Impact Of PD-L1 Expression Research Articles

Impact of PD-L1 expression on survival in patients with unresectable/recurrent gastric cancer receiving first-line chemotherapy without immune checkpoint inhibitors.

391 Background: Although high PD-L1 expression predicts a favorable response of advanced solid tumors to immune checkpoint inhibitors (ICIs), its impact on survival in patients with unresectable/recurrent gastric cancer (GC) has remained unclear. We investigated the prognostic value of PD-L1 expression for survival in unresectable/recurrent GC patients receiving first-line chemotherapy without ICIs. Methods: JCOG1013, a phase 3 randomized trial, demonstrated the addition of docetaxel to cisplatin and S-1 as first-line chemotherapy was of no benefit to patients with unresectable/recurrent GC (N=741) either for overall survival (OS) or progression-free survival (PFS). Tumor specimens prior to chemotherapy were collected for assessing PD-L1 expression for this ancillary study. PD-L1 expression was determined using immunohistochemistry (Dako, 28-8 pharmDx) and used to derive the PD-L1 combined positive score (CPS) and PD-L1 tumor proportion score (TPS). As with the CheckMate 649 study, the cutoff values for PD-L1 CPS and PD-L1 TPS were set at 5 and 1%, respectively. Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of PD-L1 CPS and PD-L1 TPS as predictors of OS and PFS. All p values were 2-sided; values <0.05 were considered statistically significant. Results: We analyzed 427 patients with unresectable/recurrent GC. The prevalence of PD-L1 CPS≥5, and PD-L1 TPS≥1% was 33% and 24%, respectively. There was no significant difference in OS and PFS between the PD-L1 CPS ≥5 group and the PD-L1 CPS <5 group (Table). The PD-L1 TPS ≥1% group had superior OS and PFS compared to the PD-L1 TPS <1% group (Table). In multivariable analyses for OS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (hazard ratio (HR) = 0.64 [95% CI: 0.50–0.83], p<0.001), but PD-L1 CPS≥5 was not (HR = 0.82 [95% CI: 0.65–1.02], p = 0.073). In multivariable analyses for PFS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (HR = 0.67 [95% CI: 0.52–0.84], p<0.001), but PD-L1 CPS≥5 was not (HR = 0.83 [95% CI: 0.67–1.03], p = 0.090). Conclusions: PD-L1 TPS≥1% is significantly correlated with longer OS and PFS in patients with unresectable/recurrent GC receiving first-line chemotherapy without ICIs. PD-L1 TPS should be considered as a stratification factor in randomized clinical trials for unresectable/recurrent GC. Clinical trial information: UMIN000007652 . [Table: see text]

The impact of PD-L1 expression and co-mutations on outcome of KRAS-driven non-small-cell lung cancer.

9090 Background: Interest has surged for KRAS mutated ( KRASmut) non-small-cell lung cancer (NSCLC) after approval of the covalent KRASG12C inhibitors sotorasib and adagrasib. It remains unclear, how prognosis of these tumors is influenced by co-mutations and which cases could benefit most from novel drugs alongside immunotherapy (IO) or chemo-immunotherapy (CHT-IO). Methods: This retrospective study included all NSCLC patients with KRASmut NSCLC treated in the Thoraxklinik Heidelberg from 01/2014 until 01/2021. For molecular profiling, PCR-based next-generation sequencing (NGS) was performed with a 40-gene panel, including TP53, KEAP1 and STK11. Date of progression was verified through reevaluation of radiologic images by the investigators according to RECIST v1.1. Stratification was performed according to the type of KRAS mutation (G12C vs. other), presence of TP53, STK11 and KEAP1 co-mutations ( vs. wild-type [WT] status), and the PD-L1 tumor proportion score (TPS < 1 aka PD-L1neg, vs. TPS 1-49, vs. TPS 50+ aka PD-L1high). Results: Among 370 identified patients, no differences (all p-values > 0.08) were observed between KRASG12C (n = 163) and KRASnon-G12C (n = 207) regarding clinicopathological features, like age (median 65 years), sex, smoking status, initial ECOG performance status, PD-L1 TPS, type of treatment in any line, number of treatment lines, and overall survival (OS, 19.4 months in median; details in the poster). In contrast, there was a strong association of PD-L1 TPS with OS (20.2 vs. 9.7 months for PD-L1high vs. PD-L1neg, p = 0.011) and progression-free survival (PFS, 5.7 vs. 1.9 months, p = 0.004) under IO. In addition, specifically within the PD-L1neg subset, OS was longer for KRASG12C compared to KRASother patients (22.6 months vs. 12.1 months, p = 0.032). This was driven by the longer PFS under CHT-IO (9.7 vs. 4.5 months for KRASG12C vs. KRASother, p = 0.005), particularly in the absence of TP53 mutations (8.5 vs. 4.0 months with p = 0.004 for TP53wt patients; p > 0.50 for TP53mut) and KEAP1 mutations (11.3 vs. 5.1 months with p = 0.01 for KEAP1wt patients; p > 0.70 for KEAP1mut). Also, across all patients, KEAP1mut cases showed a trend for shorter PFS under CHT-IO (2.7 vs. 8.0 months, p = 0.07) and IO (1.9 vs. 3.9 months, p = 0.081), as well as shorter OS (15.9 vs. 19.5 months, p = 0.068) compared to KEAP1wt, in contrast to STK11mut cases (p = 0.42-0.92 for the same comparisons). Overall, KRASmut NSCLC after chemotherapy and immunotherapy showed poor prognosis under standard therapies with a median PFS of 3 months, and a median OS of 6.8 months. Conclusions: In PD-L1neg NSCLC, KRASG12C is associated with better outcome under CHT-IO and longer OS compared to KRASother, especially in the absence of TP53 and KEAP1 co-mutations. KEAP1, but not STK11 mutations are associated with impaired benefit from (CHT-)IO in KRASmut NSCLC. Treatment of KRASmut NSCLC after chemo-immunotherapy represents an unmet medical need.

Abstract 6146: PD1 expression and immune-active lymphocytes can predict recurrence of hepatocellular carcinoma

Abstract Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Curative treatments in early-stage HCC are hampered by high recurrence rates, and targeted therapies against HCC are rare. Little is known about the impact of tumor microenvironment (TME) in this tumor. Manipulation of the immune system by tumors leads to compromised antigen recognition and an immunosuppressive microenvironment. One immunomodulatory strategy employed by malignant tumors is the expression of the programmed cell death receptor 1 ligand (PD-L1), whose receptor is expressed on activated T cells (PD-1). The use of immune checkpoint inhibitors (ICI) has shown antitumor activity and unprecedented rates of durable clinical responses in various cancer types. In HCC, nivolumab and pembrolizumab are described as possible second line therapies. Expression of PD-1 and PD-L1 in the TME has prognostic importance and can predict response to ICI. The aim of our study was to investigate the impact of PD-1 and PD-L1 expression on HCC recurrence and the relation to their cancer-immune phenotypes. Materials and methods: Immunohistochemical staining was performed on archival tissue from 91 HCC, primary and recurrence, using the following antibodies: NAT105 (PD-1) and Ventana SP263 (PD-L1). On the basis of protein expression, tumors were classified as immunologically active, excluded or deserted. PD-1 and PD-L1 immunoreactivity was evaluated as the proportion of positive staining of the total number of immune cells (0%, <1% and >1%). Results: Basic tumor characteristics were not related to recurrence of HCC. However, the immune-excluded subclass showed significant association with recurrence in HCC. The majority of non-recurrent HCC showed PD-1 expression >1% (78%; 38/49), also statistically significant. Conversely, recurrent HCC showed low PD-1 expression (0% or <1%) in 42% (19/45) of the cases. Of note, HCC classified as immune active were enriched for PD-1 positive (>1%) (77%; 49/64). An association between HCC recurrence and PD-L1 expression on tumor cells was not found. Conclusion: In concordance with previous reports, we found an association between low frequency of PD-1 expression and increased HCC recurrence, as well as the lack of impact of PD-L1 expression on HCC recurrence. Furthermore, our results suggest that HCC recurrence may be more frequent in immune-exclusive tumors. Pembrolizumab as adjuvant instead of 2nd line therapy should be further investigated. Citation Format: Gabriel Fridolin Hess, Mairene Coto-Llerena, Jasmin Zeindler, Silvio Däster, Simone Muenst, Jürg Vosbeck, Caner Ercan, Otto Kollmar, Salavtore Piscuoglio, Savas Deniz Soysal. PD1 expression and immune-active lymphocytes can predict recurrence of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6146.

Impact of PD-L1 expression on conventional urothelial bladder carcinoma (UCB) genomic alteration (GA) profile.

e16535 Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been used as a biomarker to predict immune checkpoint inhibitors response in UCB. We hypothesized that the GA profiles would differ between UCB featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UCB with known PD-L1 tumor cell expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alteration (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included in this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UCB featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amplification (P = .05). The gender, age and GA per tumor frequencies were similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p = .02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. The mean gLOH scores were similar in both groups. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UCB cases where a mutational signature could be determined, 15/33 (45%) of PD-L1H and 34/112 (30%, p = 0.14) of PD-L1N UCB featured an APOBEC gene signature; 79% of PD-L1H and 83% of PD-L1N featured European ancestry (p = 0.61). Conclusions: PD-L1H and PD-L1N subtypes of UCB differ in their genomic profiles. PD-L1N UCB features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UCB but also in designing trials that may combine ICPI with targeted therapies.[Table: see text]

Effect of durvalumab in patients with unresectable stage 3 non–small cell lung cancer post-chemoradiotherapy.

8550 Background: The PACIFIC study (PS) concluded that the use of durvalumab from 1 to 42 days after concurrent chemoradiotherapy (CXRT) in stage 3 unresectable non-small cell lung cancer (NSCLC) increased the median overall survival (mOS) from 29 to 48 months. It also showed a benefit in tumors with PD-L1 <25%. However, a post-hoc analysis of the PS showed no survival benefit with durvalumab in patients with PD-L1 <1% but was not statistically powered. Currently in the US, durvalumab is approved irrespective of PDL-1 percentage, whereas in Europe it is not approved for tumors with PDL-1 <1%. Also, there was no survival benefit in starting durvalumab within and after 2 weeks of CXRT. Our objectives in this study are to analyze the impact of PDL-1 expression and the date of initiation of durvalumab post CXRT on mOS. Methods: We conducted a retrospective observational study of stage 3 unresectable NSCLC patients who received durvalumab post CXRT at LSU Health Shreveport from 2018 to 2021. A survival analysis was done including the following variables: age, race, sex, tumor histology, tumor PD-L1 percentage, and date of initiation of durvalumab post CXRT. P-value <0.05 was considered statistically significant. Results: We identified 83 patients who received durvalumab after CXRT for treatment of stage 3 unresectable NSCLC. Baseline characteristics are provided in table 1. Among all the tumors, 25% had a PDL-1 <1%. 33% of the study population received durvalumab less than 30 days after CXRT and 67% received it after 30 days. The mOS was not impacted by race, sex, or tumor hisotology. Compared to higher PDL-1 percentage, patients with PD-L1 <1% had a statistically significant lower survival probability. At 14 months, 87% of patients with a PD-L1 <1% were alive compared to 100% in those with a PD-L1 1-50% or a PD-L1 >50%. Less than 35% of patients with PD-L1 <1% survived beyond 30 months compared to 45% for PD-L1 1-50% and 100% for PD-L1 >50% (p-value 0.02). Patients who received durvalumab 30-60 days after concurrent CXRT had a lower OS at 30 months compared to those who started before 30 days (44% versus 90%). However, statistical significance was not reached (p-value 0.45). Conclusions: This study demonstrates that patients with a PD-L1 tumor expression of <1% had a statistically significant lower survival probability compared to those with a PD-L1 expression of 1-50% and > 50% in this patient population. Time from CXRT to the start of durvalumab was not shown to affect survival outcomes.[Table: see text]

Impact of PD-L1 expression on conventional urothelial bladder carcinoma (UBC) genomic alteration (GA) profile.

563 Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been proposed a companion assay related to the approval of immune checkpoint inhibitors in UBC. We hypothesized that the GA profiles would differ between UBC featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UBC with known PD-L1 expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included with PD-L1 Low (1-49% TC expression) cases excluded from this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UBC featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amp (P =.05). The gender, age was similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p =.02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach statistical significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UBC cases where a mutational signature could be determined, 10/12 (83%) of PD-L1H and 21/29 (72%) of PD-L1N UBC featured APOBEC signature; 2 PD-L1N featured MMR signature and 6 PD-L1N UBC featured no dominant signature. Conclusions: PD-L1H and PD-L1N subtypes of UBC differ in their genomic profiles:PD-L1N UBC features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UBC but also in designing trials that may combine ICPI with targeted therapies. Limitations include small sample size, possible selection bias and lack of clinical annotation.[Table: see text]

Abstract P4-04-08: Determination of PD-L1 expression on tumorspheres cultured from the peripheral blood in patients with breast cancer

