89Zr]Zr-DFO-avelumab accumulation in resectable non-small cell lung carcinoma indicates a suppressive tumor microenvironment amendable to neoadjuvant avelumab treatment

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

Programmed Cell Death Ligand 1 Expression in Resected Non–Small Cell Lung Cancer

Adjuvant chemotherapy for surgically resected non–small cell lung cancer

Early and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy

SY13-03: Neoadjuvant immunotherapy for operable non-small cell lung cancer: Lessons learned and current challenges

Background: Antibodies against programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have recently demonstrated a survival benefit in several types of cancer, including melanoma and non-small cell lung cancer (NSCLC). PD-L1 expression has provided a predictive biomarker for anti-PD-1/PD-L1 therapy. However, the relationship between PD-L1 expression and clinical and clinicopathological characteristics remains unclear in NSCLCs. The aim of this study was to investigate the relevance of PD-L1 expression to clinical and clinicopathological factors in resected NSCLCs. Materials and Methods: PD-L1 expression was evaluated in 154 surgically resected NSCLC specimens by immunohistochemistry (IHC) using the SP142 antibody. Before the IHC of clinical samples, we performed a concordance study of Western blot analysis and IHC in 17 lung cancer cell lines. We evaluated the relationship between PD-L1 expression and clinical and clinicopathological factors by univariate and multivariate analyses. Survival curves were estimated by the Kaplan-Meier methods, and differences in survival distributions were evaluated by the log-rank test. Results: PD-L1 expression was well concordantly observed in Western blot analysis and IHC in the lung cancer cell lines analyzed. PD-L1 expression was observed in 51 of 154 (33%) surgically resected NSCLCs. PD-L1 expression was significantly correlated with male, heavy smoking history, squamous cell carcinoma, and moderate/poor differentiation of tumors by univariate analysis. In multivariate analysis, tumor differentiation had a strong relationship with PD-L1 expression (odds ratio: 6.32, 95% CI: 1.70-23.49, P = 0.006). The survival was not statistically different between patients with high and low PD-L1 expression (5-year survival rate: 44.1% versus 58.1%, P = 0.22). PD-L1 expression was not an independent prognostic factor in univariate and multivariate analyses. Conclusion: PD-L1 expression was strongly associated with tumor differentiation in resected NSCLCs. PD-L1 expression was not a prognostic factor in this cohort of resected NSCLCs. Citation Format: Yoshihito Ohhara, Ichiro Kinoshita, Utano Tomaru, Kanako C. Hatanaka, Yutaka Hatanaka, Rio Honma, Satoshi Takeuchi, Yasushi Shimizu, Kichizo Kaga, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita. Clinicopathological features of programmed cell death ligand 1 (PD-L1) expression in resected non-small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2625. doi:10.1158/1538-7445.AM2017-2625

Resectable non-small cell lung cancer (NSCLC) patients have a high risk of recurrence. Multiple randomized controlled trials (RCTs) have shown that neoadjuvant chemo-immunotherapy brings new hope for these patients. The study aims to evaluate the safety, surgery-related outcomes and oncological outcomes for neoadjuvant chemo-immunotherapy in real-world setting with a large sample size and long-term follow-up. Patients with clinical stage IB-IIIB NSCLC who received neoadjuvant chemo-immunotherapy at two Chinese institutions were included in this retrospective cohort study. Surgical and oncological outcomes of the enrolled NSCLC patients were collected and analyzed. There were 158 patients identified, of which 124 (78.5%) were at stage IIIA-IIIB and the remaining 34 (21.5%) were at stage IB-IIB. Forty-one patients (25.9%) received two cycles of neoadjuvant treatment, 80 (50.6%) had three cycles, and 37 (23.4%) had four cycles. Twenty-four patients (15.2%) experienced grade 3 or worse immune-related adverse events. The median interval time between the last neoadjuvant therapy and surgery was 37 [interquartile range (IQR), 31-43] days. Fifty-eight out of 96 (60.4%) central NSCLC patients who were expected to undergo complex surgery had the scope or the difficulty of operation reduced. Ninety-five (60.1%) patients achieved major pathologic response (MPR), including 62 (39.2%) patients with pathologic complete response (pCR). Multivariate regression analysis showed that no clinical factor other than programmed death-ligand 1 (PD-L1) expression was predictive of the pathological response. The median follow-up time from diagnosis was 27.1 months. MPR and pCR were significantly associated with improved progression-free survival (PFS) and overall survival (OS). Neither stage nor PD-L1 expression was significantly associated with long-term survival. The neoadjuvant chemo-immunotherapy is a feasible strategy for NSCLC with a favorable rate of pCR/MPR, modified resection and 2-year survival. No clinical factor other than PD-L1 expression was predictive of the pathological response. pCR/MPR may be effective surrogate endpoint for survival in NSCLC patients who received neoadjuvant chemo-immunotherapy.

