Virtual Library

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Background:
RTOG0617 found higher radiation dose does not benefit patients with unresectable stage III non-small cell lung cancer (NSCLC). To investigate the potential benefit of individual isotoxic dose escalation based on normal tissue constraints (NTC), hypothesizing that high-dose radiation therapy would be superior to standard-dose in concurrent chemoradiotherapy for unresectable stage III NSCLC.

Methods:
Data from two prospective clinical trials were merged for analysis. Individually prescribed radiation doses were calculated based on NTC. Patients with total radiation doses ≥66 Gy were assigned to the high-dose group (H-D, ≥66 Gy), and all other patients were assigned to the standard-dose group (S-D, <66 Gy). Intensity modulated radiation therapy plans were optimized to minimize the volumes of organs at risk exposed to radiation. The primary endpoint was overall survival.

Results:
From March 2006 to September 2012, 140 patients were enrolled and assigned to one of two groups: 71 patients into the H-D group and 69 patients into the S-D group. The median survival time (MST) was significantly higher in the H-D group (33.5 months) than in the S-D group (17 months), (p < 0.0001). Overall 5-year survival rates were significantly higher in the H-D group than in the S-D group (38.0% vs. 12.3%). Median progression-free survival was 19 months in the H-D group and 11 months in the S-D group (p < 0.0001). No difference in severe (grade 3–5) toxic effects was noted between the two groups.

Conclusions:
The dose-escalated radiation concurrent with chemotherapy showed an significant advantage in MST and survival rates over standard-dose. This individualized isotoxic dose chemoradiotherapy strategy may be a promising method for unresectable stage III NSCLC patients.

Clinical trial identification:


Legal entity responsible for the study:
Shandong Cancer Hospital

Funding:
This study was supported in part by National Nature Science Foundation of China (Grant NO. 81530060), and The National Key Research and Development Plan (Grant NO. 2016YFC0105106).

Disclosure:
All authors have declared no conflicts of interest.

Background:
RTOG 0617 identified cardiac dose-volume metrics as independent predictors of survival for locally advanced NSCLC patients following chemoradiotherapy with conventional and dose escalated regimes. Accelerated radiotherapy schedules such as continuous hyperfractionated accelerated radiotherapy (CHART) are widespread in the UK. In this single-centre retrospective analysis, we study the impact of cardiac dosimetry on survival of early stage and locally advanced patients radically treated with accelerated radiotherapy.

Methods:
We reviewed the records of all stage I-III NSCLC patients treated at our institution with radical accelerated radiotherapy (CHART, 54 Gy/36# over 12 days; hypofractionated, 55 Gy/20# over 4 weeks) between 2010 and 2015. Patient demographics, tumour characteristics, survival and dosimetric data were recorded. Cardiac dosimetric parameters included heart V5, V30, V33, V50, V67, V100 and mean dose. The impact of these metrics on survival was assessed using Cox regression.

Results:
We identified 563 patients treated of whom 294 had cardiac dosimetric data for analysis. For these patients, 55% were male with a mean age of 72. The percentage of patients with stage I, II and III disease were 33%, 16% and 51%, respectively. 60% had a WHO performance status of 0–1. 124 received CHART and 171 received hypofractionated radiotherapy. 2 year overall survival was 48% with a median overall survival of 22.5 months. On univariate analysis, gender, stage, tumour recurrence, PTV volume and all cardiac dosimetric parameters were significantly associated with survival. However, multivariate analysis identified only PTV volume and heart V30, V33, V50 and mean dose as independent predictors of survival with mean heart dose being the most predictive (HR = 1.027, 95% CI = 1.002–1.053, p = 0.032).

Conclusions:
We identified several cardiac dosimetric parameters as independent predictors of survival following accelerated radiotherapy. Consequently, minimising cardiac dose may improve outcomes and warrants further study.

Clinical trial identification:


Legal entity responsible for the study:
Weston Park Hospital

Funding:
Sheffield Hospital Charity

Disclosure:
All authors have declared no conflicts of interest.

Background:
The survival advantage of radiotherapy (RT) for patients with stage IV non-small cell lung cancer (NSCLC) has not been adequately evaluated.

Methods:
We analyzed stage IV NSCLC patients enrolled from the Surveillance, Epidemiology, and End Results (SEER) registry through January 2010 to December 2012. Propensity score (PS) analysis with 1:1 nearest neighbor matching method was used to ensure well-balanced characteristics of all comparison groups by histological types and metastatic sites. Kaplan-Meier and Cox proportional hazardous model were used to evaluate the overall survival (OS) and cancer-specific survival (CSS).

Results:
There was a trend towards improved OS and CSS using radiotherapy to stage IV NSCLC patients for any metastatic sites and for any histological types except AD. Radiotherapy significantly improved the survival of NSCLC patients with metastasis to brain (P < 0.001), especially for adenocarcinoma (AD) (P < 0.001). For stage IV lung cancer patients with squamous cell carcinoma (SQC), radiotherapy for any metastatic sites could universally improve the OS (P < 0.001) and CSS (P < 0.001). In particular, radiotherapy also was associated with improved OS (P < 0.001) and CSS (P = 0.012) for stage IV patients with metastases of two or more site, i.e., poly-metastatic disease. Furthermore, for those stage IV SQC patients without metastasis, radiotherapy, most likely to the primary site, also significantly improved the survival (P < 0.001).

Conclusions:
The results support the idea that radiotherapy might improve the survival of patients with metastatic NSCLC in a PS-matched patient cohort from the large SEER database. It is prudent to carefully select patients for radiotherapy in metastatic NSCLC.

Clinical trial identification:


Legal entity responsible for the study:
Dr. Zhenming Fu, Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China

Funding:
National Science Foundation of China (NSFC)

Disclosure:
All authors have declared no conflicts of interest.

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Background:
Single MET inhibition has controversial effects in MET addicted tumors. Proviral integration site for Moloney murine leukemia virus-1 (PIM1) is activated upon MET inhibition in MET addicted cells. PIM1 drives the expression of receptor tyrosine kinases (RTKs). SHP2, a non-receptor protein tyrosine phosphatase, is central in RTKs signaling and in Src activation. We have shown that the overexpression of RTKs like AXL and the transmembrane protein CUB domain-containing protein-1 (CDCP1) as well as Src activation, are mechanisms of intrinsic resistance to EGFR inhibition in EGFR mutant lung cancer. We are now testing whether RTKs, SHP2 or CDCP1 expression and activation are driven by PIM1 or Src and cause resistance to MET inhibitors in MET addicted tumors.

Methods:
We studied the inhibitory effect of the class I MET inhibitors tepotinib and savolitinib, the pan-PIM inhibitor AZD1208, and the Src inhibitor dasatinib in five MET addicted cell lines: 2 MET amplified lung cancer cells (EBC1 and H1993), 2 MET exon 14 mutant cells (Hs746T and H596) and a glioma cell line that carries the still not well recognized MET exon 7–8 splicing variant (E98). We assessed the effect of combined MET and PIM or MET and Src inhibition in cell viability and protein immunoblotting.

Results:
All the cell lines were sensitive to single MET inhibition (except H596) and resistant to single AZD1208 or dasatinib. The combination of savolitinib or tepotinib with AZD1208 was synergistic in the EBC1 cell line and slightly synergistic or additive in the H1993, Hs746T and E98 cell lines. The combination of savolitinib or tepotinib with dasatinib was highly synergistic in all four cell lines. The treatment of EBC1 cells with tepotinib monotherapy was not able to inhibit AXL activation while it induced the activation of SHP2 and CDCP1. AXL, CDCP1 and SHP2 expression or activation were downregulated when tepotinib was combined with dasatinib.

Conclusions:
Co-targeting PIM or Src with MET can be more effective than MET inhibition alone in MET addicted cell lines. Overexpression and activation of RTKs, CDCP1 and SHP2 can be mechanisms of resistance to single MET inhibition. The investigation of combinatorial strategies in MET addicted tumors, merits further investigation.

Clinical trial identification:


Legal entity responsible for the study:
IGTP – Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain

Funding:
Fundació Obra Social “La Caixa”

Disclosure:
All authors have declared no conflicts of interest.

Background:
Preclinical models suggest that MAPK pathway is implicated in the immune-resistance of tumors and MEK-inhibition can increase the CD8+ T-cell infiltration and the efficacy of PD-1/PD-L1 blockade.

