Abstract Background Expression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but little is known about factors predictive of ...efficacy in patients with locally advanced non-small cell lung cancer (NSCLC). We investigated the predictive relevance of PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy (CCRT). Methods We retrospectively reviewed 74 consecutive patients with stage III NSCLC who had received CCRT. PD-L1 expression and CD8+ TIL density were evaluated by immunohistochemical analysis. Results Univariate and multivariate analyses demonstrated that CD8+ TIL density was an independent and significant predictive factor for progression-free survival (PFS) and OS, whereas PD-L1 expression was not correlated with PFS and OS. Sub-analysis revealed that the PD-L1+/CD8 low group had the shortest PFS (8.6 months, p = 0.02) and OS (13.9 months, p = 0.11), and that the PD-L1-/CD8 high group had the longest prognosis (median PFS and OS were not reached) by Kaplan-Meier curves of the four sub-groups. Conclusions Among stage III NSCLC patients who received CCRT, there was a trend for poor survival in those who expressed PD-L1. Our analysis indicated that a combination of lack of PD-L1 expression and CD8+ TIL density was significantly associated with favourable survival in these patients. It is proposed that PD-L1 expression in combination with CD8+ TIL density could be a useful predictive biomarker in patients with stage III NSCLC.
•Inflammation as a major driver for the development and progression of cancer.•Elevated pre-treatment Neutrophil-to-Lymphocyte ratio is associated with shorter OS and PFS.•Elevated pre-treatment ...Platelet-to-Lymphocyte ratio is associated with shorter OS and PFS.
Immunotherapy with the programmed death receptor-1 (PD-1) antibody nivolumab has changed the field of metastatic non-small cell lung cancer (NSCLC) treatment. Nivolumab shows better outcome compared to standard second line chemotherapy, but reliable prognostic markers are lacking. High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation and associated with worse overall survival (OS) in several tumor types, but have not been analysed extensively in lung cancer in the era of immunotherapy.
Patients with metastatic NSCLC treated with nivolumab were enrolled. Pre-treatment NLR and PLR were calculated by division of neutrophils and platelets by lymphocytes measured in peripheral blood. Cox regression analyses were conducted to study the prognostic role of NLR and PLR on OS and progression free survival (PFS). Logistic regression was used to study the association of NLR and PLR. The combined impact of NLR and other known prognostic factors was explored with multivariable regression.
Fifty-two patients were included. Elevated NLR was associated with worse OS (HR for log(NLR)=3.64, 95% CI 1.78-7.46, p<0.001) and lower response rates (OR for log(NLR)=0.17, 95% CI 0.04-0.68, p=0.013). There was no significant association with PFS (HR for log(NLR)=1.46, 95% CI=0.91-2.34, p=0.114). The AUC for the prediction of 10-month survival using log(NLR) was 0.738, the AUC for the prediction of response to nivolumab was 0.776. Relationships with PLR were similar. NLR and PLR didn‘t correlate with other known prognostic factors (i.e histology, tobacco use, ECOG performance status,) in our cohort. Inclusion of NLR in multivariable models with these other factors significantly improved the prediction of OS.
Elevated pre-treatment NLR and PLR are associated with shorter OS and PFS and with lower response rates in patients with metastatic NSCLC treated with nivolumab independently of other prognostic factors.
Summary Background ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib ...showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period. Methods We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients. Findings Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63–82), and 2-year overall survival was 54% (40–66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached 95% CI 14 months to not reached vs 6 months 4–17, 1-year overall survival 70% 95% CI 50–83 vs 44% 23–64, and 2-year overall survival 55% 33–72 vs 12% 2–30; hazard ratio 0·36, 95% CI 0·17–0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached 95% CI 17 months to not reached vs 24 months 15–34, 1-year overall survival 71% 95% CI 58–81 vs 74% 61–83, and 2-year overall survival 57% 40–71 vs 52% 38–65; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months 95% CI 13–26 vs 15 months 13–17; p=0·244). Interpretation In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC. Funding Pfizer Inc, V Foundation for Cancer Research.
The addition of atezolizumab (anti–PD-L1 antibody) to a platinum-based chemotherapy regimen improved progression-free survival among patients who had not previously received chemotherapy for ...metastatic NSCLC, regardless of PD-L1 expression and
EGFR
or
ALK
genomic alteration status.
Visual inspection of histopathology slides is one of the main methods used by pathologists to assess the stage, type and subtype of lung tumors. Adenocarcinoma (LUAD) and squamous cell carcinoma ...(LUSC) are the most prevalent subtypes of lung cancer, and their distinction requires visual inspection by an experienced pathologist. In this study, we trained a deep convolutional neural network (inception v3) on whole-slide images obtained from The Cancer Genome Atlas to accurately and automatically classify them into LUAD, LUSC or normal lung tissue. The performance of our method is comparable to that of pathologists, with an average area under the curve (AUC) of 0.97. Our model was validated on independent datasets of frozen tissues, formalin-fixed paraffin-embedded tissues and biopsies. Furthermore, we trained the network to predict the ten most commonly mutated genes in LUAD. We found that six of them-STK11, EGFR, FAT1, SETBP1, KRAS and TP53-can be predicted from pathology images, with AUCs from 0.733 to 0.856 as measured on a held-out population. These findings suggest that deep-learning models can assist pathologists in the detection of cancer subtype or gene mutations. Our approach can be applied to any cancer type, and the code is available at https://github.com/ncoudray/DeepPATH .
