Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumors.

Shapiro, Geoffrey I.; LoRusso, P.; Kwak, E. L.; Cleary, J. M.; Musib, Luna; Jones, Christopher B.; Crespigny, Alex de; Belvin, Marcia; McKenzie, Meghan; Gates, Mary; Chan, Iris T.; Bendell, J. C.

doi:10.1200/jco.2011.29.15_suppl.3005

Cited by 40 publications

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“…Infante et al demonstrated a reduction in SUVmax of 23%-48% in 4 evaluable melanoma patients treated with GSK1120212, a dual inhibitor of MEK1 and MEK2 (21). Similarly, Shapiro et al reported that PMR was attained in 6 of 15 (40%) evaluable patients treated with a combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941 in a dose-escalation trial (22). 18 F-fluoro-39-deoxy-39-L-fluorothymidine PET to investigate inhibition of proliferation by the MEK inhibitor PD0325901 has also been investigated (23,24).…”

Section: Discussionmentioning

confidence: 99%

Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

et al. 2012

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Two mitogen-activated protein kinase kinase (MAPK2, also known as MEK) inhibitors were assessed with 18 F-FDG PET in separate phase I clinical studies, clearly illustrating the potential of metabolic imaging for dose, dosing regimen, and compound selection in early-phase trials and utility for predicting nonresponding patients. Methods: 18 F-FDG PET data were collected during 2 independent, phase I, dose-escalation trials of 2 novel MEK inhibitors (RO5126766 and RO4987655). PET acquisition procedures were standardized between the 2 trials, and PET images were analyzed centrally. Imaging was performed at baseline; at cycle 1, day 15; and at cycle 3, day 1. A 10-mmdiameter region of interest was defined for up to 5 lesions, and peak standardized uptake values were determined for each lesion. The relationship between PET response and pharmacokinetic factors (dose and exposure), inhibition of extracellularsignal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells, and anatomic tumor response as measured by Response Evaluation Criteria in Solid Tumors was investigated for both compounds. Results: Seventy-six patients underwent PET, and 205 individual PET scans were analyzed. Strong evidence of biologic activity was seen as early as cycle 1, day 15, for both compounds. 18 F-FDG PET revealed striking differences between the 2 MEK inhibitors at their recommended dose for phase II investigation. The mean amplitude of the decrease in 18 F-FDG from baseline to cycle 1, day 15, was greater for patients receiving RO4987655 than for those receiving RO5126766 (47% vs. 16%, respectively; P 5 0.052). Furthermore, a more pronounced relationship was seen between the change in 18 F-FDG uptake and dose or exposure and phosphorylated ERK inhibition in peripheral blood mononuclear cells in patients receiving RO4987655. For both investigational drugs, PET responses tended to be greatest in patients with melanoma tumors. 18 F-FDG was able to identify early nonresponding patients with a 97% negative predictive value. Conclusion: These data exemplify the role of 18 F-FDG PET for guiding the selection of novel investigational drugs, choosing dose in early-phase clinical development, and predicting nonresponding patients early in treatment.

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Section: Discussionmentioning

confidence: 99%

Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

et al. 2012

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“…Recent preclinical data show that combined RAF/MEK inhibitors can block ERK activation in resistant cells and may delay emergence of resistance (42,43). Studies with other MEK inhibitors are investigating combinations with AKT inhibitors, PI3K inhibitors, and chemotherapy agents such as paclitaxel and docetaxel (44)(45)(46)(47)(48). The optimum partners for RO4987655 remain to be determined; however, in vitro and in vivo data show that combination withPI3-kinase pathway inhibitors (mTOR, PI3K inhibitors; ref.…”

Section: Discussionmentioning

confidence: 99%

Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors

Leijen

Middleton

Tresca

et al. 2012

Clinical Cancer Research

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Purpose: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors.Patients and Methods: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule.Results: Forty-nine patients were enrolled. DLTs were blurred vision (n ¼ 1) and elevated creatine phosphokinase (n ¼ 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC 50 ). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15.Conclusion: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors.

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“…More than 10 selective MEK inhibitors are currently in clinical development (17,20,(38)(39)(40)(41)(42). So far, clinical efficacy of MEK inhibitors as single agents has been demonstrated in patients with metastatic melanoma with BRAF-mutated cancers (43), whereas it has been rarely observed in patients with unselected chemorefractory Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Primary and Acquired Resistance of Colorectal Cancer Cells to Anti-EGFR Antibodies Converge on MEK/ERK Pathway Activation and Can Be Overcome by Combined MEK/EGFR Inhibition

Troiani

Napolitano

Vitagliano

et al. 2014

Clinical Cancer Research

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Purpose: The EGFR-independent activation of the RAS/RAF/MEK/MAPK pathway is one of the resistance mechanisms to cetuximab.Experimental Design: We have evaluated, in vitro and in vivo, the effects of BAY 86-9766, a selective MEK1/2 inhibitor, in a panel of human colorectal cancer cell lines with primary or acquired resistance to cetuximab.Results: Among the colorectal cancer cell lines, five with a KRAS mutation (LOVO, HCT116, HCT15, SW620, and SW480) and one with a BRAF mutation (HT29) were resistant to the antiproliferative effects of cetuximab, whereas two cells (GEO and SW48) were highly sensitive. Treatment with BAY 86-9766 determined dose-dependent growth inhibition in all cancer cells, including two human colorectal cancer cells with acquired resistance to cetuximab (GEO-CR and SW48-CR), with the exception of HCT15 cells. Combined treatment with cetuximab and BAY 86-9766 induced a synergistic antiproliferative and apoptotic effects with blockade in the MAPK and AKT pathway in cells with either primary or acquired resistance to cetuximab. The synergistic antiproliferative effects were confirmed using other two selective MEK1/2 inhibitors, selumetinib and pimasertib, in combination with cetuximab. Moreover, inhibition of MEK expression by siRNA restored cetuximab sensitivity in resistant cells. In nude mice bearing established human HCT15, HCT116, SW48-CR, and GEO-CR xenografts, the combined treatment with cetuximab and BAY 86-9766 caused significant tumor growth inhibition and increased mice survival.Conclusion: These results suggest that activation of MEK is involved in both primary and acquired resistance to cetuximab and the inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance in patients with colorectal cancer.

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Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumors.

Cited by 40 publications

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Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors

Primary and Acquired Resistance of Colorectal Cancer Cells to Anti-EGFR Antibodies Converge on MEK/ERK Pathway Activation and Can Be Overcome by Combined MEK/EGFR Inhibition

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Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumors.

Cited by 40 publications

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Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by 18F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by 18F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors

Primary and Acquired Resistance of Colorectal Cancer Cells to Anti-EGFR Antibodies Converge on MEK/ERK Pathway Activation and Can Be Overcome by Combined MEK/EGFR Inhibition

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Product

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Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials