Iris Chan

Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study

BACKGROUND Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma. METHODS We undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803. FINDINGS 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5). INTERPRETATION The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing. FUNDING F Hoffmann-La Roche/Genentech.

Absolute bioavailability and effect of formulation change, food, or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects.

Cobimetinib is a potent and highly selective inhibitor of MEK1/2. Since cobimetinib exhibited absorption variability in cancer patients, a series of single-dose studies in healthy subjects were conducted to determine absolute bioavailability and elucidate potential effects of formulation, food, and elevated gastric pH on cobimetinib bioavailability. Three crossover trials were performed with a 20 mg cobimetinib oral dose: absolute bioavailability using a 2 mg intravenous infusion (n = 13), relative bioavailability of tablets versus capsules and food effect (n = 20), and drug interaction with a proton pump inhibitor (20 mg of rabeprazole daily for 5 days prior to cobimetinib administration; n = 20). Absolute bioavailability of cobimetinib was 46.2% (24.2, CV %), likely due to metabolism rather than incomplete absorption. The mean systemic clearance of cobimetinib was low (11.7 L/h [28.2, CV %]). Administration of cobimetinib tablets with a high-fat meal delayed drug absorption (prolonged tmax) but had no statistically significant effect on cobimetinib exposure (Cmax and AUC0-∞). Tablet and capsule formulations of cobimetinib showed comparable exposures. Cobimetinib exhibited delayed absorption (tmax) in the presence of rabeprazole, with no statistically significant effects on drug exposure (Cmax and AUC0-∞) in the fasted state. In conclusion, cobimetinib oral absorption was not affected by change in formulation, food, or elevated gastric pH.

Abstract 4716: A first-in-human phase 1 study to evaluate the MEK1/2 inhibitor GDC-0973 administered daily in patients with advanced solid tumors

Background: The RAS/RAF/MEK/ERK signaling pathway, which is deregulated in a variety of tumor types, plays a major role in mediating cell growth and differentiation. GDC-0973 is a potent, selective, orally bioavailable MEK1/2 inhibitor which has shown antitumor activity in preclinical models. Methods: A phase I dose-escalation study using a 3+3 design was initiated in patients (pts) with solid tumors to evaluate the safety and pharmacokinetic (PK) characteristics of GDC-0973. FDG-PET was evaluated as a pharmacodynamic (PD) marker. Pts were treated QD with oral GDC-0973 on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) dosing schedule. Serial plasma samples for GDC-0973 pharmacokinetic (PK) analysis were collected following first dose (Day 1) and last dose (Day 21 or Day 14, respectively) in Cycle 1. At expansion stages, pts with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule, and underwent serial FDG-PET scans (baseline, C1D10-14 (steady state) and C1D26-28 (trough). Results: In the 21/7 dose escalation, 36 pts enrolled in eight successive cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) reported were Grade 4 hepatic encephalopathy (40 mg), Grade 3 diarrhea (80 mg) and Grade 3 rash (60 mg and 80 mg). On a 21/7 dosing schedule, the MTD was 60 mg, and the most frequent adverse events (AE) attributed to GDC-0973 by the investigator were diarrhea, rash, nausea, fatigue, dry skin, and edema. In the 14/14 dose escalation, 16 pts enrolled in four successive cohorts (60-125 mg). The DLTs reported were Grade 3 rash (125 mg) and Grade 3 blurred vision associated with presence of reversible subretinal fluid (125 mg). On a 14/14 dosing schedule, the MTD was 100 mg, and the most frequent AEs attributed to GDC-0973 by the investigator were diarrhea, rash, pruritus, nausea, vomiting, blurred and impaired vision, fatigue, and abdominal pain. Preliminary GDC-0973 PK data showed dose-proportional increases in Cmax and AUC, and a mean elimination half-life of approximately 40 hours. With daily oral dosing, there was approximately 2.5-fold accumulation, consistent with the GDC-0973 half-life and dosing interval. Of 17 patients in the 21/7 cohort with PET scans read to date, 9 (53%) had a partial metabolic response (> 20% decrease in mean SUVmax from baseline) in at least one timepoint. Of 6 patients in the 14/14 cohort with PET scans read to date, 5 (83%) had a partial metabolic response in at least one timepoint. Confirmed partial responses were observed in 3 melanoma patients, of which two had BRAFV600E mutation. Six pts with prolonged stable disease (≥ 5 mo) were observed to date. Conclusion: GDC-0973 is generally well tolerated and has signs of antitumor activity. Preliminary analysis indicates GDC-0973 has linear PK with a half-life that allows once daily dosing. Updated data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4716. doi:10.1158/1538-7445.AM2011-4716

