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FGFR1 inhibition in lung squamous cell carcinoma: questions and controversies

View Article: PubMed Central - PubMed

ABSTRACT

Although the incidence of lung cancer has decreased due to the reduction of tobacco use, lung cancer remains the leading cause of cancer-related death. Lung squamous cell carcinoma represents 30% of lung cancers and only recently have possible drug-targetable mutations been identified in this disease, including fibroblast growth factor receptor 1 (FGFR1) gene amplification and genetic alterations in the phosphoinositide-3 kinase pathway. These discoveries have generated a great interest in the clinic and the initiation of clinical trials using FGFR tyrosine kinase inhibitors to treat FGFR-altered lung cancers. However, preliminary results from these studies have shown that not all patients respond to therapy. Here we review current unresolved questions on the selection of patients for their recruitment in FGFR tyrosine kinase inhibitor trials, how FGFR inhibitors could be combined with other targeted therapies or immunotherapies to improve patient outcome, and how the current preclinical models can help address these questions.

No MeSH data available.


Schematic showing possible combination of FGFR tyrosine kinase inhibitors with other targeted therapy, chemotherapy or immunotherapy.
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fig2: Schematic showing possible combination of FGFR tyrosine kinase inhibitors with other targeted therapy, chemotherapy or immunotherapy.

Mentions: Intra-tumoral heterogeneity and development of acquired resistance to targeted therapies indicate that combination of multiple therapies are likely to be required for effective long-term control of cancers. To date, clinical trials have shown that single-agent therapy using currently available FGFR inhibitors results in only modest response rates,7,8 raising the possibility that the therapeutic response could be enhanced with combination therapy.13,14,17 Strategies to improve therapeutic response to FGFR inhibitors could include combination with standard chemotherapy, other targeted therapy or immunotherapy. A recent meta-analysis comparing the activity of EGFR TKI with a combination of EGFR TKI and standard chemotherapy demonstrated no additional benefit of the combination therapy compared with single agent, but a significant increase in toxicity,20 indicating that combining TKI with chemotherapy may not prove an appropriate strategy for the patient. Another approach to enhance response to FGFR inhibition, prevent development of acquired resistance and limit the occurrence of adverse events would be to inhibit key components of the pathway downstream of FGFR, including phosphoinositide-3 kinase (PI3K) signaling, or to enhance cell death by combining FGFR inhibitors with pro-apoptotic therapies (Figure 2). Finally, with the recent description of a prolonged survival benefit of immunotherapy in patients with squamous NSCLC demonstrated in a phase-3 trial comparing nivolumab with chemotherapy,21 it will be important to investigate whether the combination of immune checkpoint inhibitors with FGFR-targeted therapy may improve patient outcome (Figure 2).


FGFR1 inhibition in lung squamous cell carcinoma: questions and controversies
Schematic showing possible combination of FGFR tyrosine kinase inhibitors with other targeted therapy, chemotherapy or immunotherapy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979434&req=5

fig2: Schematic showing possible combination of FGFR tyrosine kinase inhibitors with other targeted therapy, chemotherapy or immunotherapy.
Mentions: Intra-tumoral heterogeneity and development of acquired resistance to targeted therapies indicate that combination of multiple therapies are likely to be required for effective long-term control of cancers. To date, clinical trials have shown that single-agent therapy using currently available FGFR inhibitors results in only modest response rates,7,8 raising the possibility that the therapeutic response could be enhanced with combination therapy.13,14,17 Strategies to improve therapeutic response to FGFR inhibitors could include combination with standard chemotherapy, other targeted therapy or immunotherapy. A recent meta-analysis comparing the activity of EGFR TKI with a combination of EGFR TKI and standard chemotherapy demonstrated no additional benefit of the combination therapy compared with single agent, but a significant increase in toxicity,20 indicating that combining TKI with chemotherapy may not prove an appropriate strategy for the patient. Another approach to enhance response to FGFR inhibition, prevent development of acquired resistance and limit the occurrence of adverse events would be to inhibit key components of the pathway downstream of FGFR, including phosphoinositide-3 kinase (PI3K) signaling, or to enhance cell death by combining FGFR inhibitors with pro-apoptotic therapies (Figure 2). Finally, with the recent description of a prolonged survival benefit of immunotherapy in patients with squamous NSCLC demonstrated in a phase-3 trial comparing nivolumab with chemotherapy,21 it will be important to investigate whether the combination of immune checkpoint inhibitors with FGFR-targeted therapy may improve patient outcome (Figure 2).

View Article: PubMed Central - PubMed

ABSTRACT

Although the incidence of lung cancer has decreased due to the reduction of tobacco use, lung cancer remains the leading cause of cancer-related death. Lung squamous cell carcinoma represents 30% of lung cancers and only recently have possible drug-targetable mutations been identified in this disease, including fibroblast growth factor receptor 1 (FGFR1) gene amplification and genetic alterations in the phosphoinositide-3 kinase pathway. These discoveries have generated a great interest in the clinic and the initiation of clinical trials using FGFR tyrosine kinase inhibitors to treat FGFR-altered lung cancers. However, preliminary results from these studies have shown that not all patients respond to therapy. Here we review current unresolved questions on the selection of patients for their recruitment in FGFR tyrosine kinase inhibitor trials, how FGFR inhibitors could be combined with other targeted therapies or immunotherapies to improve patient outcome, and how the current preclinical models can help address these questions.

No MeSH data available.