Tertiary lymphoid structures (TLS) existence is correlated with favorable prognosis in many types of cancer including non-small cell lung cancer (NSCLC). However, TLS formation and its relationship with treatment response...

e21004 Background: Previous studies have demonstrated that programmed cell death-ligand 1 (PD-L1) serves as a poor prognostic biomarker for the survival in advanced-stage non-small-cell lung cancer (NSCLC) patients. However, the value of PD-L1 expression for the prognosis of early-stage NSCLC patients after complete resection remains controversial. Here, we conduct a meta-analysis to investigate the relationship between PD-L1 expression and prognosis in resected NSCLC. Methods: Electronic databases, including PubMed, EMBASE, and the Cochrane Library, were searched up until June 30 2019, for studies evaluating the expression of PD-L1 and prognosis of the resected NSCLC. Hazard ratios (HRs) with 95% confidence interval (CI) of overall survival (OS) and disease-free survival (DFS) were pooled and analyzed. Heterogeneity and publication bias analyses were also performed. Results: A total of 15 studies involving 3501 patients were enrolled. The pooled hazard ratio (HR) showed that PD-L1 expression was related to a much shorter DFS (HR = 1.63, 95% CI: 1.26-2.12, P = 0.022), as well a significantly worse OS (HR = 1.68, 95% CI: 1.32-2.14, P = 0.000). Furthermore, our analysis indicated that PD-L1 expression was significantly associated with gender (male vs. female: HR = 1.25, 95% CI:1.02-1.52, p = 0.028), tumor stage (III/IV vs. I/ II: HR = 2.39, 95% CI:1.85-3.08, p = 0.000), lymph node metastasis (N+ vs N-: HR = 3.54, 95%CI:2.56-4.88, p = 0.000) and smoking status (Yes vs No: HR = 1.37,95% CI:1.20-1.560, p = 0.000). Conclusions: The results of this meta-analysis suggest that PD-L1 expression predict an unfavorable prognosis in early-stage resected NSCLC. The role of individualized anti-PD-L1/PD-1immunotherapy in the adjuvant settings of resected NSCLC is worthy of being further investigated.

BackgroundA small proportion of patients with non-small cell lung cancer (NSCLC) experience objective clinical benefit after neoadjuvant programmed cell death 1 (PD-1) blockade. A neoadjuvant therapeutic regimen combining immune checkpoint blockade with chemotherapy might improve the treatment effect, but such a regimen has not been tested in patients with resectable stage IIIA/IIIB NSCLC.MethodsA retrospective study of 35 patients with resectable stage IIIA and IIIB NSCLC who were treated with neoadjuvant chemoimmunotherapy (NCIO) was performed. Patients were evaluated for pathological complete response (pCR), major pathologic response (MPR), safety, and feasibility. The correlations of pathologic response with various clinical factors were studied to identify predictors of pathological response.ResultsNCIO was associated with few immediate adverse events. NCIO did not delay planned surgery and led to a pCR rate of 51.43% and an MPR rate of 74.29% for the primary tumor. No association was observed between programmed death-ligand 1 (PD-L1) expression before NCIO and the pathologic response (Pearson’s r=−0.071; P=0.685). However, a significant difference was observed in pathological response in patients with intracavitary and extracavitary tumors (P<0.05). Patients with intracavitary type had a higher pCR (76.47% vs. 31.58%) and MPR (100% vs. 50.00%) rate than patients with extracavitary type (Pearson’s r=0.7280; P=0.0009).ConclusionsNCIO was associated with few side effects, did not delay surgery, and achieved a pCR in 51.43% and MPR in 74.29% of resected tumors. No significant correlation was found between pathologic response and PD-L1 expression. While the intracavitary and extracavitary tumors type T was predictive of the pathological response to NCIO.

