Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial.

BACKGROUND: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. PATIENTS AND METHODS: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis. RESULTS: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS ≥1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. CONCLUSION: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01905657.

Relationships between longitudinal neutrophil to lymphocyte ratios, body weight changes, and overall survival in patients with non-small cell lung cancer.

BACKGROUND: There is emerging evidence showing a significant relationship between overall survival (OS) in non-small cell lung cancer NSCLC patients and weight change during chemotherapy or chemoradiation. A high neutrophil/lymphocyte ratio (NLR) at baseline and at follow-up is associated with shorter survival in cancer patients and may be a surrogate for ongoing inflammation, implicated in cancer cachexia and tumor progression. The objective of this study is to explore potential relationships between OS, serial weights, and serial NLRs in advanced NSCLC patients receiving chemotherapy. METHODS: One hundred thirty-nine patients with chemotherapy-naïve NSCLC, predominantly with stage III/IV disease, were treated with first-line platinum doublets from June, 2011 to August, 2012. NLR, tumor response, and body weight were recorded at baseline, 6, and 12 weeks from initiation of therapy and correlated with OS. The association between NLR and OS was assessed using Cox PH (proportional hazards) analysis, the association between NLR and weight change was assessed using a simple regression analysis, and the association between NLR and tumor response was assessed using the Fisher's exact test. RESULTS: One hundred thirty-nine patients with median age 68, PS 0-1/2 = 83/17%, male/female = 58%/42%. Median NLR at baseline was 3.6 (range 0.1898 to 30.910), at 6 weeks 3.11 (range 0.2703 to 42.11), and at 12 weeks 3.52 (range 0.2147 to 42.93). A Higher NLR at baseline, 6, and 12 weeks was associated with decreased OS (baseline: HR 1.06, p < 0.001; 6 weeks: HR 1.07, p = 0.001; 12 weeks: HR 1.05, p < 0.001), and longitudinal NLR, as a time-dependent covariate, was also associated with decreased OS (HR = 1.06, p < 0.001). Baseline weight and NLR were inversely related (cor = -0.267, p = 0.001), and weight change and NLR were inversely related at 12 weeks (cor = -0.371, p < 0.001). Longitudinal measurements of weight and NLR were also negatively associated (slope = -0.06, p < 0.001). Using a cutoff of NLR > 5, there was a significant association between progressive disease and NLR > 5 at 6 weeks (p = 0.02) and 12 weeks (p = 0.03). CONCLUSIONS: High baseline and progressive increases in NLRs are associated with progressive disease, inferior OS and weight loss in NSCLC patients. In addition to having prognostic significance, these observations suggest that studying molecular mediators of cachexia/inflammation and their relationships to tumor progression may identify new therapeutic targets in the large subset of NSCLC patients who have cancer cachexia.

Esophageal carcinoma advances in treatment results for locally advanced disease: review.

The treatment results of patients with locally advanced esophageal carcinomas have evolved since the publication of the first trial of concurrent mitomycin C and 5-fluorouracil with radiotherapy (RT) in 1983. Subsequent studies refined and improved on the concurrent chemotherapy (chemo) with administration of cisplatin and 5-fluorouracil infusion (PF). Chemo (PF) before surgery improved overall survival (OS) in those patients in most of the randomized trials and in meta-analyses. Two courses of PF concurrent with irradiation followed by additional two courses of PF were superior to RT alone without surgery for both groups. Concurrent chemoradiotherapy followed by surgery was found to have statistically improved OS as compared with surgery only in randomized trials and meta-analyses. In most of these studies, it was found that those patients with pathologic complete response to the initial treatment(s) did better than those who had no improvement at all. Current treatment outcome for these diseases is disappointing; newer strategies including induction chemo with the optimal combination, proper dosage of each drug, and proper number of courses before concurrent chemoradiotherapy; improvement in RT; and immunotherapy with or without subsequent surgery are exciting and definitely need to be investigated in prospective randomized trial(s).

PTEN and PIK3CA gene copy numbers and poor outcomes in non-small cell lung cancer patients with gefitinib therapy.

METHODS: Fluorescent in situ hybridisation analyses of PTEN, PIK3CA, EGFR and CEN7 were performed on tumour specimens from patients treated on the expanded access gefitinib trial. Progression-free survival (PFS) and overall survival (OS) were correlated with outcomes in all patients and EGFR wild-type patients. RESULTS: Progression-free survival (hazard ratio=2.54, P<0.001) and OS (hazard ratio=4.04, P<0.001) were significantly shorter in patients whose tumours had all of the following molecular patterns: CEN7 <4 copies per cell, PTEN loss (<2 copies in at least 20% of cells), and PIK3CA gain (>2 copies in at least 40% of cells) both in all and EGFR wild-type only patients. CONCLUSION: The combination of low CEN7 copy number, PTEN loss, and PI3KCA gain may be useful for identifying NSCLC patients unlikely to benefit from treatment with EGFR (TKIs), specifically in wild-type EGFR cases.