Dogs Are More Sensitive to Antagonists of Inhibitor of Apoptosis Proteins Than Rats and Humans: A Translational Toxicokinetic/Toxicodynamic Analysis

Inhibitor of apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. GDC-0152 is a potent and selective IAP antagonist being developed as an anticancer agent. In preclinical safety studies, dogs were particularly sensitive to GDC-0152 showing adverse signs of a tumor necrosis factor alpha (TNF-α) driven systemic inflammatory response, related to cellular IAP degradation and activation of NFκB signaling, at lower exposures compared with rat. In addition, downstream increases in systemic levels of cytokines and chemokines, such as monocyte chemotactic protein-1 (MCP-1), were observed. A semimechanistic population toxicokinetic/toxicodynamic (TK/TD) model incorporating transit compartments was used to fit MCP-1 plasma concentrations from rats or dogs given iv GDC-0152 doses. Estimated TD parameters inferred that lower GDC-0152 plasma concentrations triggered more severe increases in plasma MCP-1 in dogs compared with rats. Human simulations performed using dog TD parameters and human pharmacokinetics predicted 300-2400% increases of MCP-1 in humans at iv doses from 0.76 to 1.48mg/kg. Similar simulations using rat TD parameters suggest little or no change. Patients given iv doses of GDC-0152 up to 1.48mg/kg iv showed no substantial increases in systemic MCP-1 or signs of a severe TNF-α driven systemic inflammatory response. Emerging clinical data reported for other IAP antagonists are consistent with our observations. Taken together, the data suggest dogs are more sensitive to IAP antagonists compared with humans and rats. This study illustrates how TK/TD analysis can be utilized to quantitatively translate and context an identified preclinical safety risk in dogs to humans.

Abstract CT231: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer

Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of estrogen receptor (ER)+ breast cancer (BC). However, many patients (pts) relapse or develop resistance to available hormonal agents via estrogen-dependent and estrogen-independent mechanisms. Furthermore, mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen can mediate resistance. Therefore, next generation ER targeting agents with robust activity in both wild type and mutant ER tumors are needed. GDC-0810 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader that induces tumor regression in tamoxifen-sensitive and resistant ER+ BC xenograft models. Methods: A phase I dose escalation study with 3+3 design was conducted in postmenopausal women with ER+ (HER2-) locally advanced or metastatic BC (progressing after ≥ 6 months on endocrine therapy; ≤ 2 prior chemotherapies) to determine the safety, pharmacokinetic (PK) and recommended phase II dose (RP2D) of GDC-0810. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples, CT scans, and when feasible, paired pre and on-study tumor biopsies were obtained. Results: Forty-one pts (median # of prior therapies: 4) were enrolled at 5 total daily dose levels (100-800 mg) and 2 regimens: once (QD) or twice (BID) daily given orally with and without fasting. Increases in GDC-0810 exposure were dose-dependent. The common treatment-related adverse events (AEs) were grade 1/2 diarrhea (63%), fatigue (46%), nausea (44%), flatulence (24%), vomiting (22%), and anemia (22%). Diarrhea was mostly Grade 1, intermittent in nature, and manageable with dose modifications, dietary adjustments, and treatment with PRN loperamide. There was one dose limiting toxicity of Grade 3 diarrhea at 800 mg QD (fasting). 600 mg QD given with food was determined to be single agent R2PD. Complete/near complete (>90%) suppression of FES uptake was observed in 90% of pts with FES-PET scans, including 5 pts with known ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-study biopsies. At a median follow-up of 8 months 13 of 31 (42%) pts on study achieved stable disease > 6 months while 10 pts remain active on study with followup Conclusions: GDC-0810 has a tolerable safety profile to date, with predictable PK, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER+ BC. A phase IIa study of GDC-0810 is ongoing in postmenopausal women with ER+ (HER2-) advanced or metastatic BC who have been previously treated with an aromatase inhibitor, including tumors with ESR1 mutations (clinicaltrials.gov NCT01823835). Citation Format: Maura Dickler, Aditya Bardia, Ingrid Mayer, Eric Winer, Peter Rix, Jeff Hager, Meng Chen, Iris Chan, Edna Chow-Maneval, Carlos Arteaga, Jose Baselga. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT231. doi:10.1158/1538-7445.AM2015-CT231

Abstract B75: A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors.