Radiation therapy (RT) can both suppress and stimulate the immune system. We sought to investigate the mechanisms underlying radiation-induced lymphopenia and its associations with patient outcomes ...in non-small cell lung cancer (NSCLC).
Subjects consisted of 711 patients who had received definitive RT for NSCLC. A lymphocyte nadir was calculated as the minimum lymphocyte value measured during definitive RT. Associations between gross tumor volumes (GTVs) and lung dose-volume histogram (DVH) parameters with lymphocyte nadirs were assessed with Spearman correlation coefficients. Relationships between lymphocyte nadirs with overall survival (OS) and event free survival (EFS) were evaluated with Kaplan-Meier analysis and compared with log-rank test results. Multivariate regressions were conducted with linear and Cox regression analyses. All variables were analyzed as continuous if possible.
Larger GTVs were correlated with lower lymphocyte nadirs regardless of concurrent chemotherapy receipt (with concurrent: r = -0.26, P<.0001; without: r = -0.48, P<.0001). Analyses of lung DVH parameters revealed significant correlations at lower doses (lung V5-V10: P<.0001) that incrementally decreased and became nonsignificant at higher doses (lung V60-V70: P>.05). Of note, no significant associations were detected between GTV and lung DVH parameters with total leukocyte, neutrophil, or monocyte nadirs during RT or with lymphocyte count prior to RT. Multivariate analysis revealed larger GTV (P<.0001), receipt of concurrent chemotherapy (P<.0001), twice-daily radiation fractionation (P=.02), and stage III disease (P=.05) to be associated with lower lymphocyte nadirs. On univariate analysis, patients with higher lymphocyte nadirs exhibited significantly improved OS (hazard ratio HR = 0.51 per 10(3) lymphocytes/μL, P=.01) and EFS (HR = 0.46 per 10(3) lymphocytes/μL, P<.0001). These differences held on multivariate analyses, controlling for common disease and treatment characteristics including GTV.
Lower lymphocyte nadirs during definitive RT were associated with larger GTVs and worse patient outcomes.
ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus ...vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor (
) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results.
From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and
-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat ITT population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data.
Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio HR, 0.92; 95% CI, 0.62 to 1.36;
= .674); respective 5-year OS rates were 53.2% and 51.2% (
= .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP (
= .316) and 5y DFS rates were 22. 6% and 23.2% (
= .928), respectively.
Adjuvant therapy with gefitinib in patients with early-stage NSCLC and
mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.
mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC). Despite the uniform presence of
mutations, patients with
-mutant NSCLC can have a heterogeneous clinical ...course. As the pattern of co-occurring mutations may describe different biological subsets of patients with
-mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy.
We identified patients with advanced
-mutant NSCLC and evaluated the most common co-occurring genomic alterations. Multivariate analyses were performed incorporating the most frequent co-mutations and clinical characteristics to evaluate association with overall survival as well as response to platinum-pemetrexed chemotherapy and immune checkpoint inhibitors.
Among 330 patients with advanced
-mutant lung cancers, the most frequent co-mutations were found in
(42%),
(29%), and
/
(27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in
/
HR, 1.96; 95% confidence interval (CI), 1.33-2.92;
≤ 0.001.
(HR, 1.3;
= 0.22) and
(HR 1.11,
= 0.58) co-mutation statuses were not associated with survival. Co-mutation in
/
was also associated with shorter duration of initial chemotherapy (HR, 1.64; 95% CI, 1.04-2.59;
= 0.03) and shorter overall survival from initiation of immune therapy (HR, 3.54; 95% CI, 1.55-8.11;
= 0.003).
Among people with
-mutant advanced NSCLC,
, and
/
are the most commonly co-occurring somatic genomic alterations. Co-mutation of
and
/
is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum-based chemotherapy, and survival from the start of immune therapy.
.
Summary Background Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common ...mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations. Methods In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb–IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion del19, Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18–21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov , numbers NCT00525148 , NCT00949650 , and NCT01121393. Findings Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71·1%, 95% CI 54·1–84·6) patients in group 1 had objective responses, as did two (14·3%, 1·8–42·8) in group 2 and two (8·7%, 1·1–28·0) in group 3. Median progression-free survival was 10·7 months (95% CI 5·6–14·7) in group 1, 2·9 months (1·2–8·3) in group 2; and 2·7 months (1·8–4·2) in group 3. Median overall survival was 19·4 months (95% CI 16·4–26·9) in group 1, 14·9 months (8·1–24·9) in group 2, and 9·2 months (4·1–14·2) in group 3. For the most frequent uncommon mutations, 14 (77·8%, 95% CI 52·4–93·6) patients with Gly719Xaa had an objective response, as did nine (56·3%, 29·9–80·2) with Leu861Gln, and eight (100·0%, 63·1–100·0) with Ser768Ile. Interpretation Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations. Funding Boehringer Ingelheim.
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