Abstract Background Cancer stem cells (CSCs) are the critical subpopulation of cancer cells involved in tumor formation, progression, metastasis and drug resistance. CSCs also have been considered as the main cause of cancer recurrence. The exact role of CSCs in escape of cancer from immunosurveillance is still unknown, but recent studies revealed that enhanced PDL-1 expression in cancer stem cells is linked to immune evasion and could crucially contribute to the maintenance of CSC self-renewal. Understanding the mechanisms behind this PDL-1 overexpression in cancer stem cells is critical for developing more effective anti-PD-1/PD-L1 therapy. Therefore the aim of the study was to determine the number of tumorspheres and expression of PD-L1 on tumorspheres cultured from the peripheral blood in patients with breast cancer.Methods:110 patients with breast cancer in different stages of disease were included in this study. The determination of circulating tumor cells and circulating cancer stem cells (cCSC) was performed using maintrac and tumorsphere forming assay, respectively. Additionally anti-PDL-1 antibody staining was applied to examine PDL-1 expression on breast tumorspheres.Results:We developed an innovative in vitro platform for cultivation of CSCs from peripheral blood of solid cancer patients and confirmed for the first time that tumorspheres are positive for PDL-1 in breast cancer patients. Our data also show a considerable heterogeneity in the PDL-1 expression of tumorspheres. We confirmed once again that the number of tumorspheres increased significantly with tumor progression, especially with presence of metastasis. Patients with metastatic disease had statistically more tumorspheres as compared to patients without metastasis (30 vs 10/100µl blood, p<0.05). Patients with multiple metastasis had more tumorspheres compared to patients with single metastases (60 vs 30/100µl blood, p<0.05). The number of tumorspheres was positively correlated with proliferating index Ki-67 and grade score in primary breast tumor. Moreover, patients with HER2 positive tumors had more tumorspheres compared to patients with HER2 negative primary tumors (35 vs 10/100 µl blood, p<0.005). Conclusion:The number of tumorspheres cultured from peripheral blood directly reflects aggressiveness and proliferation capacity of primary tumor. The presence of tumorspheres with expression of PDL-1 might suggest their immunregulatory potential, but further studies are needed to validate the impact of PDL-1 expression on tumorspheres in patients with breast cancer. Citation Format: Monika Pizon, Dorothea Schott, Ulrich Pachmann, Katharina Pachmann. Determination of PD-L1 expression on tumorspheres cultured from the peripheral blood in patients with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-08.

Impact of PD-L1 Expression and Tumor Microenvironments on Osimertinib Efficacy in Pretreated Non-Small-Cell Lung Cancer Harboring an Acquired EGFRT790M Mutation

Impact of PD-L1 Expression and Tumor Microenvironments on Osimertinib Efficacy in Pretreated Non-Small-Cell Lung Cancer Harboring an Acquired EGFRT790M Mutation

Immunosuppression Induced by Glutamine Deprivation Occurs via Activating PD-L1 Transcription in Bladder Cancer.

Few studies have reported whether nutrients in the tumor microenvironment can regulate the expression of PD-L1. Since tumor cells are often situated in a low-glutamine environment, we investigated PD-L1 expression under glutamine deprivation in bladder cancer cells. PD-L1 expression and the activation of the EGFR/MEK/ERK/c-Jun signaling pathway under glutamine deprivation were investigated by qPCR, Western blot, and immunofluorescence analyses. C-Jun-mediated transcriptional regulation of the PD-L1 gene was assessed by ChIP. PD-L1 expression and activation of the EGFR/MEK/ERK/c-Jun signaling pathway were assessed in T24 cells, TCCSUP cells and BALB/c mice with or without glutamine supplementation. Additionally, the impact of PD-L1 expression under glutamine deprivation on the function of T cells was investigated by ELISA. The expression of PD-L1 and EGFR/MEK/ERK/c-Jun pathway activation were elevated by glutamine deprivation, and c-Jun was enriched in the enhancer region of PD-L1. The expression of PD-L1 was considerably impaired by inhibiting the EGFR/MEK/ERK/c-Jun pathway and was elevated by activating this signaling pathway. In addition, the elevated PD-L1 expression and MEK/ERK/c-Jun signaling pathway activation were reduced by glutamine supplementation in vitro and in vivo. PD-L1 upregulation by glutamine deprivation in bladder cancer cells could reduce IFN-γ production by T cells. The expression of PD-L1 was upregulated under glutamine deprivation through the EGFR/MEK/ERK/c-Jun pathway to impair T cell function.

98: Impact of PD-L1 Expression on Oncological Outcomes for Patients Treated with Trimodality Therapy for Muscle Invasive Bladder Cancer

98: Impact of PD-L1 Expression on Oncological Outcomes for Patients Treated with Trimodality Therapy for Muscle Invasive Bladder Cancer

BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC)—Initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd).