Background: Deregulation of the RAS/RAF/MEK/ERK signaling pathway has been implicated in diverse human tumors. GDC-0623 is an orally bioavailable inhibitor of MEK1/2 which has shown antitumor activity in preclinical models (Hatzivassiliou et al. 2013). Methods: An open-label Phase I dose-escalation study using a 3 + 3 design was initiated in patients with advanced solid tumors to evaluate the safety and pharmacokinetic (PK) characteristics of GDC-0623. Patients were administered oral GDC-0623 as a QD or BID regimen on a 21-day on/7-day off dosing schedule in the fasted state (minimum 2 hour fast). In addition, two cohorts were enrolled to examine the effect of food (4 pts) and acidic beverage (3 pts) on GDC-0623 PK. Serial plasma samples for GDC-0623 PK analysis were collected over 24 hours following first dose and after 15 days of continuous dosing. Results: On the QD regimen, 45 pts enrolled in eight successive cohorts (7-160 mg). Dose-limiting toxicities (DLTs) were Grade 4 (G4) creatine phosphokinase (CPK) elevation (90 mg), transient G3 visual disturbance and the serious adverse event (SAE) of G3 dehydration both occurring in the same patient (120 mg), and G3 thrombocytopenia and G3 hyponatremia (160 mg). The maximum tolerated dose was 120 mg (QD cohort). Eight patients enrolled in a single cohort dosing at 45 mg BID. One patient had a DLT of G2 retinal pigment epithelial detachment. Further BID cohorts were not enrolled since the AE profiles between on 90 mg QD and 45 mg BID were comparable. The most frequent adverse events (AE) attributed by the investigator to be GDC-0623-related were rash, visual disturbance - including impaired or blurred vision - which was often associated with sub-retinal fluid, diarrhea, nausea and vomiting, fatigue, elevated CPK, peripheral edema, decreased appetite, headache and dizziness. Preliminarily, GDC-0623 showed dose-proportional PK over the dose range administered. GDC-0623 was rapidly absorbed and distributed, with a terminal half-life of 4-6 hours. Due to its short half-life, GDC-0623 had no accumulation at steady-state following daily oral dosing. Effect of food or acidic beverage on GDC-0623 PK was inconclusive given the inter-patient and intra-patient variability in GDC-0623 PK and very small sample size. One confirmed partial response was observed in a patient with KRAS wild type squamous cell vaginal carcinoma at the QD MTD. Six patients had stable disease ≥ 5 months. Conclusion: GDC-0623 is well-tolerated and showed dose-proportional and time-independent PK. Classic MEK-related AEs, including rash, gastrointestinal symptoms and visual disturbance occurred with similar frequency for QD and BID dosing regimens at the same total daily dose, suggesting comparable intensity of MEK target effect. Updated data will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B75. Citation Format: Anthony El-Khoueiry, Carla Kurkjian, Thomas Semrad, Luna Musib, Mary Gates, Steve Eppler, Ilsung Chang, Iris Chan, Isabelle Rooney, Johanna Bendell. A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B75.

Abstract 1304: Clinical pharmacokinetics of GDC-0973, an oral MEK inhibitor, in cancer patients: data from a Phase 1 study

Background: GDC 0973 is a potent, selective, orally administered MEK1/2 inhibitor. It has shown antitumor activity in preclinical models. A first-in-human, phase 1 dose escalation study in cancer patients was conducted using a 3+3 design with two dosing schedules, followed by an expansion at the MTD for each dosing schedule. The pharmacokinetic objective was to evaluate GDC-0973 PK in patients on both dosing schedules. Methods: GDC-0973 was administered orally, once daily on a 21 day on/7 day off (21/7) or on a 14 day on/14 day off (14/14) dosing schedule. Plasma samples for PK analysis were collected on Day 1 and Day 21 (for 21/7) or Day 14 (14/14) of Cycle 1, and during the dosing holiday to determine half-life of GDC-0973. Urine samples were collected on Day 1 and on Day 21 (21/7) or Day 14 (14/14) over a 24-hour period for exploratory analysis. Plasma samples were analyzed using a validated LC/MS/MS method. GDC-0973 pharmacokinetic data was analyzed using a non-compartmental approach with the program WinNonlin. Results: GDC-0973 pharmacokinetics was evaluated at doses administered in the 21/7 schedule (0.05, 0.1 and 0.2 mg/kg in a liquid solution and 10, 20, 40, 60, and 80 mg as capsules) and the 14/14 schedule (60, 80, 100 and 125 mg as capsules). Pharmacokinetic data was available in 41 patients on the 21/7 and 11 patients on the 14/14 schedule. GDC-0973 Cmax was observed at 1-4 hours post-dose, and was similar across the entire dose range. Cmax and AUC increased dose proportionally in the dose range up to 100 mg. The mean apparent oral clearance ranged from 4.30 to 11.7 L/h in the 0.05 mg/kg-100 mg dose range. The mean elimination half-life ranged from 31.6 to 53.5 hours in all dose levels in both schedules. Following daily oral dosing, the mean accumulation ratio was 2.0 to 4.0, which is consistent with its half-life and dosing interval, indicating that the PK was constant over time. Given the mean half-life of ∼40 hours, steady-state exposures are expected to be achieved in 8-10 days. Preliminary data suggest that approximately 1-8% of intact drug is excreted in urine; hence, renal excretion is a minor pathway for elimination. Exploratory analysis showed no clear association between exposure and demographic factors (age, weight, sex) or concomitant medications. PK was consistent between patients in the 21/7 and 14/14 dose escalation stages, as well as the expansion stages when compared at the same doses. Doses of 40 mg or higher in patients achieved steady-state concentrations consistent with antitumor activity observed in xenograft models. Conclusion: GDC-0973 preliminary PK analysis shows a moderate rate of absorption; with generally dose-proportional increases in Cmax and AUC. Updated data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1304. doi:10.1158/1538-7445.AM2011-1304

