The Experts below are selected from a list of 75 Experts worldwide ranked by ideXlab platform
Daniel B Costa - One of the best experts on this subject based on the ideXlab platform.
-
egfr exon 20 insertion mutations display sensitivity to hsp90 inhibition in preclinical models and lung adenocarcinomas
Clinical Cancer Research, 2018Co-Authors: Susan E Jorge, Zofia Piotrowska, Geoffrey R Oxnard, Mark S Huberman, Antonio R Lucenaaraujo, Hiroyuki Yasuda, Deepa Rangachari, Lecia V Sequist, Susumu Kobayashi, Daniel B CostaAbstract:Purpose: EGFR exon 20 insertions account for up to 10% of all EGFR mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor. Experimental Design: Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer. Results: We show that select first, second and third generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. We exploit this vulnerability to show that the non-geldanamycin Hsp90 inhibitor Luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis. In addition, a patient whose EGFR inhibitor-insensitive lung adenocarcinoma harbored an EGFR exon 20 insertion mutation had a confirmed radiographic response to Luminespib. Conclusions: The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor Luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.
-
activity of the hsp90 inhibitor Luminespib among non small cell lung cancers harboring egfr exon 20 insertions
Annals of Oncology, 2018Co-Authors: Zofia Piotrowska, Daniel B Costa, Geoffrey R Oxnard, Mark S Huberman, Justin F Gainor, Inga T Lennes, Alona Muzikansky, Alice T Shaw, Christopher G Azzoli, Rebecca S HeistAbstract:Abstract Background There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor Luminespib (AUY922) in NSCLC patients with EGFR ins20. Patients and methods Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype. Results Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4–5.6) and median OS (mOS) was 13 months (95% CI 4.9–19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common Luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination. Conclusion The study met its primary end point, suggesting that Luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of Luminespib and other hsp90 inhibitors in this population is warranted. Study registration (ClinicalTrials.gov) NCT01854034.
Zofia Piotrowska - One of the best experts on this subject based on the ideXlab platform.
-
egfr exon 20 insertion mutations display sensitivity to hsp90 inhibition in preclinical models and lung adenocarcinomas
Clinical Cancer Research, 2018Co-Authors: Susan E Jorge, Zofia Piotrowska, Geoffrey R Oxnard, Mark S Huberman, Antonio R Lucenaaraujo, Hiroyuki Yasuda, Deepa Rangachari, Lecia V Sequist, Susumu Kobayashi, Daniel B CostaAbstract:Purpose: EGFR exon 20 insertions account for up to 10% of all EGFR mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor. Experimental Design: Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer. Results: We show that select first, second and third generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. We exploit this vulnerability to show that the non-geldanamycin Hsp90 inhibitor Luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis. In addition, a patient whose EGFR inhibitor-insensitive lung adenocarcinoma harbored an EGFR exon 20 insertion mutation had a confirmed radiographic response to Luminespib. Conclusions: The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor Luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.
-
activity of the hsp90 inhibitor Luminespib among non small cell lung cancers harboring egfr exon 20 insertions
Annals of Oncology, 2018Co-Authors: Zofia Piotrowska, Daniel B Costa, Geoffrey R Oxnard, Mark S Huberman, Justin F Gainor, Inga T Lennes, Alona Muzikansky, Alice T Shaw, Christopher G Azzoli, Rebecca S HeistAbstract:Abstract Background There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor Luminespib (AUY922) in NSCLC patients with EGFR ins20. Patients and methods Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype. Results Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4–5.6) and median OS (mOS) was 13 months (95% CI 4.9–19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common Luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination. Conclusion The study met its primary end point, suggesting that Luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of Luminespib and other hsp90 inhibitors in this population is warranted. Study registration (ClinicalTrials.gov) NCT01854034.
Geoffrey R Oxnard - One of the best experts on this subject based on the ideXlab platform.
