Penbro（PD-L1）临床结果（ESMO2014）
Almost 60% of patients with advanced non–small cell lung cancer (NSCLC) had tumor shrinkage when treated with the PD-L1 inhibitor pembrolizumab, results of a preliminary clinical trial showed. The objective response rate was 21% among 236 evaluable patients, which included a combination of previously treated and untreated patients. Previously untreated patients had an objective response rate of 26%. Analysis of response by PD-L1 expression in a subgroup of patients showed a 37% response rate in patients whose tumors exhibited high PD-L1 expression. High PD-L1 expression was associated with a 48% reduction in the hazard for death or progression and a 41% reduction in the survival hazard, according to a report presented at the 2014 ESMO Congress. “We observed robust antitumor activity in both treatment-naïve and previously treated advanced non–small cell lung cancer,” said Edward B. Garon, MD, director of thoracic oncology at the Jonsson Comprehensive Cancer Center and the University of California, Los Angeles. “Activity was observed for all doses and schedules evaluated. Responses are durable, and treatment with pembrolizumab was associated with a manageable safety and toxicity profile.” Planning has begun for a follow-up study to validate the PD-L1 cutpoint for strong and weak expression, he added. Pembrolizumab is a humanized monoclonal antibody against PD-1 and is in development for use in a variety of solid tumors. Previous studies demonstrated promising antitumor activity in melanoma, NSCLC, head and neck cancer, gastric cancer, and urothelial cancer, said Garon. The antibody has FDA approval for use in unresectable metastatic melanoma. Garon reported data from a phase 1b trial limited to patients with advanced NSCLC. The PD-L1 status of all patients had been determined, and investigators defined a PD-L1 positive tumor as immunohistochemical (IHC) staining of at least 1% of the tumor. Eligible patients had received no systemic steroid therapy and had no active autoimmune disease and no active brain metastases. EGFR mutation or ALK rearrangement disqualified patients with no previous treatment but not those with a treatment history, including disease progression on the most recent tyrosine kinase inhibitor. The trial involved a total of 307 patients, including expansion cohorts. The primary endpoint was objective response rate as determined by RECIST criteria. A secondary response measure was investigator-assessed immune-mediated response. Treatment with pembrolizumab continued until disease progression, unacceptable toxicity, or death. Response data came from 262 evaluable patients. The cohort had a median age of 65, and men and women accounted for equal proportions of the population. Almost 70% of the patients had ECOG performance status of 1, and the rest had ECOG 0 or status was unknown. Tumor genomic data showed EGFR mutation in 16%, KRAS mutation in 26%, and ALK translocation in 3%. Two thirds of the patients were former smokers, and 28% had never smoked. The most frequent adverse event (all grades) was fatigue (20%). No other adverse event of any grade affected ≥9% of patients, with grade 3-5 adverse events occurring in <1% of patients. Garon reported that 58% of the patients had some degree of tumor shrinkage by RECIST criteria. Subgroup analysis showed consistent response rates in most cases. Smoking status represented a notable exception, as current and former smokers had an objective response rate of 27% versus 9% among never smokers. The response rate was 23% in patients with PD-L1–positive tumors and 9% in those with PD-L1–negative tumors. In general, investigator-assessed antitumor activity was consistent with assessments by RECIST criteria. The response rate for the entire cohort was 23%. Kaplan-Meier survival analyses showed a median progression-free survival (PFS) of 27 weeks and a 24-week PFS of 51% among previously untreated patients. Treatment-experienced patients had a median PFS of 10 weeks and a 24-week PFS of 26%. Pooled data for all patients yielded a median overall survival (OS) of 8.2 months and a 6-month OS of 64%. Assessment of PD-L1 expression by IHC staining and the 22C3 antibody has shown that tumor PD-L1 expression does not correlate with response, said Garon. Investigators in the pembrolizumab trial performed a separate analysis, using a different IHC assay from a different vendor but with the same 22C3 antibody. Investigators defined strong PD-L1 expression as at last 50% membranous staining in tumor cells and weak expression as 1% to 49% staining.
The analysis showed a 37% response rate among 41 patients with strongly positive tumors, 17% for patients with weakly positive tumors, and 10% for PD-L1 negative tumors.
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