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Atezolizumab for the treatment of non-small cell lung cancer.

ABSTRACT: INTRODUCTION:The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1). Areas covered: This drug profile article covers the basics of the cancer-immunity cycle and reviews some aspects of innate and adaptive immunology. We discuss the discovery of PD-L1 and PD-L2 while highlight the potential differences in targeting PD-L1 versus PD-1. In addition, we briefly summarized the available pre-clinical and clinical data of atezolizumab use in NSCLC. A special section covers the challenges of PD-L1 immunohistochemistry assay. Expert commentary: PD-1:PD-L1 blockade has taken the lead in the immunotherapeutics field and represents the backbone of developing combination immunotherapies. Atezolizumab represents a step forward in the treatment of advanced NSCLC, nonetheless PD1:PD-L1 blockade in early-stage lung cancer is still a matter of debate.

SUBMITTER: Santini FC

PROVIDER: S-EPMC6089509 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Atezolizumab for the treatment of non-small cell lung cancer.

Santini Fernando C FC Rudin Charles M CM

Expert review of clinical pharmacology 20170727 9

<h4>Introduction</h4>The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1). Areas covered: This drug profi ...[more]

PMID: 28714780

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Project description:The era of immunotherapy has changed the face of how we approach treatment for many oncologic and hematologic malignancies. Lung cancer has been in the forefront of checkpoint inhibition for the past 2 years and has paved the path for other subspecialties. While PD-1 inhibitors nivolumab and pembrolizumab have been approved for non-small cell lung cancer (NSCLC), this review focuses on atezolizumab, its landmark studies, and ongoing trials. Atezolizumab is the first programmed death ligand 1 (PD-L1) inhibitor to receive US Food and Drug Administration (FDA) approval for metastatic NSCLC patients who have progressed on frontline chemotherapy. This approval was based on two open-label Phase II multicenter trials, POPLAR (NCT01903993) and BIRCH (NCT02031458). Both studies revealed a benefit in overall survival (OS), progression-free survival, and response rate in the atezolizumab arm when compared to single-agent docetaxol. There were also fewest Grade 3-5 treatment-related adverse events (TRAEs) in the atezolizumab cohort. The open-label randomized Phase III OAK trial (NCT02008227) further established the role of atezolizumab in previously treated NSCLC. This study compared atezolizumab with docetaxel in patients with advanced NSCLC (squamous or nonsquamous histologies) who had progressed on one to two prior chemotherapy regimens. OS in the PD-L1-enriched population was superior in the atezolizumab arm (n=241) at 15.7 months compared with docetaxel (n=222) at 10.3 months (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.58-0.93; p=0.0102). Patients lacking PD-L1 also had survival benefit with atezolizumab with a median OS (mOS) of 12.6 months versus 8.9 months with chemotherapy (HR 0.75, 95% CI 0.59-0.96). Benefit was noted in both squamous and nonsquamous NSCLC subsets and regardless of PD-L1 expressivity. As seen in the POPLAR and BIRCH studies, the toxicity profile was significantly better with immunotherapy. The future is unfolding rapidly as new checkpoint inhibitors are gaining FDA approval. It is still not known if these agents will be used in combination with chemotherapy, with other immune-modulating agents, radiation therapy, or all of the above. The results of these studies investigating their use in combination with chemotherapy agents, with other immunotherapy agents such as CTLA-4 inhibitors, and with radiation therapy, are eagerly awaited.