-
egfr exon 20 insertion mutations display sensitivity to hsp90 inhibition in preclinical models and lung adenocarcinomas
Clinical Cancer Research, 2018Co-Authors: Susan E Jorge, Zofia Piotrowska, Geoffrey R Oxnard, Mark S Huberman, Antonio R Lucenaaraujo, Hiroyuki Yasuda, Deepa Rangachari, Lecia V Sequist, Susumu Kobayashi, Daniel B CostaAbstract:Purpose: EGFR exon 20 insertions account for up to 10% of all EGFR mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor. Experimental Design: Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer. Results: We show that select first, second and third generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. We exploit this vulnerability to show that the non-geldanamycin Hsp90 inhibitor Luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis. In addition, a patient whose EGFR inhibitor-insensitive lung adenocarcinoma harbored an EGFR exon 20 insertion mutation had a confirmed radiographic response to Luminespib. Conclusions: The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor Luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.
-
activity of the hsp90 inhibitor Luminespib among non small cell lung cancers harboring egfr exon 20 insertions
Annals of Oncology, 2018Co-Authors: Zofia Piotrowska, Daniel B Costa, Geoffrey R Oxnard, Mark S Huberman, Justin F Gainor, Inga T Lennes, Alona Muzikansky, Alice T Shaw, Christopher G Azzoli, Rebecca S HeistAbstract:Abstract Background There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor Luminespib (AUY922) in NSCLC patients with EGFR ins20. Patients and methods Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype. Results Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4–5.6) and median OS (mOS) was 13 months (95% CI 4.9–19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common Luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination. Conclusion The study met its primary end point, suggesting that Luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of Luminespib and other hsp90 inhibitors in this population is warranted. Study registration (ClinicalTrials.gov) NCT01854034.
Mark S Huberman - One of the best experts on this subject based on the ideXlab platform.
-
egfr exon 20 insertion mutations display sensitivity to hsp90 inhibition in preclinical models and lung adenocarcinomas
Clinical Cancer Research, 2018Co-Authors: Susan E Jorge, Zofia Piotrowska, Geoffrey R Oxnard, Mark S Huberman, Antonio R Lucenaaraujo, Hiroyuki Yasuda, Deepa Rangachari, Lecia V Sequist, Susumu Kobayashi, Daniel B CostaAbstract:Purpose: EGFR exon 20 insertions account for up to 10% of all EGFR mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor. Experimental Design: Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer. Results: We show that select first, second and third generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. We exploit this vulnerability to show that the non-geldanamycin Hsp90 inhibitor Luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis. In addition, a patient whose EGFR inhibitor-insensitive lung adenocarcinoma harbored an EGFR exon 20 insertion mutation had a confirmed radiographic response to Luminespib. Conclusions: The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor Luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.
-
activity of the hsp90 inhibitor Luminespib among non small cell lung cancers harboring egfr exon 20 insertions
Annals of Oncology, 2018Co-Authors: Zofia Piotrowska, Daniel B Costa, Geoffrey R Oxnard, Mark S Huberman, Justin F Gainor, Inga T Lennes, Alona Muzikansky, Alice T Shaw, Christopher G Azzoli, Rebecca S HeistAbstract:Abstract Background There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor Luminespib (AUY922) in NSCLC patients with EGFR ins20. Patients and methods Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype. Results Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4–5.6) and median OS (mOS) was 13 months (95% CI 4.9–19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common Luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination. Conclusion The study met its primary end point, suggesting that Luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of Luminespib and other hsp90 inhibitors in this population is warranted. Study registration (ClinicalTrials.gov) NCT01854034.
Rebecca S Heist - One of the best experts on this subject based on the ideXlab platform.
-
activity of the hsp90 inhibitor Luminespib among non small cell lung cancers harboring egfr exon 20 insertions
Annals of Oncology, 2018Co-Authors: Zofia Piotrowska, Daniel B Costa, Geoffrey R Oxnard, Mark S Huberman, Justin F Gainor, Inga T Lennes, Alona Muzikansky, Alice T Shaw, Christopher G Azzoli, Rebecca S HeistAbstract:Abstract Background There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor Luminespib (AUY922) in NSCLC patients with EGFR ins20. Patients and methods Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype. Results Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4–5.6) and median OS (mOS) was 13 months (95% CI 4.9–19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common Luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination. Conclusion The study met its primary end point, suggesting that Luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of Luminespib and other hsp90 inhibitors in this population is warranted. Study registration (ClinicalTrials.gov) NCT01854034.
