Reference Detail

Ref Type Journal Article
PMID (29320312)
Authors Hainsworth JD, Meric-Bernstam F, Swanton C, Hurwitz H, Spigel DR, Sweeney C, Burris H, Bose R, Yoo B, Stein A, Beattie M, Kurzrock R
Title Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.
Journal Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol 36
Issue 6
Date 2018 Feb 20
URL
Abstract Text Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2-amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non-small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
G606E missense unknown BRAF G606E lies within the protein kinase domain of the Braf protein (UniProt.org). G606E has been identified in sequencing studies (PMID: 29320312, PMID: 28936923, PMID: 15331929), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Mar 2019).
P731T missense unknown BRAF P731T does not lie within any known functional domains of the Braf protein (UniProt.org). P731T has been identified in the scientific literature (PMID: 29320312), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Feb 2019).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 over exp salivary gland cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 80% (4/5, all partial response) of patients with salivary gland cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 amp salivary gland cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 80% (4/5, all partial response) of patients with salivary gland cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
BRAF L597Q Advanced Solid Tumor resistant Vemurafenib Clinical Study - Cohort Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 1 of the non-responding patients harbored BRAF L597Q (PMID: 29320312; NCT02091141). 29320312
BRAF G469A Advanced Solid Tumor resistant Vemurafenib Clinical Study - Cohort Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 2 of the non-responding patients harbored BRAF G469A (PMID: 29320312; NCT02091141). 29320312
ERBB2 act mut biliary tract cancer predicted - sensitive Pertuzumab + Trastuzumab Case Reports/Case Series Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in an objective response in a patient with biliary cancer harboring an ERBB2 (HER2) activating mutation, but no amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
BRAF G596R Advanced Solid Tumor no benefit Vemurafenib Clinical Study - Cohort Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 1 of the non-responding patients harbored BRAF G596R (PMID: 29320312; NCT02091141). 29320312
ERBB2 amp biliary tract cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 29% (2/7, all partial response) and stable disease lasting over 120 days in 38% (3/7) of patients with biliary cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
BRAF V600E non-small cell lung carcinoma sensitive Vemurafenib Phase II Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response of 43% (6/14, 1 complete response, 5 partial response) in patients with non-small cell lung cancer harboring BRAF V600E, and stable disease lasting more than 120 days in 2 patients (PMID: 29320312; NCT02091141). 29320312
ERBB2 over exp biliary tract cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 29% (2/7, all partial response) and stable disease lasting over 120 days in 38% (3/7) of patients with biliary cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
BRAF G466V Advanced Solid Tumor no benefit Vemurafenib Clinical Study - Cohort Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 1 of the non-responding patients harbored BRAF G466V (PMID: 29320312; NCT02091141). 29320312
BRAF V600E Advanced Solid Tumor sensitive Vemurafenib Phase II Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response of 46% (12/26, 2 complete response, 10 partial response) in patients with advanced solid tumors harboring BRAF V600E, but only 4% (1/23, 1 partial response) in patients harboring non-V600 BRAF mutations (PMID: 29320312; NCT02091141). 29320312
ERBB2 over exp urinary bladder cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 33% (3/9, 1 complete response, 1 partial response) and stable disease lasting over 120 days in 22% (2/9) of patients with bladder cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 amp ovarian cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 13% (1/8, all partial response) of patients with ovarian cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 amp colorectal cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 38% (14/37, all partial response) and stable disease lasting over 120 days in 11% (4/37) of patients with colorectal cancer harboring ERBB2 (HER2) amplification or overexpression, with a median duration of response of 11 months (PMID: 29320312; NCT02091141). 29320312
ERBB2 amp Advanced Solid Tumor predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 26% (30/114, 2 complete response, 28 partial response) and stable disease lasting over 120 days in 14% (16/114) of patients with advanced solid tumors harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
