Peking
University School of Oncology, Beijing Cancer Hospital, Thoracic
Oncology Collaborative Group on December 16, 2011 was successfully held
in Beijing Cancer Hospital, Peking University 4th International Lung Cancer Multidisciplinary Forum (IFMMLC, International Forumon Multidisciplinary Management of Lung Cancer).
From St. James's Hospital, Trinity College Dublin, Ireland, clinical
oncologist, British Thoracic Oncology Cooperation Group (BTOG) founder
Kenneth O'Byrne professor at will between the current "non-small cell lung cancer and Limitations" for the wonderful exposition.
Lessons learned from the failed clinical studies: unknown target unsatisfactory efficacy
2008 cetuximab combined with chemotherapy first-line treatment of advanced non-small cell lung cancer (NSCLC) Phase Ⅲ randomized controlled studies (FLEX study) showed that chemotherapy plus cetuximab group, the median overall survival (OS) was 11.3 months, 1-year survival rate was 47% with chemotherapy alone 10.1 months in the control group and 42%, the difference was significant (P = 0.044), hazard ratio (HR) was 0.87, suggesting that combination therapy can reduce the 13% risk of death. But the treatment group compared with the control group, only the extension of 1.2 months, the median OS, expensive drugs, the lower titer people grounded. The main reason is the lack of effective biomarkers.
To confirm the most from cetuximab benefit patients, follow-up studies retested FLEX study population tumor EGFR expression levels and efficacy of relevance. Researchers collected tumor EGFR expression data for the FLEX study population immunohistochemical score from 0 to 300. By statistical method to determine the efficacy of survival associated with EGFR expression threshold, that EGFR expression by immunohistochemistry score of 200. Analysis of low EGFR [removed]immunohistochemistry score <200) and high [removed]≥ 200) of patients with treatment outcomes.
1125 cases in 1121 cases of patients with EGFR immunohistochemistry data, 345 cases (31%) showed a high expression of EGFR, 769 cases (69%) showed a low EGFR expression. Patients with high expression of EGFR, chemotherapy plus cetuximab group, the median OS was significantly longer than
Chemotherapy group (12.0 months vs. 9.6 months, HR = 0.73, P = 0.011). Low expression patients, cetuximab group had no OS benefit (9.8 months vs. 10.3 months, HR = 0.99, P = 0.88).
However, EGFR expression detection and analysis system studied retrospectively. High expression of chemotherapy plus cetuximab group's overall OS is far more unfiltered who has been extended, but still unsatisfactory. It can be seen, prospective determine the efficacy, survival molecular markers of molecular targeted drugs will be the cornerstone of success.
From the success of clinical research for inspiration: be precise targets with less
Chinese University of Hong Kong, Professor TonyMok initiated IPASS study comparing single-agent gefitinib or carboplatin + paclitaxel doublet chemotherapy as first-line treatment of NSCLC difference in efficacy. The results showed that compared with carboplatin + paclitaxel chemotherapy compared to patients harboring EGFR mutations, gefitinib their death risk reduction 52% (P <0.001), the effective rate was 71.2%; while for wild-type EGFR, gefitinib therapy increased the risk of death (HR = 2.85, P <0.001), with an efficiency of only 1.1%.
Although the IPASS study, EGFR mutation is an exploratory analysis, but significant, because it provides a gene mutation according to screen patients, further effective and appropriate treatment is feasible. And thereafter the East-West prospective multicenter study confirmed, laid the EGFR mutation status of first-line therapy in EGFR-TKI important role in successful clinical treatment and written NCCN Guidelines.
FLEX study with different, IPASS study was aimed at first-line TKI therapy targets, find a clear molecular markers, and its success tells us: targeted can be more effective.
Molecular markers are mainly two: one is the prognostic markers, without treatment directly affect clinical outcomes around; second is the prediction marker to predict the clinical outcome of a particular treatment. May also have a predictive marker and prognostic value. Only by choosing the correct marker can effectively guide the clinical. Currently selected for the marker has the following two errors.
