Immune Checkpoint Inhibitors Nivolumab Research Articles

Efficacy and Safety of Axitinib Therapy After Nivolumab for Patients With Metastatic Renal Cell Cancer.

Tyrosine kinase inhibitors (TKI) and immune-checkpoint inhibitors (ICI) are treatment options for metastatic renal cell cancer (mRCC). However, the treatment options after nivolumab are unclear. The medical records of 57 consecutive Japanese mRCC patients who underwent treatment with axitinib were reviewed. Among those, 17 patients received axitinib treatment after nivolumab and 40 patients received axitinib treatment after other chemotherapy regimens except nivolumab. Of the 57 patients with mRCC, only 17 underwent axitinib therapy after nivolumab. Among these 17 patients, the objective response rate (ORR) and median tumor shrinkage rate were 56.3% and -30%, respectively. They were significantly better in patients who underwent axitinib therapy after nivolumab than after other therapies (p=0.026 and p=0.012, respectively). However, all 17 patients experienced some adverse events and nine patients (52.9%) required a dose reduction or axitinib treatment interruption. Axitinib therapy after the immune checkpoint inhibitor nivolumab showed good efficacy with a moderate risk of adverse events. Careful management by skilled professionals may be required.

Cultivation of Clear Cell Renal Cell Carcinoma Patient-Derived Organoids in an Air-Liquid Interface System as a Tool for Studying Individualized Therapy

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer accounting for 80% of all renal cancers as well as the majority of renal cancer-associated deaths. During the last decade, the treatment paradigm for ccRCC has radically changed. In particular, the recent development of immune checkpoint inhibitors (ICI) has led to an increased overall survival in the metastatic setting. Moreover, novel immune therapies targeting the tumor microenvironment have been developed. In this rapidly evolving treatment landscape, precise tools for personalized cancer therapy are needed. Here, we collected fresh tissue from 42 patients who underwent surgical resection for renal cell carcinoma. Part of the tissue was used to obtain formalin-fixed, paraffin-embedded samples or RNA. The remaining tissue was minced and cultured in a collagen-based three-dimensional, air-liquid interface (ALI) culture system. The generated patient-derived tumor organoids (ALI PDOs) were characterized by immunohistochemistry staining and RNA sequencing to validate their close similarity to the matched tumor. Immune cells and stromal cells within the microenvironment could be identified. Finally, we treated 10 ALI PDOs with the commonly used targeted cancer drug cabozantinib or the ICI nivolumab. Interestingly, we observed varying responses of ALI PDOs to these treatments and future studies are needed to investigate whether the ALI PDO approach could inform about treatment responses in patients. In conclusion, this three-dimensional ccRCC culture model represents a promising, facile tool for monitoring tumor responses to different types of therapies in a controlled manner, yet, still preserves the key features of the tumor of origin.

Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment

Simple SummaryColorectal cancer (CRC) causes a high number (more than 800,000) of deaths worldwide each year. Better methods for early diagnosis and the development of strategies to enhance the efficacy of the therapeutic approaches used to complement or substitute surgical removal of the tumor are urgently needed. Currently available pharmacological armamentarium provides very moderate benefits to patients due to the high resistance of tumor cells to respond to anticancer drugs. The present review summarizes and classifies into seven groups the cellular and molecular mechanisms of chemoresistance (MOC) accounting for the failure of CRC response to the pharmacological treatment.The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).

Abstract LB-110: Computational discovery and preclinical validation of therapeutic leads with novel MOAs for hepatocellular carcinoma and pancreatic ductal adenocarcinoma

