Current standards for clinical management of small cell lung cancer

Farago, Anna F.; Keane, Florence K.

doi:10.21037/tlcr.2018.01.16

Cited by 182 publications

(169 citation statements)

References 70 publications

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“…Despite a median survival limited to approximately 10 months, there has been no significant improvement in overall survival (OS) in more than 20 years. 1,2 In the phase I/III IMpower133 trial (NCT02763579), the addition of the anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab (Tecentriq Ò , F. Hoffmann-La Roche Ltd, Basel, Switzerland/Genentech, Inc., South San Francisco, CA) to carboplatin and etoposide (CP/ET) resulted in a significant improvement in OS, compared with placebo plus CP/ ET [median 12.3 months versus 10.3 months, hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.54e0.91; P ¼ 0.007]. Progression-free survival (PFS) was also significantly improved (median 5.2 months versus 4.3 months, HR 0.77; 95% CI 0.62e0.96; P ¼ 0.02).…”

Section: Introductionmentioning

confidence: 99%

Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial

et al. 2020

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Background: The addition of atezolizumab to carboplatin and etoposide (CP/ET) significantly improved progression-free and overall survival for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the IMpower133 study (NCT02763579). We have evaluated adverse events (AEs) and patient-reported outcomes in IMpower133 to assess the benefiterisk profile of this regimen. Patients and methods: Patients received four 21-day cycles of CP/ET plus intravenous atezolizumab 1200 mg or placebo (induction phase), followed by atezolizumab or placebo (maintenance phase) until progression or loss of benefit. AEs were assessed and patient-reported outcomes were evaluated every 3 weeks during treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire e Core 30 (QLQ-C30) and QLQ-LC13. Results: Overall, 394 patients were assessable for safety in the induction phase and 318 in the maintenance phase. The frequency of AEs, grade 3e4 AEs, and serious AEs was similar between arms in both phases. Immune-related AEs were more frequent in the atezolizumab arm during both induction (28% versus 17%; leading to atezolizumab/placebo interruption 9% versus 5%, leading to withdrawal 4% versus 0%) and maintenance (26% versus 15%; leading to atezolizumab/placebo interruption, 3% versus 2%, leading to withdrawal 1% versus 1%), most commonly rash (induction 11% versus 9%, maintenance 14% versus 4%), and hypothyroidism (induction 4.0% versus 0%, maintenance 10% versus 1%). Changes in patient-reported treatment-related symptoms commonly associated with quality of life impairment were generally similar during induction and most of the maintenance phase. Patientreported function and health-related quality of life (HRQoL) improved in both arms after initiating treatment, with more pronounced and persistent HRQoL improvements in the atezolizumab arm. Conclusions: In patients with ES-SCLC, atezolizumab plus CP/ET has a comparable safety profile to placebo plus CP/ET, and the addition of atezolizumab did not adversely impact patient-reported HRQoL. These data demonstrate the positive benefiterisk profile of first-line atezolizumab plus CP/ET in ES-SCLC and further support this regimen as a new standard of care in this setting. Clinical trials number: NCT02763579.

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Section: Introductionmentioning

confidence: 99%

Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial

et al. 2020

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“…Small cell lung carcinoma (SCLC) is a high-grade neuroendocrine cancer that accounts for ∼15% of all lung cancers and causes over 200,000 deaths worldwide each year (Sabari et al , 2017). The ability of SCLC cells to leave the primary tumor and establish inoperable metastases is a major cause of death and a serious impediment to successful therapy (Farago and Keane, 2018, van Meerbeeck et al , 2011). SCLC is one of the most metastatic human cancers, with over 60% of SCLC patients presenting with disseminated disease at the time of diagnosis, often including liver, bone, brain, and secondary lung metastases (Nakazawa et al , 2012, Riihimaki et al , 2014).…”

