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ARRY: ASCO abstracts (5 ea.) for ARRY 886 (AZN 6244):

1. Efficacy and safety of AZD6244 (ARRY-142886) as second/third-line treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC).
Sub-category: Metastatic Lung Cancer
Category: Lung Cancer--Metastatic Lung Cancer
Meeting: 2008 ASCO Annual Meeting

Abstract No: 8029
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 8029)
Author(s): V. Tzekova, C. Cebotaru, T. E. Ciuleanu, D. Damjanov, H. Ganchev, V. Kanarev, P. J. Stella, N. Sanders, G. Pover, J. D. Hainsworth
Abstract: Background: The Raf/MEK/ERK signaling pathway is necessary for oncogenic function, and in NSCLC pts constitutive activation of this pathway has been correlated with BRAF/KRAS gene mutations. MEK1/2 inhibition block the Raf/MEK/ERK pathway since these kinases lie downstream of Ras, and ERK1/2 are the only known substrates of MEK1/2. Here we evaluate the efficacy and safety of oral AZD6244 - a potent, selective, ATP uncompetitive inhibitor of MEK1/2 - vs pemetrexed (PEM), which is currently approved and widely used for second/third-line treatment, in pts with advanced NSCLC. Methods: Pts who have previously received one or two chemotherapy regimens (prior surgery and/or localized radiation allowed) were randomized 1:1 to oral AZD6244 (100 mg BID) or iv infusion of PEM (500 mg/m2 over 10 min q3w). Pts in the PEM arm also received corticosteroid premedication and vitamin supplementation. The primary objective of this Phase II exploratory study was to evaluate the efficacy of AZD6244 vs PEM as second- or third-line treatment of advanced NSCLC by assessment of disease progression. Results: Of 84 pts aged 21-80 years, 40 were randomized to AZD6244 and 44 to PEM. The majority (79%) were second-line. Baseline characteristics of the two groups were comparable. There were 28 (70%) and 26 (59%) pts with a progression event in the AZD6244 and PEM groups, respectively (HR 1.35; 80% CI 0.93, 1.94; p=0.30). A secondary analysis of PFS (AZD6244: median 67 days; PEM median 90 days; HR 1.08, 80% CI 0.75, 1.54; p=0.79) supported the primary endpoint. Two objective responses were seen in each arm. Most pts in both arms experienced adverse events (AEs): 73% with AZD6244, 80% with PEM. Dermatitis acneiform (43%), diarrhea (33%), nausea (20%) and vomiting (20%) were the most common with AZD6244. Fatigue (37%), anemia (29%), nausea (24%) and anorexia (22%) were the most common with PEM. Of 11 pts with serious AEs (4 AZD6244) only neutropenia occurred in 2 pts (PEM). Conclusion: Although there was evidence of anti-tumor activity with AZD6244, there was no significant difference observed between AZD6244 and PEM for the primary disease progression endpoint. AZD6244 was well tolerated in this patient population.

2. AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: An open-label, randomized, multicenter, phase II study.
Sub-category: Melanoma
Category: Melanoma
Meeting: 2008 ASCO Annual Meeting
Abstract No: 9033
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 9033)
Author(s): R. Dummer, C. Robert, P. B. Chapman, J. A. Sosman, M. Middleton, L. Bastholt, K. Kemsley, M. V. Cantarini, C. Morris, J. M. Kirkwood
Abstract: Background: AZD6244 is an orally available, potent, selective, ATP uncompetitive inhibitor of MEK1/2, with preclinical and phase I data suggesting it has the potential for anti-tumor activity in pts with melanoma. Here we evaluate the efficacy and safety of AZD6244 vs TMZ in an overall population of advanced melanoma pts and in mutated BRAF (BRAF+) or mutated NRAS (NRAS+) subgroups. Methods: Eligibility included AJCC stage 3/4 malignant melanoma, RECIST measurable disease, and no prior chemotherapy for advanced melanoma. Pts were randomized 1:1 to AZD6244 (100mg BD continuously) or TMZ (200 mg/m2 for 5 days, q28d). Pts randomized to TMZ could receive AZD6244 after disease progression. The primary outcome variable was progression-free survival (PFS), which was then adjusted for source of primary tumor (uveal vs non-uveal), mutation status, LDH (> or <2 x ULN), and WHO PS (0-2). Mutation status was assessed in archival or fresh tumor samples by DNA sequencing. Results: A total of 104 and 96 pts were randomized to AZD6244 and TMZ, respectively. To date, 146 pts have their mutation status confirmed, 67 were BRAF+, and 24 NRAS+. Of the non-uveal pts, 50% were BRAF+ and 68% were either BRAF+ or NRAS+. For PFS, there was no difference between the two treatment arms in the overall population (151 events; HR 1.07; 80% CI 0.86, 1.34) or in the BRAF+ subgroup (HR 0.85; 80% CI 0.58, 1.24). Overall survival (OS) data are immature (67 deaths) but the interim analysis showed no difference between the two arms in the overall population (HR 1.23; 80% CI 0.88, 1.71). In BRAF+ pts (25 deaths) the HR estimate for OS favored AZD6244 (HR 0.68; 80% CI 0.38, 1.21). Six pts receiving AZD6244 had a confirmed PR, of which 5 were BRAF+ (12% of BRAF+ pts). Nine pts receiving TMZ had a confirmed PR, 3 of which were BRAF+ (12% of BRAF+ pts). Commonly reported adverse events with AZD6244 were acneiform dermatitis (60%), diarrhea (56%), nausea (50%), peripheral edema (38%), fatigue (27%), and vomiting (26%). Updated trial data will be presented. Conclusions: Anti-tumor activity with AZD6244 has been seen but there was no significant difference in PFS between the treatment arms. The trial is being followed for mature OS data.