BRAF N581S Advanced Solid Tumor no benefit Vemurafenib Clinical Study - Cohort Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 2 of the non-responding patients harbored BRAF N581S (PMID: 29320312; NCT02091141). 29320312
ERBB2 amp pancreatic cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 22% (2/9, all partial response) and stable disease lasting over 120 days in 11% (1/9) of patients with pancreatic cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 act mut Advanced Solid Tumor predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 11% (4/36) of patients with advanced solid tumors harboring ERBB2 (HER2) activating mutations but not amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 over exp non-small cell lung carcinoma predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 13% (2/16, all partial response) and stable disease lasting over 120 days in 13% (2/16) of patients with non-small cell lung cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 over exp uterine cancer no benefit Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in no objective response (0/7) in patients with uterine cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 amp non-small cell lung carcinoma predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 13% (2/16, all partial response) and stable disease lasting over 120 days in 13% (2/16) of patients with non-small cell lung cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
BRAF G606E Advanced Solid Tumor no benefit Vemurafenib Clinical Study - Cohort Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 1 of the non-responding patients harbored BRAF G606E (PMID: 29320312; NCT02091141). 29320312
BRAF V600E thyroid cancer conflicting Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in complete response in a patient with anaplastic thyroid cancer harboring BRAF V600E (PMID: 29320312; NCT02091141). 29320312
BRAF V600E ovarian cancer predicted - sensitive Vemurafenib Phase II Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response of 50% (2/4, 2 partial response) in patients with ovarian cancer harboring BRAF V600E, and stable disease lasting more than 120 days in 1 patient (PMID: 29320312; NCT02091141). 29320312
BRAF V600E larynx cancer predicted - sensitive Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in complete response in a patient with larynx cancer harboring BRAF V600E (PMID: 29320312; NCT02091141). 29320312
BRAF K601E Advanced Solid Tumor conflicting Vemurafenib Clinical Study - Cohort Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 6 of the non-responding patients harbored BRAF K601E (PMID: 29320312; NCT02091141). 29320312
ERBB2 amp urinary bladder cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 33% (3/9, 1 complete response, 1 partial response) and stable disease lasting over 120 days in 22% (2/9) of patients with bladder cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 amp uterine cancer no benefit Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in no objective response (0/7) in patients with uterine cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 act mut non-small cell lung carcinoma predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in partial response in 21% (3/14) and stable disease lasting over 120 days in 21% (3/14) of patients with non-small cell lung cancer harboring ERBB2 (HER2) activating mutations but not amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 over exp Advanced Solid Tumor predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 26% (30/114, 2 complete response, 28 partial response) and stable disease lasting over 120 days in 14% (16/114) of patients with advanced solid tumors harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 over exp pancreatic cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 22% (2/9, all partial response) and stable disease lasting over 120 days in 11% (1/9) of patients with pancreatic cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
ERBB2 over exp ovarian cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 13% (1/8, all partial response) of patients with ovarian cancer harboring ERBB2 (HER2) amplification or overexpression (PMID: 29320312; NCT02091141). 29320312
BRAF P731T Advanced Solid Tumor no benefit Vemurafenib Clinical Study - Cohort Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 1 of the non-responding patients harbored BRAF P731T (PMID: 29320312; NCT02091141). 29320312
BRAF G464V Advanced Solid Tumor resistant Vemurafenib Clinical Study - Cohort Actionable In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 2 of the non-responding patients harbored BRAF G464V (PMID: 29320312; NCT02091141). 29320312
ERBB2 over exp colorectal cancer predicted - sensitive Pertuzumab + Trastuzumab Phase II Actionable In a Phase II trial (MyPathway), Herceptin (trastuzumab) and Perjeta (pertuzumab) combination treatment resulted in objective response in 38% (14/37, all partial response) and stable disease lasting over 120 days in 11% (4/37) of patients with colorectal cancer harboring ERBB2 (HER2) amplification or overexpression, with a median duration of response of 11 months (PMID: 29320312; NCT02091141). 29320312