Methods:
First, we evaluated PD-L1 mRNA expression by Real Time qPCR and its protein production, togheter with MAPK proteins in a panel of non-small cell lung cancer (NSCLC) cell lines. Then, we studied the changes in PD-L1 and major histocompatibility complex class-I (MHC-I) expression and cytokines’ production, after inhibition with selumetinib or stimulation of MAPK signalling by phorbol 12-myristate 13-acetate (PMA). In addition, we explored the effect of MEK inhibition on T-cell function by using Peripheral blood mononuclear cells (PBMC) from healthy volunteers.

Results:
A consistent correlation between PD-L1 mRNA and protein expression across cell lines suggested that expression mainly depends on trascriptional regulation, and it is regulated by MAPK signal, through the bindng of p65 to the PD-L1 promoter. Moreover, MEK inhibition resulted in an increased expression of MHC-I on cancer cells and increased mRNA expression levels of IFN gamma, IL-6, IL-1B, and TNFalpha, all molecules involved in the activation and differentiation of TCD8+ cytotoxic lymphocytes (CTL) subset. In this scenario, we also tested the effect of MEK inhibitor on activated T-lymphocytes from PBMC of healthy volunteers. After five days of treatment, RT-qPCR analysis revealed a significant increase of mRNA expression of some typical CD8+ T cell pro-inflammatory cytokines, like IL-12, TNFalpha and IFNgamma.

Conclusions:
These results further support the idea that MEK inhibitor reduces PD-L1 expression and this allows the establishment of a pro inflammatory microenvironment. On the other side, pheripheral T cells, treated with selumetinib, produce pro inflammatory cytokines typical of CTL subset, that seems more involved in immune response against cancer. In this context, MEK inhibition may represent a potential mechanism to convert otherwise resistant cancers and suggest new potential treatment combination strategies of MEK-inhibitors with anti-PD-L1 antibodies in NSCLC.

Clinical trial identification:


Legal entity responsible for the study:
University of Campania “L. Vanvitelli”

Funding:
Has not received any funding

Disclosure:
All authors have declared no conflicts of interest.

Background:
Currently, there are no clinically useful predictors of efficacy and toxicity to pemetrexed (PMX) in advanced non-small-cell lung cancer (NSCLC). Using population pharmacokinetic (pop-PK) modelling, we explored whether total exposure to PMX predicts for progression-free and overall survival (PFS/OS) and occurrence of (severe) chemotherapy (CTx)-related adverse events (AEs).

Methods:
In a prospective observational multi-center study, patients with stage IIIB/IV NSCLC receiving first- or second-line PMX(/platinum) were enrolled. PMX (500 mg/m[2]) was administered as a 10-min intravenous infusion every 21 days. Prior to and weekly after each PMX administration, plasma sampling was performed (cycle PK). In a subgroup, blood samples were also collected at 10, 30 minutes and 1, 2, 4, 8, 24 hours after start of PMX infusion (24h PK). With pop-PK modelling total exposure (AUC) to PMX per patient was estimated. The relation between AUC during cycle 1 (AUC~1~) and OS/PFS in treatment-naïve patients was examined using Cox regression analyses and in all patients we compared the difference in mean AUC~1~ between patients with and without grade ≥3 CTx-related AEs (CTCAE 4.03) during total treatment of 4 cycles.

Results:
For 106 of the 165 patients, concentrations of PMX were quantified (24h PK, n = 15; cycle PK, n = 106). Median estimated AUC~1~ was 201 mg·h/L (interquartile range: 179–224). In treatment-naive patients (n = 95), AUC~1~ did neither univariably predict for OS/PFS, nor multivariably when adjusted for prognostic factors sex, disease stage and WHO performance score (OS, HR = 1.05, 95%CI: 1.00–1.11; PFS, HR = 1.03, 95%CI:0.98–1.08). Compared to patients without ≥ grade 3 CTx-related AEs (n = 51), patients with ≥ grade 3 CTx-related AEs (n = 55) had significantly higher AUC~1~ values (220 vs 191, p < 0.001). When seperating ≥ grade 3 CTx-related AEs into clinical and laboratory AEs, identical results were found.

Conclusions:
Total systemic exposure to PMX does not predict for PFS/OS, but is significantly associated with more frequent occurrence of severe CTx-related AEs. Although the impact of peak concentrations on efficacy remains unclear, our findings suggest that lower dosage might prevent severe toxicity with preservation of efficacy.