3. AZD6244 (ARRY-142886) versus capecitabine (CAP) in patients (pts) with metastatic colorectal cancer (mCRC) who have failed prior chemotherapy.
Sub-category: Colorectal Cancer (including liver metastases)
Category: Gastrointestinal (Colorectal) Cancer
Meeting: 2008 ASCO Annual Meeting
Abstract No: 4114
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 4114)
Author(s): I. Lang, A. Adenis, K. Boer, P. Escudero, T. Kim, M. Valladares, N. Sanders, G. Pover, J. Douillard
Abstract: Background: There is a strong correlation between human cancers and constitutive activation of the Raf/MEK/ERK signaling pathway. AZD6244, a potent, selective, ATP uncompetitive inhibitor of MEK1/2 has shown anti-tumor activity as monotherapy in several tumor models, including human colorectal tumors. This study aimed to compare the efficacy and safety of AZD6244 with that of CAP in pts with mCRC who had failed prior irinotecan and/or oxaliplatin therapy, where no standard of care exists. Methods: In this Phase II exploratory multicenter, open, two-arm parallel-group study, pts with histologically confirmed mCRC who had failed one or two previous oxaliplatin and/or irinotecan regimens were randomized 1:1 to either AZD6244 (100 mg BID) or CAP (1,250 mg/m2 BID) until objective and/or clinical progression. Eligibility included pts with a WHO performance status of 0-2 and life expectancy of >12 weeks. The primary objective was to assess the efficacy of AZD6244 vs CAP for the treatment of mCRC by assessment of disease progression. Results: A total of 69 pts (aged 38-81 years; 75% third-line) were randomized to AZD6244 (34) or CAP (35). The two groups were comparable for baseline characteristics. There was no significant difference between AZD6244 and CAP in the number of pts with a progression event: 28 pts (82%) vs 28 pts (80%), respectively (HR 1.08; 80% CI 0.73, 1.58; p = 0.80). This primary analysis was supported by a secondary analysis of PFS (AZD6244: median 81 days; CAP: median 88 days; HR 1.08; 80% CI 0.76, 1.52; p = 0.78). Most pts (97%) in both treatment arms experienced adverse events (AEs). The most common AEs with AZD6244 were dermatitis acneiform (56%), diarrhea (44%), asthenia (29%), and edema peripheral (26%). The most common AEs with CAP were palmar plantar erythrodysesthesia syndrome (56%), diarrhea (26%), nausea (26%), and asthenia (26%). Each group experienced 11 serious AEs (6 pts in each group), but no two pts experienced the same event. Conclusions: No statistically significant difference was observed between AZD6244 and CAP in the number of pts with a disease progression event. AZD6244 was well tolerated in this patient population.

