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A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

ABSTRACT: LESSONS LEARNED:Despite 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. BACKGROUND:Simultaneous 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. METHODS:Cobimetinib 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. RESULTS:In 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. CONCLUSION:The 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.

SUBMITTER: Weekes C

PROVIDER: S-EPMC7543243 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

Weekes Colin C Lockhart Albert A LoRusso Patricia P Murray Elaine E Park Erica E Tagen Mike M Singh Jatinder J Sarkar Indrani I Mueller Lars L Dokainish Hatem H Shapiro Geoffrey G Burris Howard H

The oncologist 20200528 10

<h4>Lessons learned</h4>Despite 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 sche ...[more]

PMID: 32311798

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Project description: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).

Project description:BACKGROUND:This multicenter, open-label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3-kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations. MATERIALS AND METHODS:Eighty-nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0-2. Binimetinib and buparlisib combinations were explored in patients with KRAS-, NRAS-, or BRAF-mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)-mutant, advanced non-small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS- or BRAF-mutant ovarian cancer; or advanced non-small cell lung cancer with KRAS mutation. RESULTS:At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF-mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies. CONCLUSION:Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose-limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies. IMPLICATIONS FOR PRACTICE:Because dysregulation of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single-agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways.

Project description:PurposeIDO1 induces immune suppression in T cells through l-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.Patients and methodsThe study consisted of a 3+3 dose-escalation stage (n = 66) and a tumor-specific expansion stage (n = 92). Navoximod was given orally every 12 hours continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day -1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle.ResultsPatients (n = 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizumab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, head and neck squamous cell carcinoma, cervical, neural sheath, non-small cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) dose-escalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response.ConclusionsThe combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab.

Dataset Information

A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

Publications

A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

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