Molecular profiling and targeted therapy for advanced thoracic malignancies a biomarker-derived, multiarm, multihistology phase ii basket trial

Ariel Lopez-Chavez, Anish Thomas, Arun Rajan, Mark Raffeld, Betsy Morrow, Ronan Kelly, Corey Allan Carter, Udayan Guha, Keith Killian, Christopher C. Lau, Zied Abdullaev, Liqiang Xi, Svetlana Pack, Paul S. Meltzer, Christopher Corless, Alan Sandler, Carol Beadling, Andrea Warrick, David J. Liewehr, Seth M. SteinbergArlene Berman, Austin Doyle, Eva Szabo, Yisong Wang, Giuseppe Giaccone

Research output: Contribution to journalArticle

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Abstract

Purpose We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently. Patients and Methods We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification. Results Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years). Conclusion This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.

Original languageEnglish (US)
Pages (from-to)1000-1007
Number of pages8
JournalJournal of Clinical Oncology
Volume33
Issue number9
DOIs
StatePublished - Mar 20 2015

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Molecular Targeted Therapy
Thorax
Biomarkers
Mutation
Non-Small Cell Lung Carcinoma
Neoplasms
Mutation Rate
Small Cell Lung Carcinoma
Standard of Care
Research Design
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Molecular profiling and targeted therapy for advanced thoracic malignancies a biomarker-derived, multiarm, multihistology phase ii basket trial. / Lopez-Chavez, Ariel; Thomas, Anish; Rajan, Arun; Raffeld, Mark; Morrow, Betsy; Kelly, Ronan; Carter, Corey Allan; Guha, Udayan; Killian, Keith; Lau, Christopher C.; Abdullaev, Zied; Xi, Liqiang; Pack, Svetlana; Meltzer, Paul S.; Corless, Christopher; Sandler, Alan; Beadling, Carol; Warrick, Andrea; Liewehr, David J.; Steinberg, Seth M.; Berman, Arlene; Doyle, Austin; Szabo, Eva; Wang, Yisong; Giaccone, Giuseppe.

In: Journal of Clinical Oncology, Vol. 33, No. 9, 20.03.2015, p. 1000-1007.

Research output: Contribution to journalArticle

Lopez-Chavez, A, Thomas, A, Rajan, A, Raffeld, M, Morrow, B, Kelly, R, Carter, CA, Guha, U, Killian, K, Lau, CC, Abdullaev, Z, Xi, L, Pack, S, Meltzer, PS, Corless, C, Sandler, A, Beadling, C, Warrick, A, Liewehr, DJ, Steinberg, SM, Berman, A, Doyle, A, Szabo, E, Wang, Y & Giaccone, G 2015, 'Molecular profiling and targeted therapy for advanced thoracic malignancies a biomarker-derived, multiarm, multihistology phase ii basket trial', Journal of Clinical Oncology, vol. 33, no. 9, pp. 1000-1007. https://doi.org/10.1200/JCO.2014.58.2007
Lopez-Chavez, Ariel ; Thomas, Anish ; Rajan, Arun ; Raffeld, Mark ; Morrow, Betsy ; Kelly, Ronan ; Carter, Corey Allan ; Guha, Udayan ; Killian, Keith ; Lau, Christopher C. ; Abdullaev, Zied ; Xi, Liqiang ; Pack, Svetlana ; Meltzer, Paul S. ; Corless, Christopher ; Sandler, Alan ; Beadling, Carol ; Warrick, Andrea ; Liewehr, David J. ; Steinberg, Seth M. ; Berman, Arlene ; Doyle, Austin ; Szabo, Eva ; Wang, Yisong ; Giaccone, Giuseppe. / Molecular profiling and targeted therapy for advanced thoracic malignancies a biomarker-derived, multiarm, multihistology phase ii basket trial. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 9. pp. 1000-1007.
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abstract = "Purpose We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently. Patients and Methods We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification. Results Six hundred forty-seven patients were enrolled, and 88{\%} had their tumors tested for at least one gene. EGFR mutation frequency was 22.1{\%} in NSCLC, and erlotinib achieved a response rate of 60{\%} (95{\%} CI, 32.3{\%} to 83.7{\%}). KRAS mutation frequency was 24.9{\%} in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11{\%} (95{\%} CI, 0{\%} to 48{\%}). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95{\%} CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95{\%} CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95{\%} CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95{\%} CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95{\%} CI, 1.61 to 2.13 years). Conclusion This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.",
author = "Ariel Lopez-Chavez and Anish Thomas and Arun Rajan and Mark Raffeld and Betsy Morrow and Ronan Kelly and Carter, {Corey Allan} and Udayan Guha and Keith Killian and Lau, {Christopher C.} and Zied Abdullaev and Liqiang Xi and Svetlana Pack and Meltzer, {Paul S.} and Christopher Corless and Alan Sandler and Carol Beadling and Andrea Warrick and Liewehr, {David J.} and Steinberg, {Seth M.} and Arlene Berman and Austin Doyle and Eva Szabo and Yisong Wang and Giuseppe Giaccone",
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T1 - Molecular profiling and targeted therapy for advanced thoracic malignancies a biomarker-derived, multiarm, multihistology phase ii basket trial

AU - Lopez-Chavez, Ariel

AU - Thomas, Anish

AU - Rajan, Arun

AU - Raffeld, Mark

AU - Morrow, Betsy

AU - Kelly, Ronan

AU - Carter, Corey Allan

AU - Guha, Udayan

AU - Killian, Keith

AU - Lau, Christopher C.

AU - Abdullaev, Zied

AU - Xi, Liqiang

AU - Pack, Svetlana

AU - Meltzer, Paul S.

AU - Corless, Christopher

AU - Sandler, Alan

AU - Beadling, Carol

AU - Warrick, Andrea

AU - Liewehr, David J.

AU - Steinberg, Seth M.

AU - Berman, Arlene

AU - Doyle, Austin

AU - Szabo, Eva

AU - Wang, Yisong

AU - Giaccone, Giuseppe

PY - 2015/3/20

Y1 - 2015/3/20

N2 - Purpose We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently. Patients and Methods We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification. Results Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years). Conclusion This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.

AB - Purpose We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently. Patients and Methods We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification. Results Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years). Conclusion This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.

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