Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC

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Abstract

The cancer-cell-killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor-mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy.

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Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells.

Andrea Facciabene, Xiaohui Peng, Ian S Hagemann … (2011)

Although immune mechanisms can suppress tumour growth, tumours establish potent, overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (T(reg)) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth. ©2011 Macmillan Publishers Limited. All rights reserved

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Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.

Martin Reck, Joachim von Pawel, Petr Zatloukal … (2009)

Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non-small-cell lung cancer (NSCLC). This randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine (CG) plus bevacizumab in this setting. Patients were randomly assigned to receive cisplatin 80 mg/m2 and gemcitabine 1,250 mg/m(2) for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. The primary end point was amended from overall survival (OS) to progression-free survival (PFS). Between February 2005 and August 2006, 1,043 patients were randomly assigned (placebo, n = 347; low dose, n = 345; high dose, n = 351). PFS was significantly prolonged; the hazard ratios for PFS were 0.75 (median PFS, 6.7 v 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (median PFS, 6.5 v 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. Objective response rates were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus CG, respectively. Duration of follow-up was not sufficient for OS analysis. Incidence of grade 3 or greater adverse events was similar across arms. Grade > or = 3 pulmonary hemorrhage rates were < or = 1.5% for all arms despite 9% of patients receiving therapeutic anticoagulation. Combining bevacizumab (7.5 or 15 mg/kg) with CG significantly improved PFS and objective response rate. Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC.

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Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.

David Johnson, Louis Fehrenbacher, William F. Novotny … (2004)

To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m(2)) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

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Author and article information

Journal

Title: New England Journal of Medicine

Abbreviated Title: N Engl J Med

Publisher: New England Journal of Medicine (NEJM/MMS)

ISSN (Print): 0028-4793

ISSN (Electronic): 1533-4406

Publication date Created: June 04 2018

Publication date (Electronic): June 04 2018

Affiliations

[1 ]From the Florida Hospital Cancer Institute, Orlando (M.A.S.); Rocky Mountain Cancer Centers, Denver (R.M.J.); US Oncology, Houston (R.M.J.); Azienda Unità Sanitaria Locale della Romagna, Ravenna, Italy (F.C.); Instituto Nacional del Torax, Santiago, Chile (F.O.); Moscow City Oncology Hospital, Moscow (D.S.); National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan (N.N.); Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria,...

Article

DOI: 10.1056/NEJMoa1716948

PubMed ID: 29863955

SO-VID: 462aa372-d52f-4243-9c23-4ab86422e1bf

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Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC

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Most cited references 10

Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells.

Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.

Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.

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