HER3 is implicated in uncontrolled cell growth and requires heterodimerization with a fully functional kinase in order to signal [12], [15], [16], [17], [18]
HER3 is implicated in uncontrolled cell growth and requires heterodimerization with a fully functional kinase in order to signal [12], [15], [16], [17], [18]. The extensive crosstalk among the HER\family receptors likely contributes to emerging reports that blockade of a particular signaling pathway can lead to activation of compensatory mechanisms such as negative feedback loops and, consequently, upregulates parallel pathways [2], [19]. according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. aRash and related MedDRA Terms included: dermatitis acneiform, rash, rash erythematous, rash maculopapular. bOne grade 5 malignant neoplasm progression was included here, but not Trolox reported in clinical database in error (the patient was discontinued from study due to death attributed to disease progression). Abbreviations: AE, adverse event; MedDRA, medical dictionary for regulatory activities; q2w, every 2 weeks; QD, once daily; wkly, weekly. Duligotuzumab and cobimetinib pharmacokinetic (PK) findings were consistent with the PK observed in the respective single\agent studies, suggesting that there was no interaction. In 23 evaluable patients, the best Response Evaluation Criteria In Solid Tumors (RECIST v1.1) response was stable disease in 9 patients (39%), with 4/9 experiencing stable disease beyond 4 cycles (Table ?(Table2).2). Among 15 patients with colorectal cancer (CRC), 5 had stable disease, with 2/5 experiencing stable disease beyond 4 cycles. Trolox Upon evaluation of past treatment history for the 4 patients experiencing stable disease beyond 4 cycles, all patients had atypical extended times on prior systemic therapy when compared with historical average time on those standard therapies, indicating that these may be atypical patients who had Trolox more indolent disease. Table 2. Efficacy summary Open in a separate window Censored. Abbreviations: , no data; CI, confidence interval; CRC, colorectal; NE, not evaluable; PFS, progression\free survival; q2w, every 2 weeks; QD, once daily; wkly, weekly. Due to limited efficacy, safety and tolerability of the combination, dose expansion was not pursued, and the combination of duligotuzumab and cobimetinib is no longer being developed in solid tumors. Trial Information DiseaseAdvanced cancer/solid tumor onlyStage of Disease/TreatmentMetastatic/advancedPrior TherapyMore than 2 prior regimensType of Study \ 1Phase IType of Study \ 2Prospective, open\label, dose findingPrimary EndpointSafetySecondary EndpointPharmacodynamicAdditional Details of Endpoints or Study Design?Primary Endpoint: Safety and tolerability of duligotuzumab plus cobimetinib?Primary Endpoint: Identify DLTs, MTD, and RP2D dose and schedule?Secondary Endpoint: Pharmacokinetics, tumor assessment?Investigator’s AnalysisLevel of activity did not meet planned endpoint Drug Information for Phase I Single Arm Drug 1?Generic/Working nameCobimetinibTrade nameCotellicCompany nameGenentech, Inc.Drug typeSmall moleculeDrug classMEKDosemilligrams (mg) per flat doseRouteoral (po)Drug 2?Generic/Working nameMEHD7945A/duligotuzumabTrade namen/aCompany nameGenentech, Inc.Drug typeBiologicalDrug classEGFRDosemilligrams (mg) per flat doseRouteIV Dose\Escalation Table Open in a separate window Abbreviation: q2w, every 2 weeks. Patient Characteristics for Phase I Single Arm Number of patients, male15Number of patients, female8Stagen/aAgeMedian (range): 58 (38C77)Number of prior systemic therapiesMedian (range): 4 (1C7)Performance Status: ECOG0 111 112 13 0unknown 0Cancer Types or Histologic SubtypesColon 10Rectum 5Lung 3Pancreas 2Salivary gland 1Anus 1Cervix 1 Primary Assessment Method for Phase I Single Arm Assessment?Number of patients enrolled23Number of patients evaluable for Edn1 toxicity23Number of patients evaluated for efficacy23Response assessment CR em n /em ?=?0 (0%)Response assessment PR em n /em ?=?0 (0%)Response assessment SD em n /em ?=?9 (39%)Response assessment PD em n /em ?=?13 (57%)Response assessment OTHER em n /em ?=?1 (4%)(Median) duration assessments PFS53 days, Trolox confidence interval (CI): 51C236 Phase I Single Arm Adverse Events Open in a separate window Abbreviation: NC/NA, No Change from Baseline/No Adverse Event. Serious Treatment\Emergent Adverse Events Regardless of Relationship to Study Treatments by Frequency of Preferred Term, Safety\Evaluable Patients Open in a separate window Abbreviations: q2w, every 2 weeks; QD, once daily; wkly, weekly Open in a separate window Abbreviation: q2w, twice weekly. Pharmacokinetics/Pharmacodynamics Duligotuzumab and cobimetinib PK consistent with single agent studies.