Myth one: mistakenly identified as the target prognosis prediction target
Early studies have shown that tumor microvessel density and survival for patients with NSCLC, patients with low density was significantly prolonged survival, so inhibiting angiogenesis drugs anti-VEGF monoclonal antibodies - bevacizumab appeared in clinical use. The E4599 bevacizumab studies suggest that first-line paclitaxel / carboplatin plus bevacizumab in a limited extent, improve the overall survival, after AVAiL and SAIL study further confirmed that chemotherapy with bevacizumab significantly increased line efficiency and progression-free survival (PFS). The success of bevacizumab to stimulate researchers to look at the multi-targeted anti-angiogenic drugs in combination with conventional chemotherapy (including: Motesanib, sunitinib, sorafenib, vandetanib, Cediranib, Aflibercept, Vadimezan etc.) , but so far there is no pivotal clinical efficacy study was confirmed.
Why? What is not NSCLC angiogenic therapeutic target? Professor O'Byrne center where the study shows: VEGF-A high expression of P53 tumor suppressor gene expression associated with defects, while high levels of VEGF and cell survival time was negatively correlated with VEGF may thus infer prognostic marker itself . Then we get in the A549 cell lines confirmed, adding significant proliferation of VEGF, anti-VEGF antibodies can inhibit proliferation. After the anti-VEGF, A549 cells were arrested at the majority of the G0/G1 phase; further confirmed through siRNA technology, VEGF and other angiogenic factors such as Neuropilin-1, Neuropilin-2 and KDR are associated with cell proliferation, ie VEGF itself with the same tumor cell proliferation that is related to prognosis and
Not suitable as a target for drug targeting.
Myth: Some markers can be both predictable and prognostic value
EML4-ALK fusion gene found in a variety of tumors, through the activation of downstream substrate molecules to pass, each transduction pathways cross each other, overlap, forming a complex signal transduction network, affect cell proliferation, differentiation and apoptosis. EML4-ALK fusion gene through a fusion partner of the extracellular domain of the spiral, the two EML4-ALK kinase molecules combined with each other to form a stable dimer, activated by autophosphorylation downstream MAPK, PI3K/AKT, JAK/STAT3 other pathways, thereby causing cell to malignant transformation. A number of studies have shown that EML4-ALK-positive patient survival is poor, it is a prognostic marker in itself.
Lessons learned from the failed clinical studies: unknown target unsatisfactory efficacy
2008 cetuximab combined with chemotherapy first-line treatment of advanced non-small cell lung cancer (NSCLC) Phase Ⅲ randomized controlled studies (FLEX study) showed that chemotherapy plus cetuximab group, the median overall survival (OS) was 11.3 months, 1-year survival rate was 47% with chemotherapy alone 10.1 months in the control group and 42%, the difference was significant (P = 0.044), hazard ratio (HR) was 0.87, suggesting that combination therapy can reduce the 13% risk of death. But the treatment group compared with the control group, only the extension of 1.2 months, the median OS, expensive drugs, the lower titer people grounded. The main reason is the lack of effective biomarkers.
To confirm the most from cetuximab benefit patients, follow-up studies retested FLEX study population tumor EGFR expression levels and efficacy of relevance. Researchers collected tumor EGFR expression data for the FLEX study population immunohistochemical score from 0 to 300. By statistical method to determine the efficacy of survival associated with EGFR expression threshold, that EGFR expression by immunohistochemistry score of 200. Analysis of low EGFR [removed]immunohistochemistry score <200) and high [removed]≥ 200) of patients with treatment outcomes.
