Pembrolizumab In Lung Cancer Research Articles

CT based radiomic approach on first line pembrolizumab in lung cancer

Clinical evaluation poorly predicts outcomes in lung cancer treated with immunotherapy. The aim of the study is to assess whether CT-derived texture parameters can predict overall survival (OS) and progression-free survival (PFS) in patients with advanced non-small-cell lung cancer (NSCLC) treated with first line Pembrolizumab. Twenty-one patients with NSLC were prospectively enrolled; they underwent contrast enhanced CT (CECT) at baseline and during Pembrolizumab treatment. Response to therapy was assessed both with clinical and iRECIST criteria. Two radiologists drew a volume of interest of the tumor at baseline CECT, extracting several texture parameters. ROC curves, a univariate Kaplan-Meyer analysis and Cox proportional analysis were performed to evaluate the prognostic value of texture analysis. Twelve (57%) patients showed partial response to therapy while nine (43%) had confirmed progressive disease. Among texture parameters, mean value of positive pixels (MPP) at fine and medium filters showed an AUC of 72% and 74% respectively (P < 0.001). Kaplan-Meyer analysis showed that MPP < 56.2 were significantly associated with lower OS and PFS (P < 0.0035). Cox proportional analysis showed a significant correlation between MPP4 and OS (P = 0.0038; HR = 0.89[CI 95%:0.83,0.96]). In conclusion, MPP could be used as predictive imaging biomarkers of OS and PFS in patients with NSLC with first line immune treatment.

Abstract 2266: Efficacy of CEACAM1-targeting immunoglobulin in combination with pembrolizumab in lung cancer

Abstract Background: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) as an immune check point molecule is expressed in lung cancer cells. The homophilic interaction of CEACAM1 inhibits killing effect of T cells by co-inhibitory signal transduction. Thus, up-regulated CEACAM1 in the tumor microenvironment is considered as a promising therapeutic target for cancer. In this study, anti-cancer effect of anti-CEACAM1 monoclonal antibody (MG1124, from GC Pharma, Yongin, South Korea) was investigated with lung cancer-xenograft humanized mice. Materials &amp; Methods: Multispectral image analysis using Vectra polaris system was performed in 49 of human lung cancers (36 adenocarcinoma; 13 squamous cell carcinoma) to evaluate the expressions of CEACAM1, PD-L1 and CD8. Four tumors (YHIM-01, YHIM-02, YHIM-03 and YHIM-04) with high CEACAM1 expression were subcutaneously implanted into humanized mice (hu-CD34 NSG) matched with HLA-A. Efficacy of MG1124 was performed by the single mouse trial format. Humanized mice were treated with MG1124 (q2w, 20 mpk, i.p. injection) with or without pembrolizumab (q2w, 10 mpk, i.p. injection). Findings: Among 49 lung cancers evaluated, proportion of tumor cells expressing CEACAM1 and PD-L1 with any intensity ranged 0.1- 89.2% (median, 15.4%) and 0.2% - 95.6% (median, 6.8%) respectively, and TIL counts ranged 0 - 1,200 cells/mm2 (median, 129 cells/mm2). Four tumors with high CEACAM1(14.5% in YHIM-01, 81.2% in YHIM-02, 23.8% in YHIM-03 and 36.7% in YHIM-04) were selected to establish humanized mouse models. MG1124 as a monotherapy demonstrated antitumor activity and also was superior to pembrolizumab in 1 (YHIM-02, TGI=63.4±1.7% for combination vs. TGI=58.7±9.1% for pembrolizumab alone) out of 4 humanized mouse models. Combination of MG1124 with pembrolizumab also demonstrated synergic anti-tumor effect in 3 models (YHIM-01, TGI= 39.6±19.7% vs. 0.6±11.4% for pembrolizumab alone, vs. 16.5±33.3% for MG1124 alone; YHIM-02, TGI=58.7±9.1% vs. 38.2±14.9% for pembrolizumab, vs. 63.4±1.7% for MG1124 alone; YHIM-03, TGI= 35.6±13.2% vs. TGI=0.0±13.2% for pembrolizumab alone, vs. TGI=3.1±13.3% for MG1124 alone). PD-L1 expression was not associated with MG1124 alone or in combination with pembrolizumab (PD-L1, 2.5% in YHIM-01, 0.5% in YHIM-02 and 14.0% in YHIM-03 respectively). Interestingly, however, combinational effects of MG1124 and pembrolizumab were shown only in 3 models showing high CD8+ T cell infiltration in the tumors (209, 432, 362 vs. 46 in a model without combination synergy). Conclusion: CEACAM1-targeting monoclonal antibody, MG1124, exhibits promising anti-cancer effects in CEACAM1-expressing lung cancers. Tumoral CEACAM1 expression and high intratumoral CD8+ T cell infiltration could serve as a predictive biomarker to MG1124 monotherapy or in combination with pembrolizumab and need to be further investigated. Citation Format: Jae-Hwan Kim, Kyoung-Ho Pyo, Min-Jee Jung, Minkyu Hur, Jonghwa Won, Byoung Chul Cho. Efficacy of CEACAM1-targeting immunoglobulin in combination with pembrolizumab in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2266.

