P2.03b-031 Impact of PD-L1 Status on Clinical Response in SELECT-1: Selumetinib + Docetaxel in KRASm Advanced NSCLC: Topic: Biomarkers

Abstract

Anti-PD-1/PD-L1 immunotherapy has delivered clinical benefit for patients with NSCLC, and PD-L1 has emerged as a predictive biomarker. In the Phase III SELECT-1 trial (NCT01933932), selumetinib (AZD6244, ARRY-142886), an oral, potent and selective, allosteric MEK1/2 inhibitor with a short half-life, plus second-line docetaxel did not provide clinical benefit for patients with KRAS-mutant (KRASm) NSCLC compared with placebo plus docetaxel (PBO+DOC). Although no incremental benefit was observed, it is important to evaluate biomarkers, such as PD-L1, to understand more about the biology of patients with KRASm NSCLC. In total, 510 patients with a prospectively, centrally confirmed KRAS mutation (cobas® KRAS Mutation Test, Roche Molecular Systems) were randomized 1:1 to selumetinib 75 mg BID, plus docetaxel 75 mg/m2 q21d (SEL+DOC), or PBO+DOC. Evaluations included progression-free survival (PFS) by investigator assessment (RECIST 1.1; primary endpoint), and overall survival (OS). Association of tumor PD-L1 status with clinical responses was assessed as an exploratory objective. PD-L1 status was centrally determined using the PD-L1 IHC 28-8 pharmDx test (Dako) for all patients with sufficient tumor sample. Samples with a pre-specified cut-off of ≥5% tumor cell staining were considered PD-L1 positive. SEL+DOC did not improve PFS or OS compared with PBO+DOC. PD-L1 status was determined for 385 (75%) patients: 224 (58%) samples were PD-L1 <5%, and 161 (42%) samples were PD-L1 ≥5%; the remaining 125 patients had unknown PD-L1 status due to insufficient tumor sample. Subgroups were balanced across treatments. PD-L1 subgroup analysis of PFS and OS is presented below.Tabled 1SubgroupEvents (%) in SEL+DOC groupEvents (%) in PBO+DOC groupHR (95% CI)PFSPD-L1 <5%94/112 (84%)101/112 (90%)0.89 (0.67, 1.18)PD-L1 ≥5%65/79 (82%)71/82 (87%)0.70 (0.50, 0.99)PD-L1 unknown59/63 (94%)57/62 (92%)1.24 (0.86, 1.79)OSPD-L1 <5%73/112 (65%)74/112 (66%)0.94 (0.68, 1.30)PD-L1 ≥5%55/79 (70%)58/82 (71%)0.89 (0.61, 1.28)PD-L1 unknown48/63 (76%)38/62 (61%)1.57 (1.02, 2.41) Open table in a new tab Prevalence of PD-L1 positive status in this KRASm cohort was similar to that reported for a pan-NSCLC cohort (Borghaei, NEJM 2015). No significant PFS or OS differences were observed between treatments in either PD-L1 positive or negative tumors. Additional biomarker analyses are planned for different KRAS codon mutations, and LKB1 and TP53 status.