Clinical trial identification:


Legal entity responsible for the study:
Erasmus MC

Funding:
ZonMw

Disclosure:
J. Aerts: Member of Scientific Committee ELCC 2018; consultant/advisory role with Eli Lilly and Company. All other authors have declared no conflicts of interest.

Abstract not provided

Background:
TKI has significantly improved survival time of NSCLC pts with sensitive mutation. However, pts present different outcome while receiving TKI treatment. We conduct a prospective multicenter clinical trial to determine whether clonality of sensitive mutation is related to the efficacy of TKI. We also evaluate the consistency of TMB between tissue and blood in this cohort.

Methods:
Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve pts with advanced NSCLC. DNA was sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR mutation was defined if EGFR mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR mutation. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥3% and ≥0.5%, respectively. TMB-high pts were identified with ≥9 mut/MB (upper quartile of data from geneplus).

Results:
During February to November 2017, 80 advanced NSCLC pts were enrolled from 9 centers. A total of 371 somatic variations were detected in tissues. Mutations occurred most frequently in TP53 (52%), EGFR (47%), ALK (13%), KRAS (11%). In matched plasma, 258 (70%) tumor-derived mutations were detected by pan-caner panel sequencing. A total of 41 EGFR mutations were detected in 37 pts, most of which occurred in tyrosine kinase domain (Ex19del, 42%; L858R, 37%). Most EGFR mutation were clonal in tissue and plasma, with a consistence of 85% in paired samples. In addition, bTMB was significantly correlated to tTMB (Pearson r = 0.75, p-value = 2.3e-12), with a consistence of 90%. Interestingly, high TMB was observed in a small fraction of patients (6%) with driver mutations, such as mutations in EGFR, ALK fusion, ERBB2 and PIK3CA.

Conclusions:
Deep sequencing with the pan-cancer panel can effectively detect mutations and evaluate TMB in both tissue and blood with high consistence. EGFR mutations can be clonal or subclonal in both tissue and blood. Prospective multicenter study is ongoing to determine the EGFR clonality as a predictive factor for the TKI efficacy in NSCLC (TRACELib-NSCLC).

Clinical trial identification:
NCT03059641

Legal entity responsible for the study:
Shanghai Chest Hospital

Funding:
Geneplus-Beijing Institute

Disclosure:
All authors have declared no conflicts of interest.

Background:
The role of adjuvant EGFR-TKIs in NSCLC is not well defined. Recently 2 randomized trials showed a significant disease free survival (DFS) benefit with the use of adjuvant TKIs compared to platinum-based chemotherapy in EGFR-mutant patients. Yet, older trials conducted on patients with any EGFR status did not demonstrate the same benefit. Herein, we conduct a systematic review and meta-analysis to assess the efficacy and safety of adjuvant TKIs in NSCLC patients.

Methods:
The electronic databases Medline (PubMed) and EMBASE were searched for relevant randomized trials between January 2000 and October 2017. Pooled hazard ratios (HR) for DFS and overall survival (OS), and pooled risk ratios (RR) and odds ratios (OR) for 2-year DFS and toxicity were extracted using the generic inverse variance and the Mantel-Haenszel and Peto method to perform a meta-analysis. To account for between-studies heterogeneity, random-effect models were used. Subgroup analyses assessed patients with a sensitizing EGFR mutation.

Results:
Six studies met the inclusion criteria and were included. In patients with any EGFR status, adjuvant TKIs marginally improved the DFS (5 trials, 1,860 participants, HR = 0.65, 95%CI 0.43–1.00) but not OS (4 trials, 662 participants, HR = 0.8, 95%CI 0.48–1.33). The risk of developing grade 3 or higher skin toxicity (6 trials, 1,831 participants, OR = 6.07, 95%CI 4.34–8.51) and diarrhea (6 trials, 1, 831 participants, OR = 4.05, 95%CI 2.44–6.74) was increased compared to chemotherapy, placebo or no treatment. In EGFR-mutant patients, adjuvant TKIs decreased the risk of disease recurrence by 48% (5 trials, 560 participants, HR = 0.52, 95%CI 0.35–0.78), improved the 2-year DFS (6 trials, 599 participants, HR = 0.53, 95%CI 0.43–0.66) but had no effect on OS (4 trials, 662 participants, HR = 0.64, 95%CI 0.22–1.89).