1125 cases in 1121 cases of patients with EGFR immunohistochemistry data, 345 cases (31%) showed a high expression of EGFR, 769 cases (69%) showed a low EGFR expression. Patients with high expression of EGFR, chemotherapy plus cetuximab group, the median OS was significantly longer than
Chemotherapy group (12.0 months vs. 9.6 months, HR = 0.73, P = 0.011). Low expression patients, cetuximab group had no OS benefit (9.8 months vs. 10.3 months, HR = 0.99, P = 0.88).
However, EGFR expression detection and analysis system studied retrospectively. High expression of chemotherapy plus cetuximab group's overall OS is far more unfiltered who has been extended, but still unsatisfactory. It can be seen, prospective determine the efficacy, survival molecular markers of molecular targeted drugs will be the cornerstone of success.
From the success of clinical research for inspiration: be precise targets with less
Chinese University of Hong Kong, Professor TonyMok initiated IPASS study comparing single-agent gefitinib or carboplatin + paclitaxel doublet chemotherapy as first-line treatment of NSCLC difference in efficacy. The results showed that compared with carboplatin + paclitaxel chemotherapy compared to patients harboring EGFR mutations, gefitinib their death risk reduction 52% (P <0.001), the effective rate was 71.2%; while for wild-type EGFR, gefitinib therapy increased the risk of death (HR = 2.85, P <0.001), with an efficiency of only 1.1%.
Although the IPASS study, EGFR mutation is an exploratory analysis, but significant, because it provides a gene mutation according to screen patients, further effective and appropriate treatment is feasible. And thereafter the East-West prospective multicenter study confirmed, laid the EGFR mutation status of first-line therapy in EGFR-TKI important role in successful clinical treatment and written NCCN Guidelines.
FLEX study with different, IPASS study was aimed at first-line TKI therapy targets, find a clear molecular markers, and its success tells us: targeted can be more effective.
Molecular markers are mainly two: one is the prognostic markers, without treatment directly affect clinical outcomes around; second is the prediction marker to predict the clinical outcome of a particular treatment. May also have a predictive marker and prognostic value. Only by choosing the correct marker can effectively guide the clinical. Currently selected for the marker has the following two errors.
Myth one: mistakenly identified as the target prognosis prediction target
Early studies have shown that tumor microvessel density and survival for patients with NSCLC, patients with low density was significantly prolonged survival, so inhibiting angiogenesis drugs anti-VEGF monoclonal antibodies - bevacizumab appeared in clinical use. The E4599 bevacizumab studies suggest that first-line paclitaxel / carboplatin plus bevacizumab in a limited extent, improve the overall survival, after AVAiL and SAIL study further confirmed that chemotherapy with bevacizumab significantly increased line efficiency and progression-free survival (PFS). The success of bevacizumab to stimulate researchers to look at the multi-targeted anti-angiogenic drugs in combination with conventional chemotherapy (including: Motesanib, sunitinib, sorafenib, vandetanib, Cediranib, Aflibercept, Vadimezan etc.) , but so far there is no pivotal clinical efficacy study was confirmed.
Why? What is not NSCLC angiogenic therapeutic target? Professor O'Byrne center where the study shows: VEGF-A high expression of P53 tumor suppressor gene expression associated with defects, while high levels of VEGF and cell survival time was negatively correlated with VEGF may thus infer prognostic marker itself . Then we get in the A549 cell lines confirmed, adding significant proliferation of VEGF, anti-VEGF antibodies can inhibit proliferation. After the anti-VEGF, A549 cells were arrested at the majority of the G0/G1 phase; further confirmed through siRNA technology, VEGF and other angiogenic factors such as Neuropilin-1, Neuropilin-2 and KDR are associated with cell proliferation, ie VEGF itself with the same tumor cell proliferation that is related to prognosis and
Not suitable as a target for drug targeting.
