Hersey, Peter

9009 Background: Programmed death-1 (PD-1) is an inhibitory T-cell co-receptor that may lead to suppression of antitumor immunity. Lambrolizumab is a humanized monoclonal IgG4 antibody against PD-1. This study explored the safety and clinical activity of lambrolizumab in patients (pts) with advanced melanoma (MEL). Methods: In this ongoing phase 1b expansion study of MEL pts with or without previous ipilimumab (IPI) treatment, lambrolizumab was administered IV every 2 or 3 weeks until disease progression or unacceptable toxicity. Tumor response was assessed every 12 weeks by independent, central, blinded radiographic review per immune-related response criteria and RECIST 1.1. Results: As of December 1, 2012, 294 pts with MEL were enrolled, including 179 IPI-naive and 115 IPI-pretreated. Pts received lambrolizumab 10 mg/kg (n = 183) or 2 mg/kg (n = 111). Preliminary data from the first 85 consecutive pts dosed before April 25, 2012, who had independent radiologic review available as of December 3, 2012, indicate a confirmed overall response rate per RECIST 1.1 of greater than 35%, pooled across all doses and schedules and including both IPI-naive and IPI-pretreated patients. The median duration of response has not been reached as only 2 pts who had initial response discontinued due to disease progression, but the duration of confirmed responses range from 28+ to 240+ days (up to 8+ months). Among 133 pts who were dosed with lambrolizumab before July 31, 2012, and evaluable for adverse events (AEs) as of September 28, 2012, fatigue (22%), rash (18%), and pruritus (14%) were the most common drug-related AEs (mostly grade 1/2). The incidence of drug-related grade 3/4 AEs was 10% (24% regardless of attribution). Four drug-related cases of pneumonitis were reported, all of grade 1/2. Grade 3/4 drug-related hypothyroidism (n = 1) and hyperthyroidism (n = 1) were noted. Conclusions: Preliminary data suggest that lambrolizumab has significant antitumor activity and is well tolerated with manageable side effects in both IPI-naive and IPI-pretreated MEL pts. These data have led to an ongoing, international, randomized study of lambrolizumab versus chemotherapy in IPI-pretreated MEL. Clinical trial information: NCT01295827.

Abstract Purpose: The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). Experimental Design: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations. Results: Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1–89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites; all P ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs. 23%; P < 0.001) and improved OS (HR, 0.38; P < 0.001). In multivariate analyses, BTS below the median remained an independent prognostic marker of OS (P < 0.001) but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1–positive tumors were independently associated with higher ORR and longer OS. Conclusions: BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma. Clin Cancer Res; 24(20); 4960–7. ©2018 AACR. See related commentary by Warner and Postow, p. 4915