Conclusions:
Adjuvant TKIs significantly decrease the risk of recurrence in EGFR-mutant NSCLC patients but do not improve OS. Yet, OS data are still immature and longer follow up is needed for a definitive assessment of this outcome measure. Further results from ongoing well-designed trials will define the role of adjuvant TKI in NSCLC and provide stronger conclusions.

Clinical trial identification:
N/A

Legal entity responsible for the study:
Jacques Raphael

Funding:
Has not received any funding

Disclosure:
All authors have declared no conflicts of interest.

Abstract not provided

Background:
SCLC represents one of the most aggressive lung malignancies, characterized by a high growth fraction and early metastatic spread. New therapeutic options are badly needed and immunotherapy might represent a promising approach. Unfortunately, so far, no molecular prognostic markers have been validated for clinical practice and data on immune microenvironment are limited.

Methods:
We have retrospectively analyzed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 (22C3 clone, DAKO) was performed on tumor cells (TCs) and on tumor-infiltrating lymphocytes (TILs): positivity was defined as PD-L1 expression on 1% or more TCs or TILs. Immunohistochemistry for CD8 (C8/144B clone, DAKO) and FOXP3 (236A/E7 clone, ABCAM) was also performed. A semiquantitative score was used and CD8 and FOXP3 TILs categorized as positive versus negative.

Results:
The analysis included 104 patients: 48 surgically resected, 18 patients treated with radical-intent chemo-radiotherapy and 38 metastatic. In overall study population, PD-L1 was expressed in TCs in 25% of cases. The expression of PD-L1 was significantly correlated with stage disease (32% stage I-III; 13% metastatic stage; p:0.034 for TCs and p:0.002 for TILs) and with outcome: median OS 46.8 months (m) (95% CI: 22.6 to 71.0) versus (vs) 10.9 m (95% CI: 6.2 to 15.7; p = 0.047) PD-L1 positive vs negative respectively; the relation with outcome however, was not confirmed in multivariate analysis. CD8-positive TILs and FOXP3-positive TILs were present in 59% and 72% of samples respectively. Neither the presence of CD8+ TILs nor that of FOXP3+ TILs was correlated to stage. The presence of FOXP3-positive TILs was associated with improved prognosis among non-metastatic patients: median OS 52.5 m (95% CI: 21.4 to 83.7) vs 20.5 m (95% CI: 0 to 49.2; p = 0.027) FOXP3-positive vs negative TILs, a relation confirmed in multivariate analysis.

Conclusions:
Expression of PD-L1 is reduced in advanced stage SCLC patients. Further studies are needed to understand if down-regulation of PD-L1 is linked to a more aggressive phenotype. The prognostic role of FOXP3 TILs in stage I-III SCLCs warrants further confirmation in larger series of patients.

Clinical trial identification:


Legal entity responsible for the study:
Istituto Oncologico Veneto (IOV), Padua, Italy

Funding:
Università degli Studi di Padova

Disclosure:
All authors have declared no conflicts of interest.

Background:
PD-L1 expression on tumour cells has been associated with improved clinical benefit from immunotherapies targeting the PD-1 pathway. We conducted a global, multicentre, retrospective observational study to determine real-world prevalence of tumour PD-L1 expression in patients with advanced NSCLC.

Methods:
Patients ≥18 years with histologically confirmed stage IIIB/IV NSCLC and a tumour tissue block (≤5 years old) obtained before treatment at or after this stage were identified in 45 centres across 18 countries. PD-L1 tumour expression was evaluated at each institution using the PD-L1 IHC 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). The percentages of patients with PD-L1 tumour proportion score (TPS) ≥50%, TPS ≥1%, and TPS <1% were described overall and by relevant clinicopathologic characteristics.