1023 Background: Chemotherapy with immune checkpoint inhibitors can improve outcomes vs chemotherapy alone in patients (pts) with metastatic TNBC; however, many still have poor clinical outcomes. BEGONIA is an ongoing 2 part, multicenter, multiarm, open-label platform study evaluating safety and efficacy of D (anti–PD-L1)+P and D±P combined with novel therapies as first-line (1L) treatment for metastatic TNBC (NCT03742102). We report initial results from Part 1 of Arm 1, D+P, and Arm 6, D+T-DXd, an antibody-drug conjugate comprising an anti-HER2 antibody, tetrapeptide-based cleavable linker, and topoisomerase I inhibitor payload. Methods: Eligible pts had untreated unresectable locally advanced or metastatic TNBC. Pts with HER2-low–expressing tumors (IHC 2+/ISH–, IHC 1+/ISH–, or IHC 1+/ISH untested) per local testing were assigned to the D+T-DXd arm. Pts received D (1500 mg IV Q4W)+P (90 mg/m2 IV Day 1, 8, 15 Q4W) in Arm 1 and D (1120 mg IV)+T-DXd (5.4 mg/kg IV) Q3W in Arm 6, until progression or unacceptable toxicity. Primary objectives are safety and tolerability. Secondary endpoints include objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS). Tumors were assessed Q8W (D+P) or Q6W (D+T-DXd). The first 6 pts treated with D+T-DXd were evaluated for dose-limiting toxicities (DLTs), with additional pts enrolled if D+T-DXd was tolerated. Study arms are noncomparable due to differing eligibility criteria, treatments, and data maturity. Results: Arm 1 D+P (data cutoff Sep 2020): 23 pts received D+P (7 ongoing); 2 discontinued D+P due to AEs. Median follow-up time was 16.6 (range 8.5–19.8) mos. Any Grade 3/4 AEs and SAEs were experienced by 10 (44%) and 1 (4%) pts, respectively. D dose was delayed for 7 (30%) pts. Confirmed ORR was 13/23 (57%) with 54% of those remaining in response at 12 mos (median DoR not reached). Median PFS was 7.3 (95% CI 5.4–13.8) mos in the D+P arm. Arm 6 D+T-DXd (data cutoff Nov 2020): 11 pts received D+T-DXd to date (all ongoing). Median follow-up time was 2.3 (0–6) mos. Any Grade 3/4 AEs and SAEs were experienced by 4 (36%) and 1 (9%) pts, respectively. Pts who received D+T-DXd had no DLTs and 1 had a Grade 1 troponin increase. D dose was delayed and T-DXd dose reduced for 2 (18%) pts each. Confirmed ORR was 4/4 (100%; only 4 pts had the opportunity to complete 2 on-treatment disease assessments) with all 4 remaining in response at data cutoff (median DoR not reached). Conclusions: D+P demonstrated a tolerable safety profile and response rate as expected for a 1L TNBC IO/taxane combination. D+T-DXd showed promising early safety and efficacy in 1L HER2-low–expressing TNBC; pt evaluation and enrollment for D+T-DXd are ongoing. D+T-DXd data will be updated and the impact of PD-L1 expression in both arms will be examined. Clinical trial information: NCT03742102 .

Prognostic value of programmed death-ligand 1 in solid tumors: A meta-analysis.

e19121 Background: The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway plays a crucial role in cancer immuno-surveillance and is the target of approved immunotherapeutic drugs. Available data suggest a variable prognostic impact of PD-L1 expression in solid tumors. Methods: A systematic literature search of electronic databases identified publications exploring the effect of PD-L1 on overall survival (OS) and/or progression-free survival (PFS). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on disease site, stage of disease, and method of PD-L1 quantification using the Deeks method. Results: One hundred eighty-eight studies comprised of 212,748 patients met the inclusion criteria. PD-L1 expression was associated with worse OS (HR 1.32, 95% confidence interval (CI) 1.25 - 1.38; P < 0.001). There was significant heterogeneity between disease sites (subgroup P = 0.002) with pancreatic, hepatocellular and genitourinary cancers being associated with the highest magnitude of adverse outcome (Table). PD-L1 was also associated with worse overall PFS (HR 1.19, 95% CI 1.09 - 1.30; P < 0.001). Stage of disease did not significantly affect the results (subgroup P = 0.52), nor did the method of quantification (immunohistochemistry or mRNA) (subgroup P = 0.70). Conclusions: High expression of PD-L1 is associated with worse cancer outcomes albeit with significant heterogeneity between disease sites. The effect seems consistent in early stage and metastatic disease and is not sensitive to method of PD-L1 quantification. [Table: see text]

Prognostic relevance of programmed death-ligand 1 expression and microsatellite status in small bowel adenocarcinoma

