combination of atezolizumab (anti-PD-L1) and bevacizumab with carboplatin and paclitaxel as a therapeutic option in patients with non-squamous mNSCLC, and a PS of 0-1, in the absence of contraindications to the use of immunotherapy and may be an option also in the second-line setting [IV, C] (Figure 3). However, following the meeting in Guangzhou, two publications [192,193] reported a lack of efficacy for ICT mAbs as single-agents second-line, in TKI naive, PD-L1þ, EGFRmutant patients with advanced NSCLC, including those with PD-L1 expression 50%. These data suggest that these agents may not be an appropriate therapeutic choice in this setting.…”

Section: T1mimentioning

confidence: 99%

Pan-Asian adapted Clinical Practice Guidelines for the management of patients with metastatic non-small-cell lung cancer: a CSCO–ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS

et al. 2019

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The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of metastatic non-small-cell lung cancer (NSCLC) was published in 2016. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Chinese Society of Clinical Oncology (CSCO) to convene a special guidelines meeting immediately after the Chinese Thoracic Oncology Group Annual Meeting 2018, in Guangzhou, China. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic NSCLC cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic NSCLC representing the oncological societies of China (CSCO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the six participating Asian countries. During the review process, the updated ESMO 2018 Clinical Practice Guidelines for metastatic NSCLC were released and were also considered, during the final stages of the development of the Pan-Asian adapted Clinical Practice Guidelines.

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“…42 The activity and safety of nivolumab in routine clinical practice was also investigated in three different expanded access programs (EAPs) in Canada, France, and Italy, including a pretreated PS 2 population. [43][44][45] Although the safety profile evaluating TRAEs and TRAEs leading to discontinuation was comparable with the overall population, median survival was worse in patients with ECOG PS 2 (Canadian EAP: 5.9 v 9.1 months; Italian EAP: PS 2 was a predictive factor for both PFS and OS). 43,45 However, all these studies just proved that PS 2 patients have a poorer prognosis than patients with PS 0 or 1, consistent with prior knowledge.…”

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confidence: 99%

Immunotherapy in Non–Small-Cell Lung Cancer Patients With Performance Status 2: Clinical Decision Making With Scant Evidence

Passaro

Spitaleri

Gyawali

et al. 2019

JCO

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Italian Nivolumab Expanded Access Program in Nonsquamous Non–Small Cell Lung Cancer Patients: Results in Never-Smokers and EGFR-Mutant Patients

Abstract: The data on the Italian expanded access program in populations with nonsquamous NSCLC suggest that subgroups of patients could benefit differently from nivolumab according to their EGFR mutational status and smoking habits. These results warrant further investigation.

Cited by 78 publications

References 24 publications

<p>M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer</p>

<p>M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer</p>

Pan-Asian adapted Clinical Practice Guidelines for the management of patients with metastatic non-small-cell lung cancer: a CSCO–ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS

Immunotherapy in Non–Small-Cell Lung Cancer Patients With Performance Status 2: Clinical Decision Making With Scant Evidence

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