Results:
Of 2634 patients who met inclusion criteria, 2435 (92%) had PD-L1 data; 540 (22%) of these were TPS ≥50%, 1256 (52%) were TPS ≥1%, and 1179 (48%) were TPS <1% (Table). The percentage of patients with PD-L1 TPS ≥50% and TPS ≥1%, respectively were: 22%/51% in Europe; 22%/53% in Asia Pacific; 22%/47% in the Americas, and 24%/54% in other countries. The prevalence of EGFR mutations (19%) and ALK alterations (3%) was consistent with prior reports in metastatic NSCLC. Among 1088 patients negative for both EGFR mutation and ALK alteration, the percentage of patients with PD-L1 TPS ≥50% and TPS ≥1%, respectively, were 26% and 53%.

Characteristic, n (%)[a]	N	TPS ≥50%	TPS ≥1%	TPS <1%
All patients	2435	540 (22.2)	1256 (51.6)	1179 (48.4)
Age, years
≥75	457	107 (23.4)	227 (49.7)	230 (50.3)
<75	1977	433 (21.9)	1029 (52.0)	948 (48.0)
Sex
Female	925	191 (20.6)	477 (51.6)	448 (48.4)
Male	1509	348 (23.1)	778 (51.6)	731 (48.4)
Region
Asia Pacific	691	152 (22.0)	366 (53.0)	325 (47.0)
Europe	849	183 (21.6)	431 (50.8)	418 (49.2)
The Americas[b]	369	80 (21.7)	175 (47.4)	194 (52.6)
Other[c]	526	125 (23.8)	284 (54.0)	242 (46.0)
Specimen type
Surgical resection	618	127 (20.6)	330 (53.4)	288 (46.6)
Biopsy	1743	400 (22.9)	895 (51.3)	848 (48.7)
Specimen source
Primary	1735	377 (21.7)	892 (51.4)	843 (48.6)
Metastases	632	143 (22.6)	321 (50.8)	311 (49.2)
Histology
Squamous	507	114 (22.5)	288 (56.8)	219 (43.2)
Nonsquamous	1906	420 (22.0)	956 (50.2)	950 (49.8)
Smoking status
Never	553	100 (18.1)	255 (46.1)	298 (53.9)
Former	660	159 (24.1)	358 (54.2)	302 (45.8)
Current	762	187 (24.5)	401 (52.6)	361 (47.4)
ALK translocation status
Positive	77	15 (19.5)	50 (64.9)	27 (35.1)
Negative	1470	352 (23.9)	765 (52.0)	705 (48.0)
EGFR mutation status
Positive	464	60 (12.9)	200 (43.1)	264 (56.9)
Negative	1286	324 (25.2)	682 (53.0)	604 (47.0)

aThe number of patients with the specific characteristic (row total) is the denominator for percentages in TPS columns.bIncludes Argentina, Canada, and Colombia.cIncludes Russian Federation, Saudi Arabia, and Turkey.

Conclusions:
This is the largest real-world study in advanced NSCLC to date evaluating PD-L1 tumour expression using the 22C3 pharmDx kit. Testing failure rate was low despite local evaluation of PD-L1 TPS across a large number of sites. Prevalence of PD-L1 TPS ≥50% and TPS ≥1% was similar across geographic regions and broadly consistent with central testing results from clinical trial screening populations (Aggarwal et al. Ann Oncol 2016;27:1060P).

Clinical trial identification:


Legal entity responsible for the study:
Merck & Co., Inc., Kenilworth, NJ, USA

Funding:
This study and medical writing assistance were funded by Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure:
G. Bigras: Advisory board member for Merck. T. Hida: Grants and personal fees from AstraZeneca, Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly, Novartis, Taiho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim, Pfizer, Bristol-Meyers Squibb, Clovis Oncology, MSD, and Kissei; grants from Eisai, Takeda Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma, Abbvie, Merck Serono, Kyowa Hakko Kirin, Daiichi Sankyo, Astellas, Ignyta, and Servier. B. Piperdi, T. Burke, S. Khambata-Ford, A. Deitz: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA. All other authors have declared no conflicts of interest.

Abstract not provided

Background:
To define prognostic and potentially predictive immune profiles in NSCLC patients receiving nivolumab, an integrated analysis of tissue and circulating parameters was performed.

Methods:
Peripheral blood (PB) from 31 advanced NSCLC patients was analyzed by FACS to assess CD3, CD8, CD4, NK, Treg, and MDSC (CD14[pos]/CD33[pos]/DR[neg]) number, function (PD-1, CD3ζ, Granzyme B, Perforin) and proliferation (Ki67). Data were collected at baseline (T0), and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. PD-L1 (H-score) and TILs subpopulations were immunohistochemically investigated. Merged tissue and circulating parameters were correlated to clinico-pathological features, response to treatment (RECIST 1.1) and survival outcomes.