Abstract Hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) have among the lowest 5-year survival rates of all cancer types at 18% and 9%, respectively. Treatment options for patients with liver or pancreatic cancer are relatively unchanged over the past 10 years. HCC has seen the recent FDA-approval of multi-kinase inhibitor therapies with similar mechanisms of action, including cabozantinib, regorafenib, and lenvatinib, and the immune checkpoint inhibitor nivolumab (conditionally). Despite these advances, the survival rate and median survival time for HCC patients remain poor. The picture for PDAC patients is similar, although with even greater need for new therapies. We present results from a powerful and efficient computational drug discovery platform that produces drug discovery hits with first-in-class mechanisms of action that can advance rapidly and successfully through preclinical validation studies. The twoXAR discovery platform uses an artificial-intelligence framework to integrate diverse patient-derived data sets and build holistic and unbiased models of human disease biology. The utilization of diverse, proprietary algorithms and deep learning principles provides a highly sensitive platform to elucidate detailed disease-specific associations between biology and biomedical data that are integrated with a library of existing drug molecules to deliver novel, high-value drug discovery hits. The twoXAR platform delivers drug discovery hits with known pharmacological properties and preserves the data-driven links to disease biology; this facilitates validation and optimization studies. We employed the twoXAR platform to build in-silico disease models of HCC and PDAC using disease-specific data and generated a set of 10 molecules with predicted efficacy in HCC and a second, independent set of 11 molecules with predicted efficacy in PDAC. These independent sets of disease-specific drug discovery hits represented novel mechanisms of action that had not been tested previously as potential clinical therapies for HCC or PDAC, respectively. TXR-311 and TXR-312, and TXR-405 and TXR-411 were discovered as validated hits for HCC and PDAC, respectively, using in vitro cell proliferation and viability assays with HCC and PDAC tumor cell lines. In these studies, TXR-311 inhibited proliferation and viability of five different HCC tumor cell lines with IC50 values that were 70-fold lower than IC50 values for sorafenib and displayed greater than 500-fold selectivity against primary human hepatocytes. In subsequent in vivo efficacy studies using two HCC patient-derived xenograft (PDX) tumor models, TXR-311 showed excellent tolerability and displayed significant tumor growth inhibition efficacy compared to vehicle-treated controls. TXR-311 presents a first-in-class lead for further development as a potential HCC therapy. Citation Format: Isaac Hakim, Mei-Sze Chua, Wei Wei, Li Ma, Elizabeth Noblin, Samuel So, Aaron C. Daugherty, Timothy S. Heuer. Computational discovery and preclinical validation of therapeutic leads with novel MOAs for hepatocellular carcinoma and pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-110.

Abstract CT130: Evidence for synergistic immune responses in the first-in-human (FIH) combination of B cell-activating immunotherapy (IO) with anti-PD1 immune checkpoint inhibitor nivolumab (N) as 2nd-line therapy in patients (pts) with advanced non-small cell lung cancer (aNSCLC)

Abstract Introduction: While combined immunotherapeutic activation of B and T cells is predicted to synergistically enhance both humoral and cell-mediated immunity, this has not been previously tested in human cancer patients. To assess this, we conducted the FIH trial combining B cell-activating IO (CIMAvax-EGF (C)) with T cell-activating IO (PD-1 blockade with nivolumab (N)). C activates B cells to produce endogenous anti-epidermal growth factor (EGF) antibodies (Abs) that deplete EGF from circulation. As a single agent maintenance therapy in aNSCLC, C prolonged overall survival (OS) in a randomized phase III trial. We now present immune correlates of improved OS with this novel combination. Methods: We reported safety and preliminary efficacy data from 13 pts from the phase I study of C+N (AACR 2019). Serial blood samples were analyzed by Luminex for dynamic changes in circulating cytokines and proteins implicated in EGF signaling, and by flow cytometry for peripheral blood mononuclear cell immunophenotype. Cox regression analysis was used to analyze association with OS. Results: 71% of pts achieved anti-EGF Ab titers of >1:4000 after 3 doses of C, compared to historical controls of 39% with C alone. Baseline increase in CD8+ naive T cells, memory B cells, and decrease in MDSC and Th17 T cells all significantly correlated with better OS. Baseline increase of inflammatory cytokines/markers (IL7, IL15, IFNα, IL8, sCD40L and CRP) significantly correlated with worse OS. Despite enrichment for pts with tumor proportion score (TPS) PD-L1 0%, median OS (mOS) of the intent-to-treat population (pts who received at least 1 dose of C+N, n=13) was 13.7 months (mo) vs. 9.9 mo in Checkmate 057 aNSCLC pts with tumor proportion score (TPS) PD-L1 <10%. mOS of per-protocol pts (all 4 loading doses of C+N given over 8 weeks, n=11) was 18.5 mo. In contrast to Checkmate 057 results, where OS benefit of N favored aNSCLC with KRAS mutation (KRASm), C+N showed better mOS of 22.4 mo in EGFR/ALK/KRAS wildtype (wt) pts versus 12.3 mo in KRASm/STKwt pts. Conclusion: This study provides evidence for synergistic effects of combining B and T cell activating IO in aNSCLC pts. C+N generated higher anti-EGF titers in more pts at an earlier time point vs. C alone, which is the first demonstration in pts of enhancement of Ab responses by immune checkpoint blockade. Immune analysis identified new specific immune cell populations and inflammatory markers that significantly correlate with OS with C+N that have not been previously identified with C or N as single agents. C+N improved OS compared to historical controls of aNSCLC pts receiving N in phase III trials. Of particular note, C+N showed better OS in pts with EGFR/ALK/KRAS wt aNSCLC versus KRASm/STKwt pts. The Phase II portion of the study is ongoing. Citation Format: Tania Crombet, Jason Muhitch, Circe Mesa, Rachel Evans, Danay S. Hernandez, Patricia L. Luaces, Zaima Mazorra, Orestes Morales, Carlos Cedeno, Aileen Cinquino, Daniel T. Fisher, Kelvin Lee, Mary Reid, Grace Dy. Evidence for synergistic immune responses in the first-in-human (FIH) combination of B cell-activating immunotherapy (IO) with anti-PD1 immune checkpoint inhibitor nivolumab (N) as 2nd-line therapy in patients (pts) with advanced non-small cell lung cancer (aNSCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT130.

