Phase II trial of Sorafenib in conjunction with chemotherapy and as maintenance therapy in extensive-stage small cell lung cancer

Sharma, Neelesh; Pennell, Nathan A.; Nickolich, Myles; Halmos, Balázs; Ma, Patrick; Mekhail, Tarek; Fu, Pingfu; Dowlati, Afshin

doi:10.1007/s10637-013-0061-6

Cited by 34 publications

(22 citation statements)

References 29 publications

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“…However, following the principle of “non-oncogene addiction” 72 , some factors and pathways can be essential for the growth and maintenance of tumors without being genetically altered. Thus, it is entirely possible that RAF-MEK-ERK pathway inhibition in SCLC thus far has had limited effects simply due to the strong cytotoxicity of inhibitors in this pathway 73 . Emerging research additionally suggests that RAF-MEK-ERK pathway inhibition may block a number of pro-metastatic mechanisms in SCLC cells.…”

Section: Discussionmentioning

confidence: 99%

Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Cristea

Sage

2016

Journal of Thoracic Oncology

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The activity of the RAF-MEK-ERK signaling pathway is critical for the proliferation of normal and cancerous cells. Oncogenic mutations driving the development of lung adenocarcinoma often activate this signaling pathway. In contrast, pathway activity levels and their biological roles are not well established in small cell lung cancer (SCLC), a fast-growing neuroendocrine lung cancer subtype. Here we discuss the function of the RAF-MEK-ERK kinase pathway and the mechanisms leading to its activation in SCLC cells. In particular, we argue that activation of this pathway may be beneficial to the survival, proliferation and spread of SCLC cells in response to multiple stimuli. We also consider evidence that high levels of RAF-MEK-ERK pathway activity may be detrimental to SCLC tumors, including in part by interfering with their neuroendocrine fate. Based on these observations, we examine when small molecules targeting kinases in the RAF-MEK-ERK pathway may be useful therapeutically in SCLC patients, including in combination with other therapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Cristea

Sage

2016

Journal of Thoracic Oncology

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“…Moreover, these drugs have generally been considered ideal for the maintenance approach, because they are well tolerated and conveniently administered for long-term use. However, a phase II trial of sorafenib in conjunction with chemotherapy as maintenance therapy in extensive-stage small-cell lung cancer showed that combination therapy has significant toxicity at current dose levels and is associated with disappointing efficacy data (Sharma et al 2014). …”

Section: Introductionmentioning

confidence: 99%

Apatinib as maintenance therapy in extensive-stage small-cell lung cancer: results from a single-center retrospective study

Yan

Wang

et al. 2018

J Cancer Res Clin Oncol

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PurposeTo evaluate the efficacy of maintenance apatinib after chemotherapy for extensive-stage (ED) small-cell lung cancer (SCLC).Patients and methodsThis was a retrospective analysis of 23 cases of extensive-stage SCLC admitted to the Affiliated Cancer Hospital of Zhengzhou University from January 2015 to December 2017. The patients without progression after induction chemotherapy received apatinib 250 mg per day until disease progression or unacceptable toxicity occurred. We analyzed the median progression-free survival (PFS), median overall survival (OS) and safety.ResultsOf 23 enrolled patients, 1 was lost to follow-up. The median PFS from the time of maintenance therapy was 4.1 months (95% CI 3.63–4.57 months). The median PFS from the time of induction chemotherapy was 8.3 months (95% CI 7.20–9.40 months). The median OS from the time of maintenance therapy was 12.5 months (95% CI 5.51–19.49 months). The median OS from the time of induction chemotherapy was 17.0 months (95% CI 9.86–24.14 months). The most frequent treatment-related adverse events were hand–foot syndrome (43.5%, 10/23) and secondary hypertension (30.4%, 7/23), followed by fatigue, proteinuria, nausea, and oral mucositis (17.4%, 13.0%, 13.0%, and 8.7%, respectively). Hematologic toxicity included thrombocytopenia (30.4%), leucopenia (26.1%), and anemia (17.4%). The main grade 3 or 4 toxicities were hand–foot syndrome (8.7%, 2/23) and hypertension (4.3%, 1/23).ConclusionMaintenance apatinib was safe and achieved encouraging PFS and OS in extensive-stage SCLC.

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“…The effect of EP plus concurrent and sequential sorafenib on untreated extensive-stage SCLC was evaluated 36. The patients received four cycles of EP chemotherapy concurrently with sorafenib.…”

Section: Sorafenibmentioning

confidence: 99%

“…Those without progression after four cycles were further administered a higher sorafenib dose as maintenance for ≤12 months. The regimen of EP combined sorafenib at current dose levels has significant toxicity, and the efficacy results have been disappointing 36. The suitable dose of sorafenib combined EP is still unknown, and toxicity should be paid more attention.…”

Section: Sorafenibmentioning

confidence: 99%

Advances in antiangiogenic treatment of small-cell lung cancer

Lu¹,

Jiang²

2017

OTT

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Small-cell lung cancer (SCLC), a poorly differentiated neuroendocrine malignancy, has a rapid growth rate, strong aggressiveness, early metastases, and poor prognosis. Angiogenesis greatly contributes to the metastatic process of SCLC, which has a higher vascularization compared with non-small-cell lung cancer (NSCLC). SCLC might constitute an ideal malignancy for assessing new antiangiogenic drugs and therapeutic strategies. Combining bevacizumab with paclitaxel has therapeutic benefits in chemoresistant, relapsed SCLC. The cisplatin–etoposide and bevacizumab combination, as the first-line treatment for extensive-stage SCLC, can improve progression-free survival (PFS), with an acceptable toxicity profile. Ziv-aflibercept combined with topotecan is promising for platinum-refractory SCLC. Chemotherapy combined with thalidomide cannot prolong survival. Maintenance sunitinib of 37.5 mg/day in extensive-stage SCLC patients following induction chemotherapy with platinum/etoposide improves median PFS by 1.6 months. Serum angiopoietin-2 concentrations and vascular endothelial growth factor levels correlate with poor prognosis. Bevacizumab, ziv-aflibercept, and sunitinib are worthy of further evaluation. Thalidomide, sorafenib, pomalidomide, and cediranib may not be suitable for SCLC.

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Phase II trial of Sorafenib in conjunction with chemotherapy and as maintenance therapy in extensive-stage small cell lung cancer

Abstract: The combination of platinum based chemotherapy and sorafenib has significant toxicity at current dose levels and is associated with disappointing efficacy data.

Cited by 34 publications

References 29 publications

Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Apatinib as maintenance therapy in extensive-stage small-cell lung cancer: results from a single-center retrospective study

Advances in antiangiogenic treatment of small-cell lung cancer

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