Abstract LB-89: Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study in patients with advanced solid tumors

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction : The RAS/RAF/MEK/ERK and PI3K/PTEN/AKT signaling pathways are both deregulated in multiple tumor types. Therefore, targeting both pathways may be more efficacious than targeting either pathway alone. GDC-0973 is a novel, potent, selective, MEK1/2 inhibitor. GDC-0941 is a novel, potent, highly-specific, Class I PI3K inhibitor. In single agent Phase 1 trials, both GDC-0973 and GDC-0941 have demonstrated suitable tolerability and PK properties. In preclinical models, concurrent administration of GDC-0973 and GDC-0941 has shown improved efficacy in combination when compared to efficacy of either agent alone. Methods : A phase Ib dose-escalation study using a 3+3 design in patients (pts) with advanced solid tumors was initiated to evaluate the safety and PK of oral combination dosing of GDC-0973 and GDC-0941. Pts received once daily GDC-0973 and GDC-0941 on a 21-day on/7-day off (21/7) schedule. A unique dose escalation schema allowed for increasing the dose level of each single agent independently. GDC-0973 and GDC-0941 PK samples were collected following first and last doses of combination dosing in Cycle 1. Serial FDG-PET scans were obtained at baseline, Cycle 1 steady state, and Cycle 2 trough drug concentrations. Results : Twenty-seven pts have been enrolled in six cohorts on a 21/7 schedule. One pt in Cohort 4 (40 mg GDC-0973 + 100 mg GDC-0941) had a DLT of Grade 3 lipase elevation without clinical symptoms, which resolved with study drug interruption. One pt in Cohort 5 (40 mg GDC-0973 + 130 mg GDC-0941) had a DLT of Grade 4 CPK elevation. The common adverse events attributed to GDC-0973 and/or GDC-0941 were diarrhea (90%; all G1/2), fatigue (61%: 50% G1/2, 11% G3), nausea (61%; all G1/2), rash (50%; 45% G1/2, 5% G3), vomiting (33%; all G1/2), decreased appetite (17%; all G1/2), and dysgeusia (17%; all G1/2). Preliminary analysis indicates PK of GDC-0941 and GDC-0973 are not altered when administered in combination. 6 of 15 pts with PET scans read to date demonstrated a partial metabolic response (> 20% decrease in mean % change-from-baseline SUVmax) at one or more timepoints. Decreases in RECIST measurable target lesions were seen in 5 pts: 2 melanoma (−75%, BRAF wt; −27%, BRAF mut), 1 prostate cancer (−21%), and 2 KRAS mutant NSCLC (−18%; −13%). 3 pts (1 KRAS mut NSCLC and 2 BRAF mut melanoma) had prolonged stable disease > 6 months. Conclusions : To date, clinical combination dosing of the MEK inhibitor GDC-0973 with the Class I PI3K inhibitor GDC-0941 is generally well tolerated, with PK and toxicities similar to those observed in the single agent GDC-0973 and GDC-0941 Phase 1 trials. There are early signs of anti-tumor activity. Dose escalation is continuing and updated data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-89. doi:10.1158/1538-7445.AM2011-LB-89

Abstract 1280: Preclinical and Clinical Evidence for MEK Pathway Inhibition by GDC-0973 using FDG-PET