Myth: Some markers can be both predictable and prognostic value
EML4-ALK fusion gene found in a variety of tumors, through the activation of downstream substrate molecules to pass, each transduction pathways cross each other, overlap, forming a complex signal transduction network, affect cell proliferation, differentiation and apoptosis. EML4-ALK fusion gene through a fusion partner of the extracellular domain of the spiral, the two EML4-ALK kinase molecules combined with each other to form a stable dimer, activated by autophosphorylation downstream MAPK, PI3K/AKT, JAK/STAT3 other pathways, thereby causing cell to malignant transformation. A number of studies have shown that EML4-ALK-positive patient survival is poor, it is a prognostic marker in itself.
ALK inhibitor
Crizotinib is ALK / C-met pair of small molecule inhibitors target. 2010
ASCO Annual Meeting, Bang et al. Reported a phase Ⅰ clinical study
enrolled a total of 82 cases of EML4-ALK-positive NSCLC patients, the
results showed patients receiving Crizotinib more than 90% tumor
shrinkage, 57% of patients achieved objective response. In the 2011 ASCO
Annual Meeting, Shaw Professor updated the clinical trial data: 82 cases of patients receiving Crizotinib, one-year survival rate was 77%, 2-year survival rate was 64%, with a median OS
No data; survival of patients with gender, race, smoking history or age had no significant correlation. In this phase Ⅰ clinical trial, 37 patients Crizotinib ALK-positive patients did not receive treatment, this group of patients a year and 2-year survival rates were 73% and 33%, the median OS was 20 months. Then researchers has conducted a subgroup analysis, the 24 cases of ALK-positive patients who did not receive treatment with Crizotinib received 32 cases of patients with ALK inhibitor therapy data were compared. The results show that in ALK-positive patients, patients receiving Crizotinib 1-year survival rate was significantly higher than patients who did not receive Crizotinib, 2-year survival rates are also significant differences; ALK inhibitors in patients receiving second-line, 1-year and 2-year survival rates were 49% and 33%, the median OS was 11 months. Thus, the researchers concluded: in ALK-positive group, patients receiving Crizotinib treatment can achieve significant survival benefit. 2011 "Journal of ThoraicOncology" magazine published a study suggests, with EGFR, KRAS mutations contrast, ALK-positive patients treated with pemetrexed significantly improved PFS. The study confirmed that, EML4-ALK is also a preferred predictive markers.
Should be solved: reversal drug combination
No matter how advanced NSCLC EGFRTKI efficacy, are able to escape the fate of drug resistance, 2010 ESMO conference report a study suggests, T790M mutation may be secondary to the emergence of drug resistance of the fuse, then C-MET gene amplification been reported so TKI resistance may be one of the mechanisms. How to solve the drug is our current urgent problems faced.
Afatinib the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor -2 (HER2) tyrosine kinase investigational oral irreversible inhibitor. 2008 a study, Afatinib can effectively inhibit expression L858R and T790M mutation H1975 cells. Afatinib Phase Ⅲ clinical study, Afatinib compared with placebo treatment first-or second-line TKI therapy
Patients with advanced NSCLC after progression, the results did not reach the main objective of suppressing the overall survival rate, but compared with placebo, Afatinib prolonged tumor latency, PFS was significantly longer (3.3 months vs. 1.1 months). On this basis, 2011
ASCO Annual Meeting reported in a study results suggest, Afatinib and cetuximab combination therapy EGFR-TKI (median treatment time of 2 to 4 years) resistant patients, disease control (SD) rate of 76%, which 8/22 cases (36%) achieved a partial response (PR), including four cases T790M mutations (19%).