TPS8117 Background: Co-blockade of lymphocyte activation gene 3 (LAG-3) and programmed cell death-1 (PD-1) may enhance the efficacy of anti–PD-1 therapies. Fianlimab (anti–LAG-3) and cemiplimab (anti–PD-1) are high-affinity, fully human, immunoglobulin G4 monoclonal antibodies. In a Phase 1 study (NCT03005782), fianlimab + cemiplimab showed promising clinical activity with durable responses and an acceptable risk–benefit profile in patients with programmed death-ligand 1 (PD-L1)-naïve, advanced NSCLC. Immuno-oncology + chemotherapy is a new standard of care in the perioperative setting, but potential improvements to outcomes in early-stage disease remain under investigation. Methods: This is a randomized, multicenter, double-blind, Phase 2 peri-operative study (NCT06161441) in patients with fully resectable stage II–IIIB (N2), operable, and treatment-naïve NSCLC with squamous or non-squamous histology. The aim of this study is to investigate the efficacy and safety of fianlimab + cemiplimab + chemotherapy versus cemiplimab + chemotherapy as peri-operative treatment. The study will be conducted globally at ∼130 sites. Key inclusion criteria: age ≥18 years; newly diagnosed, histologically confirmed, fully resectable stage II–IIIB (N2) NSCLC; no distant metastases; evaluable PD-L1 immunohistochemistry results; no cancer treatment in the past 3 years, except adjuvant hormone therapy for hormone-sensitive cancers in long-term remission; Eastern Cooperative Oncology Group performance status ≤1; no known EGFR mutations or ALK aberrations; and adequate organ and bone marrow function. Mediastinal lymph node sampling is required for patients with mediastinal adenopathy. Enrolled patients (n=∼180) will be stratified by clinical TNM stage (II vs III), histology (nonsquamous vs squamous), and PD-L1 expression (&lt;1%, 1–49%, ≥50%), and randomized (1:1:1) to the following study arms for the neoadjuvant period (≤4 cycles; each cycle is every 3 weeks): arm A, placebo + cemiplimab 350 mg + platinum doublet chemotherapy; arm B, fianlimab dose 1 + cemiplimab 350 mg + platinum doublet chemotherapy; arm C, fianlimab dose 2 + cemiplimab 350 mg + platinum doublet chemotherapy. After surgery, in the adjuvant period (≤14 cycles), patients in all arms will continue the same IO regimen with approved maintenance chemotherapy. Treatment will last ∼12 months (12 weeks’ neoadjuvant therapy + 42 weeks’ adjuvant therapy), or until disease recurrence, unacceptable toxicity, or a decision from the patient or investigator. Primary endpoint: pathological complete response as determined by blinded independent pathological review (BIPR). Key secondary endpoints: event-free survival and tumor response by investigator assessment, major pathological response by BIPR, safety, pharmacokinetics, immunogenicity, and patient-reported outcomes. Clinical trial information: NCT06161441 .

e20582 Background: The advantage of combining chemotherapy and immune checkpoint inhibitors (ICIs) in resectable non-small cell lung cancer (NSCLC) patients has recently been studied in clinical trial settings. We aim to systematically revise the evidence of efficacy and safety of neoadjuvant chemoimmunotherapy treatment. Methods: We carried out a systematic search on MEDLINE, Scopus, Cochrane, and ASCO meetings library. Screening was done to include clinical trials of stage I-IIIA NSCLC patients who underwent any combination of ICIs and chemotherapy. The primary outcomes were major pathological response (MPR) and pathological complete response (pCR), and the secondary outcomes were 24-month overall survival (OS) and safety measured by adverse events (AEs). A meta-analysis was conducted for intention-to-treat MPR and pCR outcomes, in addition to a mixed-effects meta-regression model to investigate the effect of PD-L1 expression, tumor mutational burden (TMB), N stage (AJCC 8th), tumor size and tumor histology on MPR and pCR. PD-L1+ patients were defined to have a tumor proportion score of more or equal to 1%. Results: We included 9 phase II clinical trials and 1 phase III trial, all consisting of 471 patients. Trials administered neoadjuvant chemotherapy agents like carboplatin (N = 6 studies), cisplatin (N = 5), nab-paclitaxel (N = 4), pemetrexed (N = 2), and others, either as a doublet- or a triplet-agent regimen. ICIs used were anti-PD-1 (N = 5), anti-PD-L1 (N = 3), or anti-CTLA-4 agents (N = 2). Meta-analysis of 447 patients from 9 trials showed a pooled MPR of 49.2% (95% CI: 34.8 to 63.7%) with high heterogeneity (I2 = 87%, p &lt; 0.01). Pooling the pCR from 10 trials including 471 patients results in an estimate of 27.5% (95% CI: 17.2 to 38.2%) with significant heterogeneity (I2 = 80%, p &lt; 0.01). Meta-regression has found a significant association between being PD-L1+ and achieving MPR (odds ratio = 3.82, 95% CI: 1.55 to 9.58). However, this effect diminished in the multiple meta-regression that included age, tumor histology, in addition to PD-L1 status. None of these factors was correlated to achieving a pCR. Investigating the effect of tumor size, T stage, N stage, or TMB on MPR or pCR was not possible due to underreported data. Three trials of 137 patients reported a 24-month OS of 84.4% (95% CI: 77.6 to 90.2%) with low heterogeneity (I2 = 11%, p = 0.33). The most prevalent grade 3/4 AEs from the neoadjuvant treatment were neutropenia in 7.2% of patients, diarrhea in 3.2%, fatigue in 3.0%, and anemia in 2.1% of patients. The commonest any-grade AEs were fatigue (43.9%), alopecia (38.4%), diarrhea (31.6%), anemia (23.8%) and neutropenia (17.0%). Conclusions: The addition of ICIs to chemotherapy in neoadjuvant settings is an effective and feasible option. Effect of tumor size, PD-L1 status and TMB on MPR and pCR should be further investigated for better selection of treatment candidates.