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Inhibitors of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) can cause potent growth arrest leading to tumor stasis or even regression, especially in BRAF mutant tumors. Seeking a pharmacodynamic marker of drug action, the effect of MEK inhibition on FDG PET signals was studied in rodent xenograft models using responsive and non-responsive cell lines. Colo205, HCT116, and A375 tumors showed substantial (30-50 %) signal (FDG flux, Ki, measured by a Patlak analysis) decreases within 72 h of beginning MEK inhibition and a rebound to baseline signal within 72 h of discontinuing treatment. BT474 tumors showed no effect. In MEK responsive tumors immunohistochemistry showed that glucose transporter GLUT1 redistributes away from the plasma membrane during treatment, which may explain the FDG PET findings. Fluorothymidine (FLT) uptake is also modulated by MEK inhibition, but the relative availability of clinical FDG PET centers and the robust preclinical results suggested the use of FDG PET, and not FLT PET, in clinic. FDG PET was implemented at all 4 Phase 1 study sites according to a standardized scanning charter. Scans were acquired at screening, at days 10-14 of cycle 1 (steady state drug concentration) and at days 26-28 of cycle 1 (trough drug concentration). Patients with RAS or RAF mutant tumors were treated at GDC-0973 MTD on the 21/7 and 14/14 dosing schedules. CT scans were acquired just prior to cycle 3 (∼ day 56) for response assessment. PET images were collected and read centrally. Up to 5 hypermetabolic lesions were assessed for mean and maximum standardized uptake value (SUV). A decrease of more than 20% in mean (across lesions) percentage change-from-baseline in SUVmax was considered a partial metabolic response (PMR). Compliance with the scanning guidelines across sites was generally good. Out of a total of 23 patients from both cohorts with PET scans read to date, 7 patients appeared to show a temporal profile of decreased FDG uptake at steady state with a rebound towards baseline at trough, mirroring the preclinical findings. Of 17 patients in the 21/7 MTD cohort whose PET scans were measured, 9 patients (∼53%) demonstrated a PMR at least one timepoint during cycle 1. Two of these patients demonstrated a PR per CT at 2 months (first tumor assessment) and also showed a robust PET response at both timepoints (Patient 1: -55% and -61% respectively; Patient 2: -63% and -53%). In addition, 2 other patients with a PMR at one or both timepoints had stable disease for at least 5 months. Of 6 patients in the 14/14 MTD cohort with PET scans read, 5 patients (83%) demonstrated a PMR at least one timepoint. Taken together, the preclinical PET evidence for a mechanistic effect of MEK inhibition on tumor glucose metabolism combined with the significant proportion of patients demonstrating PMR in this phase 1 study are consistent with hypothesis that GDC-0973 is achieving pathway modulation when given as single agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1280. doi:10.1158/1538-7445.AM2011-1280

Abstract A250: Preclinical combination efficacy and identification of biomarkers of MEK and PI3K inhibitors in phase I

Introduction: The Raf/MEK/ERK and PI3K/Akt/mTOR pathways are two major effector pathways downstream of activated Ras and receptor tyrosine kinases. While Ras is an attractive cancer target, direct pharmacological targeting has so far been unsuccessful. We describe preclinical studies combining GDC‐0973, an inhibitor of MEK, and GDC‐0941, an inhibitor of PI3K, both of which are in Phase I trials. Summary of Results: GDC‐0973 is a selective allosteric orally bioavailable small molecule inhibitor of the MEK1/2 dual specificity kinases. It has nanomolar potency against MEK1/2 in cells, and has potency across a broad range of cancer cell lines, most notably in those that are mutated for B‐Raf and K‐Ras. GDC‐0941 is a selective orally bioavailable small molecule inhibitor of Class I PI3 kinases that has been described previously. Given the widespread and frequently concurrent activation of the Ras/Raf/MEK and Ras/PI3K/Akt pathways in tumors such as melanoma, colorectal, non‐small cell lung cancer, and pancreatic cancer, we carried out cellular and in vivo xenograft studies to evaluate the efficacy of GDC‐0973 and GDC‐0941, both individually and in combination. We demonstrate strong combination efficacy in B‐raf or K‐ras mutant melanoma, colon and NSCLC models, driven primarily by increased apoptosis. The combination resulted in modulation of markers of both the MEK and PI3K pathways, and we discovered several markers whose modulation correlated with the induction of apoptosis. Continuous suppression of the two pathways is not required for combination efficacy. Conclusions: The preclinical data indicate that combined use of MEK and PI3K inhibitors can produce greater efficacy than either agent alone at tolerated doses. Additionally, biomarkers have been identified which correlate with induction of apoptosis in the combination regimens. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A250.