Met gene amplification, the T790M secondary resistance is considered as an indicator, in untreated NSCLC patients rate was 3% to 7%, whereas in EGFR TKI resistant mutations in patients up to 20%. Its main role is to activate HER3, PI3K-AKT pathway. Immunohistochemical detection of tips, 54% of TKI-resistant patients Met gene overexpression. MetMAB is a specific combination of price Met receptor monoclonal antibody, 2011 ASCO Annual Meeting announced a global, randomized, double-blind phase Ⅱ study evaluated MetMAB erlotinib erlotinib monotherapy were second or third line Treatment of 128 cases of efficacy in patients with advanced NSCLC. The results showed that the combined group and monotherapy group, the median PFS and OS were not significantly
different. Further analysis revealed that, Met immunohistochemistry combined with high expression of Met antibody prolonged PFS and OS, while the combined treatment failed to give Met immunohistochemistry bring negative PFS and OS benefit. Tip Met gene expression may be MetMAB sensitive predictor of survival benefit. In Met expression screening based Ⅲ clinical studies are in progress, the results worth the wait.
Genotyping era: find the real target
Lung cancer treatment has entered genotyping based on a new era of targeted therapies, biomarkers individualized treatment under the guidance of lung cancer has become the leading direction, only to find the real target, in order to eyesight.
The present study showed that patients with lung cancer worldwide carrying various mutations in 54% of the population. Therefore, instead of a single gene through a multi-gene test results for patients with individualized treatment, is an important direction for the development of lung cancer.
2011 ASCO meeting reported a study enrolled 1144 patients, 955 cases for tissue samples, genetic abnormalities found in 852 cases, including 354 cases (40%) for a number of points changed. On 175 cases of patients with a single abnormal gene loci to give the corresponding targeted drug therapy, and the other on the 116 cases do not correspond to targeted therapies available for patients with standard chemotherapy. The results show that individualized targeted therapy group and standard chemotherapy complete remission (CR) rates were 2% and 0%, PR were 25% and 5%, objective response (ORR) was 27% and 5%. The median survival time was 13.4 months and 9.0 months. The results showed that key genes detected molecular abnormalities and appropriate targeted therapy drugs, efficacy is better. Future biomarkers should attach great importance to the role of each drug must find appropriate biomarkers can greatly enhance the therapeutic effect.
Conclusion:
Research into the development of cancer treatment is the core essence of targeted targeted therapy is based on genomic or proteomic ensure the presence of cancer cells or expressing "targets." New treatment should be individualized based on the pursuit of maximizing efficacy and to improve symptoms and quality of life. Only based on the effective molecular markers for targeted drug clinical trials to achieve breakthrough results.
Non-small cell lung cancer genotyping time has come! Just as in 2001 when the market imatinib, the U.S. "Time magazine" described on the fight against cancer on the road we have a new weapon, which is a revolutionary, and bullets targeted drugs is our only target tumor cells, which is exactly what we expect a huge breakthrough.
No data; survival of patients with gender, race, smoking history or age had no significant correlation. In this phase Ⅰ clinical trial, 37 patients Crizotinib ALK-positive patients did not receive treatment, this group of patients a year and 2-year survival rates were 73% and 33%, the median OS was 20 months. Then researchers has conducted a subgroup analysis, the 24 cases of ALK-positive patients who did not receive treatment with Crizotinib received 32 cases of patients with ALK inhibitor therapy data were compared. The results show that in ALK-positive patients, patients receiving Crizotinib 1-year survival rate was significantly higher than patients who did not receive Crizotinib, 2-year survival rates are also significant differences; ALK inhibitors in patients receiving second-line, 1-year and 2-year survival rates were 49% and 33%, the median OS was 11 months. Thus, the researchers concluded: in ALK-positive group, patients receiving Crizotinib treatment can achieve significant survival benefit. 2011 "Journal of ThoraicOncology" magazine published a study suggests, with EGFR, KRAS mutations contrast, ALK-positive patients treated with pemetrexed significantly improved PFS. The study confirmed that, EML4-ALK is also a preferred predictive markers.
Should be solved: reversal drug combination
No matter how advanced NSCLC EGFRTKI efficacy, are able to escape the fate of drug resistance, 2010 ESMO conference report a study suggests, T790M mutation may be secondary to the emergence of drug resistance of the fuse, then C-MET gene amplification been reported so TKI resistance may be one of the mechanisms. How to solve the drug is our current urgent problems faced.
