Ilsung Chang

Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma

BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

Phase I Trial of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Refractory, Locally Advanced or Metastatic Solid Tumors

Purpose: The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed. Experimental Design: Sixty-eight patients received GDC-0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed. Results: Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of GLI1 down-modulation was observed in noninvolved skin. Conclusions: GDC-0449 has an acceptable safety profile and encouraging anti-tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted. Clin Cancer Res; 17(8); 2502–11. ©2011 AACR.

Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial

BACKGROUND The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. METHODS In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. FINDINGS Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. INTERPRETATION These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma. FUNDING F Hoffmann-La Roche-Genentech.

Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors

Purpose: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. Experimental Design: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. Results: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. Conclusions: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations. Clin Cancer Res; 17(17); 5774–82. ©2011 AACR.

A Phase II, Randomized, Placebo-Controlled Study of Vismodegib as Maintenance Therapy in Patients with Ovarian Cancer in Second or Third Complete Remission

Purpose: Hedgehog pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor–stromal interactions. Vismodegib is an orally available Hedgehog pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR). Experimental Design: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: One hundred four patients were randomized to vismodegib (n = 52) or placebo (n = 52); median PFS was 7.5 months and 5.8 months, respectively [HR 0.79; 95% confidence interval (CI), 0.46–1.35]. The HR was 0.66 (95% CI, 0.36–1.20) for second CR patients (n = 84) and 1.79 (95% CI, 0.50–6.48) for third CR patients (n = 20). The most common adverse events in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues. Conclusions: In this study, the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hedgehog ligand expression was lower than expected. Clin Cancer Res; 18(23); 6509–18. ©2012 AACR.

A Single Dose Mass Balance Study of the Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Humans Using Accelerator Mass Spectrometry

Vismodegib (GDC-0449), a small-molecule Hedgehog pathway inhibitor, was well tolerated in patients with solid tumors and showed promising efficacy in advanced basal cell carcinoma in a Phase I trial. The purpose of the study presented here was to determine routes of elimination and the extent of vismodegib metabolism, including assessment and identification of metabolites in plasma, urine, and feces. Six healthy female subjects of nonchildbearing potential were enrolled; each received a single 30-ml oral suspension containing 150 mg of vismodegib with 6.5 μg of [14C]vismodegib to yield a radioactivity dose of approximately 37 kBq (1000 nCi). Plasma, urine, and feces samples were collected over 56 days to permit sample collection for up to 5 elimination half-lives. Nonradioactive vismodegib was measured in plasma using liquid chromatographic-tandem mass spectrometry, and total radioactivity in plasma, urine, and feces was measured using accelerator mass spectrometry. Vismodegib was slowly eliminated by a combination of metabolism and excretion of parent drug, most of which was recovered in feces. The estimated excretion of the administered dose was 86.6% on average, with 82.2 and 4.43% recovered in feces and urine, respectively. Vismodegib was predominant in plasma, with concentrations representing >98% of the total circulating drug-related components. Metabolic pathways of vismodegib in humans included oxidation, glucuronidation, and uncommon pyridine ring cleavage. We conclude that vismodegib and any associated metabolic products are mainly eliminated through feces after oral administration in healthy volunteers.

Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity. WHAT THIS STUDY ADDS This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing. AIM Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of (14) C-vismodegib with single and multiple oral doses. METHODS Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry. RESULTS Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h(-1) and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. CONCLUSION Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.

Clinical and Pharmacologic Study of the Farnesyltransferase Inhibitor Tipifarnib in Cancer Patients With Normal or Mildly or Moderately Impaired Hepatic Function

PURPOSE This study explored the feasibility of treating patients with impaired hepatic function with tipifarnib. The safety profile, pharmacokinetics, and relationship between the pharmacokinetics and toxicities were evaluated. PATIENTS AND METHODS Patients with mildly or moderately impaired hepatic function (Child-Pugh classification) were treated with tipifarnib bid on days 1 to 5 of cycle 1. Further dosing was based on the individual day 5 pharmacokinetic data and absolute neutrophil count. For patients with normal hepatic function, tipifarnib was dosed on days 1 to 14, followed by 1 week of rest. For all patients, in subsequent cycles, tipifarnib was administered for 21 consecutive days out of every 28 days. RESULTS Twenty-eight patients were included in the normal (n = 16), mild (n = 9), and moderate (n = 3) impairment groups. The most important grade 3 to 4 hematologic toxicity was leukocytopenia/neutropenia, which was mostly observed in patients with moderate impairment. Common nonhematologic toxicities were fatigue, nausea, and vomiting. The pharmacokinetic data showed higher plasma concentrations of tipifarnib in patients with liver impairment compared with patients with normal hepatic function. CONCLUSION In patients with mildly impaired hepatic function, tipifarnib can be administered safely at a starting dose of 200 mg bid, but it is not safe to treat patients with moderate hepatic impairment.

The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics.

Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAFV600‐mutant metastatic melanoma. It is important to understand the effects of a high‐fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open‐label, multicenter, randomized, 2‐period crossover study was performed to evaluate the effect of food (high‐fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high‐fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0−∞ 119 to 360 µg·h/mL after a single 960 mg dose of vemurafenib (N = 13–15 patients). An effect of food on single‐dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0−∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAFV600‐mutant metastatic melanoma. A high‐fat meal increased the exposure to vemurafenib without altering the mean terminal half‐life.

coBRIM: a phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAFV600 mutation–positive patients with unresectable locally advanced or metastatic melanoma (NCT01689519)

coBRIM: a phase 3, double-blind, placebocontrolled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAF mutation–positive patients with unresectable locally advanced or metastatic melanoma (NCT01689519) Paolo A Ascierto, Grant A McArthur, Brigitte Dréno, James Larkin, Gabriella Liszkay, Michele Maio, Mario Mandala, Lev Demidov, Daniil Stroyakovskiy, Luc Thomas, Luis de la Cruz-Merino, Victoria Atkinson, Caroline Dutriaux, Claus Garbe, Ilsung Chang, Stephen P. Hack, Antoni Ribas