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Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.

ABSTRACT: BACKGROUND:Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors. PATIENTS AND METHODS:This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21?days on, 7?days off. Atezolizumab was dosed at 800?mg intravenously every 2?weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival. RESULTS:Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ?1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n?=?84), melanoma (n?=?22), non-small-cell lung cancer (NSCLC; n?=?28), and other solid tumors (n?=?16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases. CONCLUSIONS:Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study. CLINICALTRIALS.GOV IDENTIFIER:NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online).

SUBMITTER: Hellmann MD

PROVIDER: S-EPMC6931236 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.

Hellmann M D MD Kim T-W TW Lee C B CB Goh B-C BC Miller W H WH Oh D-Y DY Jamal R R Chee C-E CE Chow L Q M LQM Gainor J F JF Desai J J Solomon B J BJ Das Thakur M M Pitcher B B Foster P P Hernandez G G Wongchenko M J MJ Cha E E Bang Y-J YJ Siu L L LL Bendell J J

Annals of oncology : official journal of the European Society for Medical Oncology 20190701 7

<h4>Background</h4>Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors.<h4>Patients and methods</h4>This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a do ...[more]

PMID: 30918950

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Project description:BackgroundAlthough introduction of immune checkpoint inhibitors has revolutionized the treatment of cancer, their response rates are generally low. Preclinical and early phase clinical data suggest that MEK inhibition may sensitize tumors to immune checkpoint inhibitors by upregulating tumor antigen expression, programmed death-ligand 1 (PD-L1) expression, and tumor T-cell infiltration. We evaluated the efficacy and safety of cobimetinib plus atezolizumab in patients with advanced solid tumors in the open-label, multicohort phase II COTEST study.Patients and methodsThis analysis of the COTEST trial included patients from cohorts 1-4 [1-3: anti-programmed cell death protein 1 (PD-1)/PD-L1 treatment-naive patients; 4: patients with disease progression on anti-PD-1/anti-PD-L1 treatment] who received cobimetinib 60 mg once daily for the first 21 days and intravenous infusions of atezolizumab 840 mg on days 1 and 15 of each 28-day cycle. Efficacy endpoints included objective response rate, overall survival, progression-free survival (PFS), and disease control rate.ResultsOverall, 77 patients were enrolled in cohorts 1-4 (78% male; median age 62.8 years). Objective response rate was 20% in cohort 1 [squamous cell carcinoma of the head and neck (SCCHN)], 30% in cohort 2 (urothelial carcinoma), and 18% in cohort 3 (renal cell carcinoma); there were no responders among 20 patients in cohort 4 (SCCHN). The disease control rates in cohorts 1-4 were 50%, 40%, 24%, and 25%, respectively. The median PFS was 5.5, 3.4, 3.4, and 3.6 months in cohorts 1-4, respectively, and the median overall survival was 16.8, 18.7, 21.7, and 7.7 months, respectively. Most adverse events were of grade 1/2 and were manageable.ConclusionsCobimetinib plus atezolizumab had moderate activity in patients with anti-PD-1/PD-L1 treatment-naive SCCHN and urothelial carcinoma, and weak activity in anti-PD-1/PD-L1 treatment-naive renal cell carcinoma, and no activity in checkpoint inhibitor-treated patients.

Project description:Lessons learnedDespite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug-drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1.BackgroundSimultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors.MethodsCobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle.ResultsIn total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1-2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug-drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response.ConclusionThe safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor-related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination.

Project description:BACKGROUND:Expressed on activated T and natural killer cells, 4-1BB/CD137 is a costimulatory receptor that signals a series of events resulting in cytokine secretion and enhanced effector function. Targeting 4-1BB/CD137 with agonist antibodies has been associated with tumor reduction and antitumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed in various solid tumor indications and associated with poor prognosis. This phase Ib, open-label study in patients with advanced solid tumors assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of utomilumab (PF-05082566), a human monoclonal antibody (mAb) agonist of the T-cell costimulatory receptor 4-1BB/CD137, in combination with mogamulizumab, a humanized mAb targeting CCR4 reported to deplete subsets of regulatory T cells (Tregs). METHODS:Utomilumab 1.2-5?mg/kg or 100?mg flat dose every 4?weeks plus mogamulizumab 1?mg/kg (weekly in Cycle 1 followed by biweekly in Cycles ?2) was administered intravenously to 24 adults with solid tumors. Blood was collected pre- and post-dose for assessment of drug pharmacokinetics, immunogenicity, and pharmacodynamic markers. Baseline tumor biopsies from a subset of patients were also analyzed for the presence of programmed cell death-ligand 1 (PD-L1), CD8, FoxP3, and 4-1BB/CD137. Radiologic tumor assessments were conducted at baseline and on treatment every 8?weeks. RESULTS:No dose-limiting toxicities occurred and the maximum tolerated dose was determined to be at least 2.4?mg/kg per the time-to-event continual reassessment method. No serious adverse events related to either treatment were observed; anemia was the only grade 3 non-serious adverse event related to both treatments. Utomilumab systemic exposure appeared to increase with dose. One patient with PD-L1-refractory squamous lung cancer achieved a best overall response of partial response and 9 patients had a best overall response of stable disease. No patients achieved complete response. Objective response rate was 4.2% (95% confidence interval: 0.1-21.1%) per RECIST 1.1. Depletion of Tregs in peripheral blood was accompanied by evidence of T-cell expansion as assessed by T-cell receptor sequence analysis. CONCLUSIONS:The combination of utomilumab/mogamulizumab was safe and tolerable, and may be suitable for evaluation in settings where CCR4-expressing Tregs are suppressing anticancer immunity. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02444793.

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Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.

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Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.

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