Results:
T cells were more represented in PB from ADC patients (p < 0.01 vs SqCC), while KRAS mutation conditioned higher number of CD3, CD8, CD4, and NK, and lower MDSC (p < 0.05). Active smoking and BPCO directly correlated with T and NK cells proliferation (p < 0.05). Additionally, steroid naïve patients had increased effector and reduced immune suppressive (p < 0.05) phenotypes. Clinical benefit (CB, n = 19) group, compared to non-responder (NR, n = 12), displayed a distinctive PB immune profile at baseline, including higher NK (tot, CD3ζpos, Pfnpos, GrzBpos) and CD8pos/PD-1pos cells (p < 0.01). These CB immune features were maintained during nivolumab, while MDSC progressively rose in NR (p < 0.05). Prolonged OS (p < 0.05) and PFS (p < 0.01) were recorded in cases with high NK and CD8pos/PD-1pos number at T0. At tissue level, while high PD-L1 score had a modest clinical impact, low PD-1 expression in CD8pos TILs was a distinctive feature of CB (p < 0.001 vs NR) and correlated with better OS (ns) and PFS (p < 0.01). Strikingly, the combination of predetermined PB (high NK and CD8pos/PD-1pos) and tissue (low CD8pos/PD-1pos) positive prognostic factors characterized an immune privileged context provided by significantly prolonged PFS (p < 0.001) and OS (p < 0.01).

Conclusions:
A divergent PD-1 expression in blood and tissue cytotoxic cells associated with a preserved functional pool of circulating NKs portrays an immune profile prone to nivolumab efficacy.

Clinical trial identification:


Legal entity responsible for the study:
University of Parma, Italy

Funding:
Has not received any funding

Disclosure:
All authors have declared no conflicts of interest.

Background:
The ability of tumors to avoid immune surveillance has emerged as therapeutically approachable in several types of cancer, especially through the blockade of immune checkpoints such as PD-L1/PD-1. Our purpose is to determine the contribution of somatic genomic alterations in lung cancer (LC) to the capability of tumour cells to escape the immune surveillance checkpoints.

Methods:
The mutation status of recurrent driver genes in lung cancer (e.g. EGFR, KRAS, MET) and the expression of immune-related molecules (PD-L1, HLA-complex, and tumour infiltrating lymphocytes CD8+, TILs) were assessed in a cohort of 155 primary resected non-small cell lung cancer (NSCLC). Correlations between genomic alterations and immune markers were determined by Chi-square test and validated in genetically characterized cancer cell lines. Functional assays were performed using appropriate treatments, including IFNγ, to modulate selected pathways. RNA-Seq analysis was performed to analyse differential gene expression with these treatments.

Results:
MET activation, comprising MET exon 14 skipping mutations and MET amplification, was found in 3% of samples in our cohort and these tumors were more likely to have positive immunostaining (≥5%) of PD-L1 (p = 0.05), with no specific TILs CD8+ pattern. In MET altered cancer cell lines, PD-L1 was upregulated through MET activation, independently of JAK-STAT pathway. Interestingly, we reported JAK2 loss of function mutations in LC cell lines that co-occurred with MET alterations, and abrogated the response to IFNγ. RNA-Seq analysis showed that both MET activated signature (MA-Sign) and IFNγ treatment (IFN-Sign), included genes involved in negative regulation of immune response such as CD274 (PD-L1), PDCD1LG2 (PD-L2), SOCS1 and SOCS3. However, none of the pro-immune response genes commonly found in IFN-Sign were upregulated in MA-Sign.

Conclusions:
MET oncogenic is not mutually exclusive with JAK2 inactivating mutations in LC and promotes the intrinsic expression of several negative checkpoints of the immune response, including PD-L1. Both genetic alterations are likely to promote tumor growth by enabling immune tolerance.

Clinical trial identification:


Legal entity responsible for the study:
IDIBELL

Funding:
Has not received any funding

Disclosure:
All authors have declared no conflicts of interest.

Abstract not provided