Programmed death-ligand 1 testing in patients with non-small cell lung cancer: Ready for prime time?

P07.03 The Impact of PD-L1 Expression on the Prognosis of Early-Stage Resected NSCLC: A Meta-Analysis of Literatures

Background: In recent years, great improvement has been made in immunotherapies for non-small cell lung cancer (NSCLC). Current data have suggested that Programmed cell death ligand 1 (PD-L1) expression might not be an ideal marker for patient selection in isolation. Evidence has been increasing that alternative markers, such as neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation response (SIR) previously associated with outcomes in a variety of cancers including NSCLC, might be a predictor for patient selection and the response to therapy. No reports have examined the prognostic value of combination of PD-L1 expression and inflammatory markers such as NLR in NSCLC. This retrospective study explores the relationship between NLR and PD-L1 expression in NSCLC as well as the prognostic value of combination of PD-L1 expression and NLR.Method: We evaluated tumor PD-L1 expression in 235 surgically resected NSCLC cases by immunohistochemical analysis. Carcinoma cells showing membranous staining for PD-L1 were considered PD-L1-positive cells (Figure 1). Cases with ≥1% tumor membrane staining were considered PD-L1-positive. The association of clinicopathological characteristics with PD-L1 expression was assessed by univariate and multivariate analyses. Moreover, univariate and multivariate analyses were performed to evaluate the predictive impact of PD-L1 expression and other factors on disease-free survival (DFS) and overall survival (OS).Result: PD-L1 protein expression was elevated in 34.0% of patients at cut-off value of 1%. Univariate analyses showed that PD-L1 expression was significantly higher in men (χ2 =5.226, P=0.030), heavy smokers (χ2 =18.650, P<0.001), and patients with squamous cell carcinoma (χ2 =4.036, P=0.045). No correlations were noted between PD-L1 expression and age, EGFR mutation status or clinical stage. No significant correlations between PD-L1 protein expression and NLR were found. Multivariate logistic regression revealed that smoking index ≥400 was independent predictor of PD-L1 expression (odds ratio [OR], 3.375; P < 0.001). The results of univariate survival analyses showed that clinical stage (log-rank χ2 =7.876, P=0.019) was associated with DFS. Smoking index (log-rank χ2 =4.832, P=0.028), clinical stage (log-rank χ2 =7.582, P=0.023) and adjuvant treatment (log-rank χ2 =5.440, P=0.020) were significantly associated with OS. Neither PD-L1 expression nor NLR was found to be associated with DFS or OS. Of interest, when patients were divided in two groups according to combined PD-L1/NLR: patients with PD-L1+/ high NLR as Group 1, other patients as Group 2, Group 1 had significantly shorter DFS as well as OS than Group 2 (DFS: log-rank χ2 =5.231, P=0.022, Figure 2A; OS: log-rank χ2 =4.742, P=0.029, Figure 2B). In the multivariate analysis, Cox proportional hazards regression models showed that, PD-L1+/ high NLR was associated with a significantly shorter DFS and OS (hazard ratio [HR], 1.394, P=0.040; HR, 1.442, P=0.042, respectively). Stratified analysis showed that the prognostic value of combined PD-L1/NLR can only be observed in cases without epidermal growth factor receptor (EGFR) mutations (DFS: log-rank χ2 =5.593, P=0.018, Figure 2C, OS: log-rank χ2 =9.323, P=0.002, Figure 2D). In EGFR mutation subgroup, combination of PD-L1 expression and NLR has no relationship with DFS or OS.Conclusion: We found that combination of PD-L1 expression and NLR may be a promising prognostic indicator, and may also be a good marker for tumor recurrence, especially in the patients with wild-type EGFR.