Chow, Laura Q.M.

2510 Background: Blocking the interaction between programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, and its ligand PD-L1 may enhance T-cell function. Here we describe the safety and activity from the first clinical study of BMS-936559 in patients (pts) with advanced solid tumors, further validating the importance of the PD-1/PD-L1 pathway as a target for cancer therapy. Methods: BMS-936559 was given Q2 wk IV in a 6-wk cycle at doses of 0.3−10.0 mg/kg during dose escalation and/or cohort expansion; pts could receive up to 16 cycles (48 doses). Results: As of August 1, 2011, 162 pts with melanoma (MEL, n=53), non-small-cell lung (NSCLC, n=50), colorectal (n=18), renal cell (RCC, n=17), ovarian (n=17), and pancreatic (n=7) cancer were treated. Median therapy duration was 11 wks (max 99 wks). Common related adverse events (rAEs; ≥5% pts) included fatigue, diarrhea, infusion reaction, arthralgia, rash, and pruritus. The incidence of grade 3-4 rAEs was 8.6%. AEs of special interest included hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, and myasthenia gravis; there were no drug-related deaths. Clinical activity was observed in MEL, RCC, and NSCLC. Objective responses (ORs; RECIST 1.0) were observed in heavily pretreated pts. ORs were durable; among 16 pts with ORs, 7 had responses lasting ≥1 yr. Two other pts had ongoing ORs with durations of 2.3 and 8.5 mo at data lock. Several pts had prolonged stable disease. Some pts had a persistent reduction in overall tumor burden in the presence of new lesions but were not categorized as responders. In NSCLC, ORs were observed irrespective of histology. Conclusions: BMS-936559 was active and generally well tolerated in pts with NSCLC, RCC, and MEL. In conjunction with data from anti-PD-1/BMS-936558 trials, this study concurrently validates the importance of the PD-1/PD-L1 pathway for cancer immunotherapy and supports further clinical development of anti-PD-1/PD-L1 directed therapy. [Table: see text]

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.