Abstract 4081: Efficacy of MERTK inhibitor in combination with pembrolizumab in lung cancer

Abstract Introduction: MERTK is thought to play a role in cancer immune evasion mechanism based on M2 type macrophage-driven immunosuppression in tumor microenvironment (TME). Thus, MERTK is a highly promising target for anti-cancer therapy under high tumor associated macrophages (TAMs) condition. We evaluated the anti-tumor effects and immune reaction of combination or single MERTK inhibitor in two lung squamous patients derived xenograft (PDX) tumor engrafted Hu-CD34-NSG models. Methods: The aPD-1 sensitive (YHIM2004) and aPD-1 non-sensitive (YHIM2009) squamous cell carcinoma PDX models were selected from pre-test with pembrolizumab. The selected two models were composed four groups; control, pembrolizumab, MERTK inhibitor, and combination. We applied pembrolizumab as aPD-1 blockade (10 mpk, q2w, i.p. inj.). The dose of MERTK inhibitor was 50 mpk, q1d by orally. The treatment was started when tumor size reached 100 mm3. Whole exome sequencing (WES), microarray (mRNA), flow cytometry, and multispectral image analysis were performed on the tumors. To elucidate the involvement of MERTK inhibitor in tumor, the tumor mutation burden, tumor microenvironment and immune cell phenotype were deconvoluted. Results: The TMB of YHIM2004 and YHIM2009 was 3.23 and 2.64 (mutations/Mb) respectively. The PD-L1 and TIL level of YHIM2004 were relatively higher than YHIM2009. Both two models were observed high macrophage in tumor. The two PDX-models, YHIM2004 (aPD-1 sensitive), YHIM2009 (aPD-1 non-sensitive) were observed anti-tumor effects in MERTK inhibitor single treatment groups (TGI = 44.23%, 67.40% respectively, p &amp;lt; 0.05, t-test). Especially, YHIM2004 tumor was reduced after combination therapy more than single treatment. Of note, the NOG-PDX model demonstrated no anti-tumor effect in MERTK inhibitor monotherapy, suggesting that this drug involves anti-cancer immune responses. Flow cytometry data showed increased PD-1+ and granzyme B+ T cells (p &amp;lt;0.05, t-test) in the combined group (YHIM2004) and MERTK inhibitor monotherapy group (YHIM2009) as much as the tumor suppressive effect. Conclusion: We concluded that MERTK signaling involves regulation of anti-cancer immune responses. Our results suggest an anti-cancer therapeutics of MERTK selective inhibitor on aPD-1 sensitive or non-sensitive tumors under high TAM tumor microenvironment. Citation Format: Kyoung-Ho Pyo, Ha-Ni Cho, Chun-Feng Xin, Jae Seok Cho, Han Na Kang, Jiyeon Yun, Hye Ryun Kim, Byoung Chul Cho. Efficacy of MERTK inhibitor in combination with pembrolizumab in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4081.