Background: Small bowel adenocarcinoma (SBA) is a dreadful disease. Patient prognosis is limited due to late presentation and ineffective chemotherapy. PD-1/PD-L1 checkpoint immunotherapy is regarded as a promising approach in several cancer entities. The association of PD-1/PD-L1 expression and its impact on patient prognosis with SBA is unclear. Material and methods: Seventy-five consecutive patients who underwent surgery for SBA were retrospectively analyzed and stained for PD-L1 expression in the tumour or the stroma. Analysis of mismatch repair genes was performed to determine microsatellite status. Kaplan–Meier estimate was used to analyze patient survival. Univariate and multivariable Cox regression-analyses were used to assess the impact of PD-L1 expression and microsatellite status on patient survival.Results: PD-L1 was weakly upregulated within the tumour or the stroma and associated with prolonged survival (p = .0071 and p = .0472, respectively). Fifty-one tumours (68%) revealed microsatellite stability (MSS) and 24 tumours (32%) were microsatellite instable (MSI) without correlating with patient survival (p = .611). Neither PD-L1 expression in the tumour nor in the stroma was identified as an independent risk factor influencing survival (p = .572 and p = .3055).Conclusion: Although PD-L1 expression is associated with prolonged survival, it was not identified as an independent prognostic marker. Microsatellite status did not influence long-term survival.

Clinicopathological significance of PD-L1 expression in colorectal cancer: Impact of PD-L1 expression on pFOXO1 expression

ObjectiveThis study aimed to evaluate the clinicopathological significance of PD-L1 expression and its impact on phospho-Forkhead box O 1 (pFOXO1) expression in colorectal cancer (CRC). MethodsImmunohistochemical analysis for PD-L1 and pFOXO1 was performed on 265 human CRC tissues. PD-L1 expression was evaluated in the tumor and immune cells. The impact of PD-L1 expression on survival was investigated in relation to the pattern of pFOXO1 expression. ResultsPD-L1 was expressed in 25 (9.4%) and 41 (17.7%) patients in the tumor and immune cells of the 265 CRC tissues, respectively. PD-L1 expression in immune cells (I-PD-L1) was significantly correlated with less lymphatic invasion, lymph node metastasis, and distant metastasis and lower pT and pTNM stages. Additionally, there was a significant correlation between PD-L1 expression in tumor cells (T-PD-L1) and tumor location (right colon), but not the other clinicopathological characteristics. pFOXO1 expression was significantly lower in CRC with high I-PD-L1 expression than in CRC with low or negative I-PD-L1 expression. However, there was no significant correlation between pFOXO1 and T-PD-L1 expression in CRC. Patients with positive pFOXO1 and low or negative I-PD-L1 expression exhibited the worst survival among patients with CRC. ConclusionCollectively, our results indicate that I-PD-L1 expression was significantly correlated with favorable tumor behaviors and better survival. In addition, patients with high I-PD-L1 and low pFOXO1 expressions had a favorable prognosis than those with other I-PD-L1 and pFOXO1 expression patterns.

Assessment of PD-L1 expression and oncogenic gene status in patients with small-cell lung cancer: Immuno-oncology biomarker study in LC-SCRUM-Japan.

8558 Background: The clinical impact of PD-L1 expression and oncogenic gene status in patients with small cell lung cancer (SCLC) is not well characterized. We initiated this immuno-oncology biomarker study as part of nationwide genomic screening by LC-SCRUM-Japan (LC-SCRUM-IBIS). Methods: Tumor samples from lung cancer patients enrolled in LC-SCRUM-IBIS were primarily subjected to targeted next-generation sequencing (NGS) with Oncomine™ Comprehensive Assay. The PD-L1 expression was also analyzed by 4 immunohistochemistry (IHC) assays for 22C3, 28-8, SP263 and SP142. At this analysis, 22C3, 28-8, and SP263 were assessed in tumor cells (TC) as positive in > 1%, and SP142 in both TC and tumor-infiltrating immune cells (IC) as positive in > TC1/IC1, as previously reported. The association of PD-L1 expression, oncogenic gene status and clinical outcome was investigated in SCLC patients. Results: Between Feb 2017 and May 2018, 1017 lung cancer patients were enrolled in LC-SCRUM-IBIS. Among them, 933 patients had adequate tumor samples including 101 SCLC and 832 non-small cell lung cancer. Of 101 SCLC patients, the results of PD-L1 expression by 4 IHC assays were 18% in 22C3, 17% in 28-8, 11% in SP263 and 8% in SP142, respectively. Targeted NGS showed that 8 patients had at least one targetable oncogenic alterations, including 3 PIK3CA and 1 KRAS as mutations and 3 PTEN and 1 TSC2 as inactivating mutations. PD-L1 expression by 22C3 was associated with good performance status (P = 0.05) and the presence of oncogenic alterations (P = 0.004). PD-L1 status was not associated with response to cytotoxic chemotherapy and progression-free survival and overall survival in first-line treatment of SCLC patients. Conclusions: The frequency of PD-L1 expression in SCLC patients was relatively lower compared with that reported in other solid tumors. PD-L1 status by TC in 22C3 appears to be not correlated with clinical outcomes for cytotoxic chemotherapy of SCLC patients. Further investigation is needed to explore a predictive biomarker for immune checkpoint inhibitors. Updated results will be presented at the meeting.