Efficacy of second and subsequent lines of chemotherapy for recurrent and metastatic head and neck cancer

ObjectiveThe increase in treatment options resulted in successful treatment with multiple lines of chemotherapy for recurrent and metastatic (RM) head and neck cancer (HNC). The present study aimed to elucidate the beneficial effect of successive treatment for RM-HNC. MethodsWe included 78 patients with RM-HNC who received one or multiple lines of chemotherapy from January 2008 to December 2019. We divided the patients into three groups according to treatment period: January 2008 to November 2012 included those who underwent cancer chemotherapy only with cytotoxic agents (Tox group), December 2012 to March 2017 included those who received cytotoxic agents and cetuximab (Cet group), and March 2017 to December 2019 included those who received cytotoxic agents, cetuximab and immune checkpoint inhibitor nivolumab (Nivo group). Moreover, we compared the overall survival of the three groups. ResultsIn total, 18, 33, and 27 patients were included in the Tox, Cet, and Nivo groups, respectively. The median overall survival were 8.5 months in the Tox group, 16 months in the Cet group, and 19 months in the Nivo group, and the difference in the result was significant. ConclusionsSuccessive treatment with second and subsequent lines of chemotherapy in patients with RM-HNC improves prognosis.

Real-world data on patients with metastatic non-small-cell lung cancer treated with checkpoint inhibitors in an Italian Teaching Hospital in 2015-2018.

Non-small-cell lung carcinoma (NSCLC) accounts for 85-90% of all forms of lung cancer. Immuno-oncology represents a valid new approach but the high cost requires a specific evaluation of the health outcomes. This study describes the real-world efficacy, safety and cost profiles of the new anti-PD-1 immune-checkpoint inhibitors nivolumab and pembrolizumab on a cohort of 56 selected patients with advanced NSCLC. A retrospective, observational analysis was conducted on patients treated with immune checkpoint inhibitors from September 2015 to September 2018 at Azienda Ospedaliera Universitaria "Mater Domini" in Catanzaro, Italy. Data sources were medical records, internal prescription cards and reports of adverse reactions. Fifty-six patients were diagnosed with advanced NSCLC, 64.3% characterized by a non-squamous histology, 30.3% squamous and 5.4% not specified. First-line treatment with pembrolizumab was administered to 11 patients for an average of 4.4 months, while 45 patients were treated with nivolumab for an average of 8.6 months. Data showed a survival rate of 95% after 6 months and 88% after 12 months. Most patients received immunotherapy as a second-line or subsequent treatment. In terms of prior therapy among all the patients, 43 had received platinum-based treatments. Indirect comparison with other real-world data studies showed variability in methodologies and an alignment in terms of results. This study, based on real-world data, was a first step in the assessment of the impact of the introduction of a significant new class of treatments, i.e. immunotherapy, and covers patients, treatments and outcomes, as well as organizational and economic variables.

Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study

BackgroundThe prognosis of patients with unresectable or metastatic biliary tract cancer (BTC) is unacceptably low. This study aimed to determine the efficacy, safety and predictive biomarkers of the immune checkpoint...