Section: Introductionmentioning

confidence: 99%

Axon-like protrusions promote small cell lung cancer migration and metastasis

Yang

Cai

et al. 2019

Preprint

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14Metastasis is the main cause of death in cancer patients but remains a poorly understood 15 process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic types of 16 human cancer. SCLC cells normally express neuroendocrine and neuronal gene programs but 17 accumulating evidence indicates that these cancer cells become relatively more neuronal and less 18 neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human 19 SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The 20 formation of these protrusions is controlled by multiple neuronal factors implicated in 21 axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like 22 protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option 23 of developmental neuronal programs is a novel molecular and cellular mechanism that 24 contributes to the high metastatic ability of SCLC. 25 65 cells that have transitioned to a more neuronal cell state. 66 5 68 To investigate SCLC migration, we developed an assay in which SCLC cells, which 69 classically grow in culture as floating spheres or aggregates, are grown as a monolayer under 70 Matrigel ((Denny et al., 2016) and Methods). Unexpectedly, we noticed that cells from some 71 SCLC cell lines (N2N1G, 16T, 6PF) derived from the Rb f/f ;p53 f/f (DKO) and Rb f/f ;p53 f/f ;p130 f/f 72 (TKO) genetically engineered mouse models form long cellular protrusions into cell-free spaces 73 ( Figure 1A-B). To determine whether these structures specifically project into cell-free areas or 74 they also exist within monolayers, we cultured a minor fraction of fluorescently-labeled, RESULTS 67 SCLC cells can form long cellular protrusions in culture and in vivo 75GFP positive SCLC cells with control SCLC cells. We found that SCLC cells also form protrusions 76 when they are in close contact with surrounding cancer cells (Figure S1A). Similar mixing 77 experiments performed in subcutaneous allografts also documented the growth of protrusions by 78 SCLC cells in vivo (Figure 1C-D). Finally, similar structures also extend from SCLC micro-79 metastases in the liver in the autochthonous TKO mouse model and after intravenous 80 transplantations of SCLC cells (Figure S1B-C). 81Human SCLC patient-derived xenografts (PDXs) recapitulate many important features of the 82 human disease (e.g. (Gardner et al., 2017, Saunders et al., 2015). To label rare cancer cells 83 within human SCLC PDXs and identify whether they had protrusions in unperturbed tumors, we 84 used DiI tracing. DiI is a lipophilic dye that diffuses within cell membranes and has been widely 85 employed to label projections from individual neurons (Heilingoetter and Jensen, 2016, Mufson 86 et al., 1990). Protrusions from SCLC cells were easily identifiable in two out of three PDX 87 models ( Figure 1E-F). In the 2D monolayer culture system, not all human SCLC cell lines 88 formed protrusions, but NCI-H446 cells formed long protru...

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“…SCLC is the most aggressive and devastating lung cancer type, which progresses rapidly. However, ES‐SCLC treatment strategies have not changed over the past two decades, 2 in contrast with NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Atezolizumab in combination with carboplatin and etoposide for heavily treated small cell lung cancer

et al. 2020

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Atezolizumab was the first immune checkpoint inhibitor (ICI) to be introduced as a first‐line treatment option for extensive‐stage small cell lung cancer (ES‐SCLC), in combination with carboplatin and etoposide (CE) chemotherapy. However, SCLC treatment options after progression to first‐line chemotherapy are limited, warranting the readministration of previously used drugs. In combination with atezolizumab, CE readministration may theoretically be effective, based on two tentative mechanisms: its additive and synergistic effects on cytotoxic chemotherapy. The additive effect is based on the IFCT‐1603 trial in which the Kaplan‐Meier estimates of both progression‐free survival (PFS) and overall survival (OS) in the atezolizumab group exhibited a tail plateau in the selected population. Conversely, an anti‐PD‐L1 antibody synergistic effect on platinum compounds was assessed in a preclinical study, which was reinforced by clinical data. Thus, atezolizumab in combination with CE may be a treatment option in heavily treated patients. Here, we describe the first case of a heavily treated ES‐SCLC patient treated with chemoimmunotherapy, resulting in a partial response and a durable PFS. Key points Significant findings of the study and what this study adds CE readministration with atezolizumab may be effective based on two tentative mechanisms. Additive and synergistic effects of atezolizumab on CE have been previously suggested via a clinical trial and preclinical study, respectively. This is reflected in the current case in clinical settings.

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Current standards for clinical management of small cell lung cancer

Cited by 182 publications

References 70 publications

Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial

Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial

Axon-like protrusions promote small cell lung cancer migration and metastasis

Atezolizumab in combination with carboplatin and etoposide for heavily treated small cell lung cancer

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