Project description:Purpose: Atezolizumab is a programmed death ligand 1 (PDL-1) blocking antibody that was approved for metastatic non-small cell lung cancer (NSCLC) in patients with disease progression. Various studies have been initiated to explore the effectiveness of atezolizumab among different patient cohorts and disease statuses, including as first-line therapy. The purpose of this paper is to identify and summarize the trials that use atezolizumab as a first-line agent in chemotherapy-naïve patients with NSCLC. Methods: A database search was performed on Pubmed, Embase, and Wiley Cochrane Library-Central Register of Controlled Trials to identify clinical trials using atezolizumab as first-line therapy in NSCLC. Additionally, ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) were searched to identify relevant clinical trials. Conference abstracts from the American Society of Clinical Oncology, the European Society for Medical Oncology, and the American Association for Cancer Research were hand-searched. Any trial in which atezolizumab was used as first-line therapy in chemotherapy-naive patients with NSCLC was included. Results: Fifteen studies were ultimately included, all of which are current and ongoing. Of the 15 studies, 5 have reported results. When given in the first-line setting, atezolizumab had higher rates of objective response, progression-free survival, and overall survival, compared to the second and third-line settings. Among the 15 studies, atezolizumab is used as monotherapy (n = 5), in combination with chemotherapy (n = 6), in combination with targeted therapy such as bevacizumab (n = 1), as neoadjuvant/adjuvant therapy (n = 3), in combination with stereotactic body radiation therapy (n = 1), and in combination with or following chemoradiation (n = 1). Conclusion: Available evidence shows promising safety and efficacy with the use of atezolizumab as first-line therapy in NSCLC. Atezolizumab is currently being studied in a variety of treatment settings. If clinical benefits are shown, atezolizumab may deem to be a useful first-line agent in NSCLC.

Project description:ImportanceImmune checkpoint inhibitor combination therapy has recently become the standard of care for first-line treatment of metastatic nonsquamous non-small cell lung cancer. The implications of these first-line treatments are considerable, given the potential population of patients eligible to receive them and their high cost.ObjectiveTo evaluate the cost-effectiveness of adding atezolizumab to bevacizumab, carboplatin, and paclitaxel as a first-line treatment strategy for patients with metastatic nonsquamous non-small cell lung cancer in the United States.Design, setting, and participantsIn this economic evaluation, a primary microsimulation model was developed to assess atezolizumab combination vs bevacizumab, carboplatin, and paclitaxel alone in the first line (base case 1). A secondary model was developed to assess these treatments along with pembrolizumab combination and platinum doublet chemotherapy (base case 2). Treatment strategies and other simulated conditions were based on those from the IMpower150 and KEYNOTE-189 clinical trials. The study perspective was the US health care sector. One million patients with metastatic nonsquamous non-small cell lung cancer were simulated for each treatment group. This study was performed from February 2019 through May 2019.Main outcomes and measuresIncremental cost-effectiveness ratios were compared with a willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY).ResultsIn base case 1, in which 1 million patients were simulated, treating with bevacizumab, carboplatin, and paclitaxel in the first line was associated with a mean cost of $112 551 (95% CI, $112 450-$112 653) and a mean survival of 1.48 QALYs (95% CI, 1.47-1.48 QALYs) per patient. Atezolizumab plus bevacizumab, carboplatin, and paclitaxel was associated with a mean cost of $244 166 (95% CI, $243 864-$244 468) and a mean survival of 2.13 QALYs (95% CI, 2.12-2.13 QALYs) per patient, for an estimated incremental cost-effectiveness ratio of $201 676 per QALY (95% CI, $198 105-$205 355 per QALY). In base case 2, in which 1 million patients were simulated, pembrolizumab combination therapy was associated with a mean cost of $226 282 (95% CI, $226 007-$226 557) and a mean survival of 2.45 QALYs (95% CI, 2.44-2.46 QALYs) per patient. Pembrolizumab combination dominated atezolizumab plus bevacizumab, carboplatin, and paclitaxel, leading to an incremental cost-effectiveness ratio of $116 698 per QALY (95% CI, $115 088-$118 342 per QALY) between pembrolizumab combination and bevacizumab, carboplatin, and paclitaxel. Atezolizumab combination was not cost-effective at a willingness-to-pay threshold of $100 000 per QALY.Conclusions and relevanceIn this simulated model economic analysis, atezolizumab combination was not cost-effective compared with bevacizumab, carboplatin, and paclitaxel and provided suboptimal incremental benefit compared with cost vs pembrolizumab combination for first-line treatment. Although atezolizumab combination therapy provides clinical benefits, price reductions may be necessary for this treatment strategy to become cost-effective.

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.

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Atezolizumab for the treatment of non-small cell lung cancer.

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Atezolizumab for the treatment of non-small cell lung cancer.

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