Afatinib the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor -2 (HER2) tyrosine kinase investigational oral irreversible inhibitor. 2008 a study, Afatinib can effectively inhibit expression L858R and T790M mutation H1975 cells. Afatinib Phase Ⅲ clinical study, Afatinib compared with placebo treatment first-or second-line TKI therapy
Patients with advanced NSCLC after progression, the results did not reach the main objective of suppressing the overall survival rate, but compared with placebo, Afatinib prolonged tumor latency, PFS was significantly longer (3.3 months vs. 1.1 months). On this basis, 2011
ASCO Annual Meeting reported in a study results suggest, Afatinib and cetuximab combination therapy EGFR-TKI (median treatment time of 2 to 4 years) resistant patients, disease control (SD) rate of 76%, which 8/22 cases (36%) achieved a partial response (PR), including four cases T790M mutations (19%).
Met gene amplification, the T790M secondary resistance is considered as an indicator, in untreated NSCLC patients rate was 3% to 7%, whereas in EGFR TKI resistant mutations in patients up to 20%. Its main role is to activate HER3, PI3K-AKT pathway. Immunohistochemical detection of tips, 54% of TKI-resistant patients Met gene overexpression. MetMAB is a specific combination of price Met receptor monoclonal antibody, 2011 ASCO Annual Meeting announced a global, randomized, double-blind phase Ⅱ study evaluated MetMAB erlotinib erlotinib monotherapy were second or third line Treatment of 128 cases of efficacy in patients with advanced NSCLC. The results showed that the combined group and monotherapy group, the median PFS and OS were not significantly
different. Further analysis revealed that, Met immunohistochemistry combined with high expression of Met antibody prolonged PFS and OS, while the combined treatment failed to give Met immunohistochemistry bring negative PFS and OS benefit. Tip Met gene expression may be MetMAB sensitive predictor of survival benefit. In Met expression screening based Ⅲ clinical studies are in progress, the results worth the wait.
Genotyping era: find the real target
Lung cancer treatment has entered genotyping based on a new era of targeted therapies, biomarkers individualized treatment under the guidance of lung cancer has become the leading direction, only to find the real target, in order to eyesight.
The present study showed that patients with lung cancer worldwide carrying various mutations in 54% of the population. Therefore, instead of a single gene through a multi-gene test results for patients with individualized treatment, is an important direction for the development of lung cancer.
2011 ASCO meeting reported a study enrolled 1144 patients, 955 cases for tissue samples, genetic abnormalities found in 852 cases, including 354 cases (40%) for a number of points changed. On 175 cases of patients with a single abnormal gene loci to give the corresponding targeted drug therapy, and the other on the 116 cases do not correspond to targeted therapies available for patients with standard chemotherapy. The results show that individualized targeted therapy group and standard chemotherapy complete remission (CR) rates were 2% and 0%, PR were 25% and 5%, objective response (ORR) was 27% and 5%. The median survival time was 13.4 months and 9.0 months. The results showed that key genes detected molecular abnormalities and appropriate targeted therapy drugs, efficacy is better. Future biomarkers should attach great importance to the role of each drug must find appropriate biomarkers can greatly enhance the therapeutic effect.
Conclusion:
Research into the development of cancer treatment is the core essence of targeted targeted therapy is based on genomic or proteomic ensure the presence of cancer cells or expressing "targets." New treatment should be individualized based on the pursuit of maximizing efficacy and to improve symptoms and quality of life. Only based on the effective molecular markers for targeted drug clinical trials to achieve breakthrough results.
Non-small cell lung cancer genotyping time has come! Just as in 2001 when the market imatinib, the U.S. "Time magazine" described on the fight against cancer on the road we have a new weapon, which is a revolutionary, and bullets targeted drugs is our only target tumor cells, which is exactly what we expect a huge breakthrough.
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