4. The first-in-human study of the solid oral dosage form of AZD6244 (ARRY-142886): A phase I trial in patients (pts) with advanced cancer.
Sub-category: Other Novel Agents
Category: Developmental Therapeutics: Molecular Therapeutics
Meeting: 2008 ASCO Annual Meeting
Abstract No: 3535
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 3535)
Author(s): R. Agarwal, U. Banerji, D. R. Camidge, K. H. Brown, M. V. Cantarini, C. Morris, I. M. Desar, C. M. van Herpen
Abstract: Background: AZD6244 is a potent, selective, uncompetitive inhibitor of MEK1/2 being tested in phase II clinical trials for a number of solid tumors. To date, clinical trials have studied a freebase oral suspension formulation. A solid oral formulation, incorporating the hydrogen sulfate salt of AZD6244, has been developed to enable more convenient dosing. Methods: This phase I dose escalation study determines the maximum tolerated dose (MTD), safety and pharmacokinetic (PK) profile of the AZD6244 hydrogen sulfate formulation. Pts with advanced cancer were dosed in sequential cohorts of 6 pts from 25 mg to 100 mg BID. Plasma PK samples were collected at frequent timepoints on days 1 and 8. Results: Twenty-eight pts have been enrolled into this phase of the study. Pts received 25 mg (6), 50 mg (7), 75 mg (7) or 100 mg (8). Frequent tumor types were colorectal (9), melanoma (8), NSCLC (3), and esophageal carcinoma (2). The MTD was 75 mg BID. Three dose-limiting toxicities have been observed: G3 fatigue at 75 mg BID; G3 pleural effusion and G3 rash at 100 mg BID. The most common adverse events were acneiform rash, fatigue, nausea, diarrhea, dyspnea, peripheral edema, and vomiting. Increased blood pressure and asymptomatic LVEF reduction were also observed. Progressive disease was the most common reason for discontinuing treatment. On visual inspection, the AUC is approximately dose proportional across the 25 to 100 mg dose range tested. The median Cmax and AUC for AZD6244 hydrogen sulfate 75 mg BID is higher than historical data for the first-in-human study of the AZD6244 freebase 100 mg BID. Part B is investigating the relative bioavailability of the two formulations. Preliminary data on one pt with melanoma (pretreated with dacarbazine with PD after 6 cycles) reveal a complete response within 16 weeks of commencing therapy. Updated data on all pts will be presented. Conclusions: AZD6244 continues to show promising anti-cancer activity, notably in melanoma. This first-in-human study of the solid oral dosage form of AZD6244 demonstrates that the MTD of this formulation was 75 mg BID. Relative bioavailability studies of this dose, compared with the MTD of the oral suspension formulation, are ongoing.

5. Continuous MEK inhibition by AZD6244 (ARRY-142886) results in exhaustion of the cutaneous keratinocytic stem cell pool and resembles senescence driven skin aging.
Sub-category: Melanoma
Category: Melanoma
Meeting: 2008 ASCO Annual Meeting
Abstract No: 9075
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 9075)
Author(s): K. Schad, K. Baumann Conzett, V. Enderlin, M. V. Cantarini, M. Nief, L. French, R. Dummer
Abstract: Background: The Raf/MEK/ERK signaling pathway is constitutively activated in melanoma. AZD6244 blocks MEK1/2, inhibiting ERK phosphorylation, and is associated with cutaneous toxicities similar to EGF targeting molecules but can also induce depigmentation. Methods: 28 patients (pts) with unresectable melanoma stage III/IV were randomized to temozolomide (TMZ 200mg/m2) or AZD6244 (100 mg po bid). 13 pts received AZD6244 initially, and 9 pts AZD6244 following tumor progression with TMZ. Acute and chronic skin reactions were documented and lesion biopsies were compared to matched controls in normal skin. Immunohistochemistry (p53, Ki67, pancytokeratin) was performed. Results: 19/22 (86,3%) AZD6244-treated pts presented with cutaneous eruptions. 17 pts (77,2%) developed acute papulopustular rash in seborrhoic regions within the first treatment weeks. Chronic skin changes (> 6-8 weeks) included xerosis, paronychia and pulpitis sicca, which is similar to that observed with EGFR-inhibition. In addition, we observed hair depigmentation and vitiligo correlating with the AZD6244 treatment period. Hair abnormalities such as nonscarring alopecia, trichomegaly of the eyebrows, facial hypertrichosis and thinning of the hair as seen with EGFR-Inhibitors were not observed. Histology of acute skin lesions revealed apoptotic keratinocytes (p53 positive) and destruction of the adnexal structures by neutrophilic infiltrates, reduced expression of cytokeratins and a shift of the proliferation (Ki67) from basal to the suprabasal keratinocytes reflecting self amplifying cells. Chronic lesions revealed a reduced stratum corneum, thinning of the epidermal cell layers with apoptotic keratinocytes and focal infiltrates mainly of neutrophils and occasional lymphocytes. The number of melanocytes was not reduced. Conclusions: The clinical presentation of AZD6244 associated skin reactions partly overlaps with those observed upon EGFR-Inhibition. Additionally melanocytic function is affected. We postulate that continuous MEK inhibition by AZD6244 results in exhaustion of the cutaneous keratinocytic stem cell pool thus resembling skin senescence.