A phase Ib/II, multicenter, open-label study of DSP-7888 dosing emulsion in combination with immune checkpoint inhibitors (CPI) nivolumab or pembrolizumab in adult patients (pts) with advanced solid tumors, including platinum-resistant ovarian cancer (PROC).

TPS6099 Background: DSP-7888 is a therapeutic cancer vaccine composed of two synthetic peptides derived from Wilms’ tumor 1 (WT1) to promote both cytotoxic and helper T-lymphocyte-mediated immune responses against WT1-expressing tumors. WT1 is overexpressed in various solid tumors, including ovarian cancer. Combining cancer vaccines like DSP-7888 with a CPI may reduce resistance to immunomodulators and improve clinical benefit. A phase Ib/II study is being conducted to evaluate DSP-7888 in combination with a CPI in pts with advanced solid tumors, including PROC (NCT03311334). Methods: This phase Ib/II, open-label, multicenter, two-part dose-search/dose-expansion study investigates DSP-7888 + nivolumab or pembrolizumab in pts with advanced solid tumors (phase Ib), including PROC (phase II). The phase Ib primary objectives are safety, tolerability, and identification of the recommended phase II dose (RP2D). The phase II primary objective is evaluation of objective response rate (ORR); secondary objectives are clinical activity, safety, and tolerability. Pts aged ≥18 years with unresectable, metastatic cancer approved for treatment with nivolumab (phase Ib, Arm 1, n=6–12, 7 enrolled) or pembrolizumab (phase Ib, Arm 2, n=6–12, 6 enrolled), or with PROC (phase II) are eligible. Phase II will enroll ~40 pts into two groups based on programmed death-ligand 1 status (combined positive score of ≥10 [Group 1] or <10 [Group 2]). Clinical activity will be assessed continuously using Bayesian analysis and actual enrollment may increase by ~20 pts/group based on this analysis. Pts in phase II will receive DSP-7888 intradermally (RP2D from phase Ib) once a week (wk) for 6 wks in the induction phase then every 3 wks in the maintenance phase. Beginning Day 1, pembrolizumab will be administered intravenously every 3 wks. In phase II, objective disease will be assessed every 6 wks for 24 wks, then every 12 wks until progression. Endpoints include ORR (per RECIST v1.1) (primary), duration of response, disease control rate (DCR), progression-free survival (PFS), 6-month PFS rate (per RECIST v1.1), and overall survival, immune (i)ORR, iDCR, and iPFS (per iRECIST) (secondary). Exploratory endpoints include blood and tumor tissue biomarkers. Safety and tolerability, assessed by adverse events, will be evaluated throughout the duration of the study and follow-up. This study is currently recruiting patients. Clinical trial information: NCT03311334.

Therapeutic effect of Nivolumab for advanced / recurrent temporal bone squamous cell carcinoma

ObjectiveThe immune checkpoint inhibitor Nivolumab was approved for the treatment of platinum-refractory head and neck squamous cell carcinoma (SCC), expanding the treatment options for recurrent or advanced head and neck SCC. However, since temporal bone squamous cell carcinoma (TB-SCC) is very rare cancer, the effectiveness of Nivolumab remains unclear. We investigated the effects of Nivolumab for TB-SCC. MethodChart information was collected for all patients who underwent the first administration of Nivolumab for recurrent or residual TB-SCC in our hospital between September 2017 and December 2019. Tumor staging followed the modified Pittsburgh classification. Changes in the tumor burden and survival outcome were examined. ResultsWe examined 9 patients with recurrent or residual TB-SCC who started administration of Nivolumab. In these cases, recurrent or residual SCC was observed after chemotherapy and/or chemoradiotherapy including platinum. The duration of Nivolumab was 2–54 weeks (median 20.0 weeks). The evaluation of the therapeutic effect according to the RECIST method showed partial response in 1 case, stable disease in 2 cases, progressive disease in 4 cases, and size unevaluated in 2 case. Although the number of cases was small, comparing with 5 cases without Nivolumab, these cases showed longer overall survival (1-year OS 33.3% vs 20.0%). ConclusionWe used Nivolumab as palliative chemotherapy in 9 patients with recurrent/residual TB-SCC, and we were able to obtain a certain therapeutic effect on TB-SCC as well as other head and neck SCC.

Plasma-derived cfDNA to reveal potential biomarkers of response prediction and monitoring in non-small cell lung cancer (NSCLC) patients on immunotherapy.