P2.02-026 Impact of PD-L1 Expression on 18F-FDG-PET in Pulmonary Squamous Cell Carcinoma

P2.02-026 Impact of PD-L1 Expression on 18F-FDG-PET in Pulmonary Squamous Cell Carcinoma

Tumor cell PD-L1 predicts poor local control for rectal cancer patients following neoadjuvant radiotherapy.

The tumor cell (TC) PD-L1 expression has been reported by several studies in various types of cancer, and it reduces the cytotoxicity of T-cells toward cancer and evades the anticancer immune response. Herein, our study focuses on the impact of PD-L1 expression in prognosis and the correlation with clinical prognostic factors for local advanced rectal cancer with neoadjuvant radiotherapy (RT). A total of 68 rectal cancer patients treated with neoadjuvant RT were retrospectively enrolled in the present study. PD-L1 expression was investigated using immunohistochemistry. A regression model was used to identify prognostic factors associated with the disease-free survival, the local recurrence-free survival (LRFS), and the overall survival rates. The median follow-up was 32.5 months. Seven patients presented TC PD-L1 positive (TC PD-L1+), while the others were TC PD-L1 negative (TC PD-L1−). TC PD-L1+ patients showed frequent tumor recurrence than TC PD-L1− patients. Several patients with TC PD-L1− underwent long-course RT. TC PD-L1 expression was similar to interstitial cell (IC) PD-L1 expression, and the relationship between IC PD-L1 and pathological T stage was observed. TC PD-L1+ was related to poor LRFS. The multivariate analysis showed TC PD-L1+ as an independent negative prognostic factor for LRFS. In conclusion, TC PD-L1 expression putatively predicts the LRFS for patients with rectal cancer following neoadjuvant RT. The patients with TC PD-L1+ are susceptible to high local recurrent rate, thereby proposing a novel immunotherapeutic strategy for PD-L1 inhibition-mediated control.

Prevalence and clinical correlation of programmed cell death 1 ligand (PD-L1) expression in patients with resected non-small cell lung cancer (NSCLC): Results from the European Thoracic Oncology Platform (ETOP) Lungscape cohort.

8516 Background: Conflicting data exists on the potential prognostic impact of PD-L1 expression in NSCLC. The Lungscape project, a fully annotated large biobank of resected stage I-III NSCLC, allows detailed analysis of this issue. Methods: Prevalence of PD-L1 positivity and its association with clinicopathological characteristics and patient outcome - Relapse-free Survival (RFS), Time-to-Relapse (TTR) and Overall Survival (OS) - was explored in the ETOP Lungscape cohort. PD-L1 expression was assessed on tissue microarrays (TMAs) using the DAKO 28-8 immunohistochemistry assay. Positivity cut-off points of ≥1%, 5% and 50% for neoplastic cell membrane staining were considered. Results: PD-L1 data were available for 2182 patients, from 15 ETOP centers, with median follow-up 4.8 years; 1191 patients still alive; median age 66 years; 64% male, 32/54/11% for current/former/never smokers; 49/29/22% for stages I/II/III; 51/42/4/3% adenocarcinomas (AC)/squamous cell (SCC) /large cell and sarcomatoid (LCS)/other. Median RFS/TTR/OS were 53/99/69 months (AC: 52/84/72, SCC: 54/not reached/64; and LSC 52/103/74). PD-L1 prevalence with 1% cut-off was, overall: 43%, 95% confidence interval (95%CI): 41-46; (AC: 42%, 95%CI: 39-46; SCC: 44%, 95%CI: 40-47; and LCS: 53%, 95%CI: 42-65), while for 5% threshold, prevalence was 34%, 95%CI: 32-36. PD-L1 1% positivity was a significant predictor only for AC: HRRFS: + vs - = 0.82; 95%CI: 0.69-0.97, HRTTR: + vs - = 0.83; 95%CI: 0.68-1.01, HROS: + vs -= 0.83; 95%CI: 0.69-1.01 (adjusted p = 0.024, 0.064, 0.063 respectively). This effect is found also for the 5% cut-off, and preserved in the overall model including all histologies. Using the 50% cut-off, PD-L1 positivity was detected in 17% of patients; 95%CI: 15-18, but was no longer a significant predictor of outcome, overall and by histology type. Conclusions: PD-L1 positivity (1% and 5% cut-offs) was present in more than one third of resected NSCLC and was associated with a better prognosis for AC patients.

978P - Prevalence, pattern, and impact of PD-L1 expression and HPV-status in head and neck squamous cell carcinoma

Early phase clinical studies showed activities of anti PD-L1/PD-1 antibody in head and neck squamous cell carcinomas (HNSCC). PD-L1 expression was extensively evaluated as a biomarker though no standardized method of detection has been defined. HPV status is a well-established prognostic maker of HNSCC. Prevalence, pattern, and impact of PD-L1 expression in HPV-associated HNSCC remain unclear and may vary in different ethnicity. HNSCC patients treated at the Ramathibodi Cancer Center between 1/2007 and 12/2013 were identified through the cancer registry database. Patient characteristics, treatments, and survivals were abstracted. Archrival formalin-fixed paraffin-embedded (FFPE) tissues were retrieved for PD-L1 and p16 analyses. PD-L1 expression was evaluated by using an anti-human PD-L1 rabbit monoclonal antibody (clone SP142; Ventana) on an automated staining platform (Ventana). PD-L1 was evaluated on tumor cells (TC) and tumor-infiltrating immune cells (IC), and scored ranging between 0-100%. For overall survival (OS) analysis, specimens were scored as ≥5% on TCs or ICs to define PD-L1 positive. HPV status was determined by p16 immunohistochemistry. 204 HNSCC patients with available FFPE tissues were analyzed. PD-L1 on TCs was expression (≥1%) and highly expressed (≥50%) in 72.2% and 18.4% of patients, respectively. With a definition of PD-L1 ≥5% on TCs or ICs, 79.7% of patients was considered as PD-L1+. No statistically difference in patient characteristics between PD-L1 positive and negative, except age ≥65 was associated with a higher incidence of PD-L1 positive (53.4% vs 21.1%; p = 0.001). Overall, 74 patients (36.3%) was p16+. No association of PD-L1 and p16 was observed (p = 0.116). OS was significantly longer in PD-L1+ patients (34.5 vs 21.5 months; p = 0.044). In subgroup analysis of PD-L1/p16 status, OS was superior in patients with +/ + , +/-, -/-, and -/ + , respectively (67.4 vs 23.6 vs 21.5 vs 15.8 months; p = 0.006). A high prevalence of PD-L1 expression was observed in HNSCC. PD-L1 expression was a strong prognostic maker for OS, especially in p16+ HNSCC patients. These results support further development of anti PD-L1/PD-1 antibody in HNSCC.

Abstract 3997: The impact of PD-L1 expression in patients with metastatic GEP-NETs

Abstract Programmed death-ligand 1 (PD-L1), which is expressed on many cancer cells, interacts with PD1 expressed on the surface of T cells, inhibiting the T cells and blocking the antitumor immune response. Expression of PD-L1 in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has not been studied. We investigated the impact of PD-L1 expression in 32 patients with metastatic GEP-NET. The expression of PD-L1 was evaluated using an anti-PD-L1 immunohistochemistry (IHC) antibody optimized for staining of formalin-fixed paraffin-embedded (FFPE) tissue samples. The correlation between PD-L1 and clinicopathological data including survival and response to systemic treatments was analyzed. Primary sites were 24 foregut-derived GEP-NETs, including stomach (n = 1), duodenum (n = 2), biliary tract (n = 7), and pancreas (n = 14), and 8 hindgut-derived GEP-NETs of the distal colon and rectum. Among the 32 patients with metastatic GEP-NET analyzed in this study, 7 (21.9%) had expression of PD-L1 in tumor tissues. Expression of PD-L1 was significantly associated with high-grade WHO classification (grade 3) (p = 0.008) but not with gender, primary site, and number of metastatic sites (p>0.05). The status of PD-L1 expression was statistically associated with progression-free survival (PFS) for first-line systemic treatment (p = 0.047). Moreover, the status of PD-L1 expression could significantly predict overall survival (p = 0.037). The expression of PD-L1 was associated with higher WHO tumor grade (grade 3) in metastatic GEP-NETs. PD-L1 expression had both predictive and prognostic value for survival of patients with metastatic GEP-NETs. Citation Format: Seung T. Kim, Won Lee. The impact of PD-L1 expression in patients with metastatic GEP-NETs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3997.