9588 Background: Immune checkpoint inhibitors have shown promising results in many advanced cancers, but the response rate remains low. Various molecular and cellular biomarkers, such as elevated tumor-infiltrating cytotoxic T cells and Natural Killer (NK) cells at baseline, are associated with response. Blood-based biomarkers to predict or monitor response remain challenging to develop. Here we investigate the potential of cell-free DNA (cfDNA) biomarkers to predict response to the PD-1 immune checkpoint inhibitor nivolumab in patients with refractory metastatic non-small cell lung cancer (NSCLC). Methods: Plasma from stage IV NSCLC patients enrolled in ALCINA (NCT02866149) was collected before (baseline, BL, n = 30) and at week 8 (W8, n = 17) of nivolumab therapy. Response was determined using RECIST 1.1 (responders n = 5; non-responders n = 25). Whole-genome sequencing was performed to characterize cfDNA fragments. Tumor fraction (TF) was assessed using ichorCNA. Cellular composition was estimated by deconvolution of cfDNA co-fragmentation patterns, and transcription factor activity was estimated by measuring binding site accessibility across the genome. Results: Although estimated TF at baseline did not predict response to nivolumab, NK cell levels estimated by cell-mixture deconvolution were significantly higher in responders at BL (p < 0.05). Furthermore, estimated monocyte levels at W8 strongly correlated with overall survival (r = 0.75, p < 0.0005, HR = 15.02) and were significantly higher in responders (p < 0.05). By evaluating changes in transcription factor binding activity, we identified factors with greater accessibility in non-responders at baseline (DEAF1, THAP11) and W8 (DUX4, PDX-1). Conclusions: Plasma cfDNA signatures may be useful for response prediction and monitoring in NSCLC patients on immunotherapy. Our results suggest that changes in the immune system, as reflected by cellular composition and transcriptional activity inferred from cfDNA, may provide biological insights beyond TF alone that may benefit biomarker discovery and drug target identification.

Nivolumab in Metastatic Melanoma: Good Efficacy and Tolerability in Elderly Patients

Nivolumab is an anti-PD-1 antibody that restores the antitumour immune function of T cells, blocking the binding of PD-1 with its ligand PD-L1. PD-1 is expressed on T cells and interacts with PD-L1 on tumour cells. The PD-1-PD-L1 link inhibits T cell activation. In metastatic melanoma, PD-1-PD-L1 binding plays a critical role, and the advent of the immune checkpoint inhibitor nivolumab has delivered new and effective treatment options with proven clinical benefit. In the present study, we evaluated the efficacy of nivolumab in elderly patients with metastatic melanoma. The study enrolled 55 elderly patients (75 years of age and older) with a diagnosis of metastatic melanoma. Primary endpoints of the study were progression-free survival (pfs) and the objective response rate; secondary endpoints were overall survival, reduction in serum lactate dehydrogenase (ldh) from before to after treatment, and tolerability. Nivolumab was well tolerated and resulted in good disease control, with a manageable toxicity profile and significant clinical benefit. The duration of pfs was 5.1 months (95% confidence interval: 3.5 months to 6.8 months). A significant correlation was observed between reduction in serum ldh and pfs: 0.60 (95% confidence interval: 0.28 to 0.86; p = 0.002). Nivolumab is an immunotherapy treatment that has proved to be an effective and well-tolerated therapeutic option in elderly patients with metastatic melanoma.

A Rare Case of Autoimmune Encephalitis in a Patient After Treatment of Metastatic Melanoma with a Combination of Immune Checkpoint Inhibitors Nivolumab and Ipilimumab (447)

A Rare Case of Autoimmune Encephalitis in a Patient After Treatment of Metastatic Melanoma with a Combination of Immune Checkpoint Inhibitors Nivolumab and Ipilimumab (447)

Systemic therapy in advanced-stage hepatocellular carcinoma

SummaryHepatocellular carcinoma (HCC) is a complex disease, since both choice of treatment and prognosis depend not only on tumor-specific but also on liver-related characteristics. Therefore, a multidisciplinary approach in specialized clinics is required for the optimal management of HCC patients. Almost half of patients present with advanced-stage tumor with no curative therapeutic options. According to international guidelines, palliative systemic therapy is recommended in these patients. The multikinase inhibitor sorafenib was the first drug to show antitumor efficacy and was the only approved treatment for almost a decade, as several other agents failed to improve patient survival. In recent years, treatment practices have changed with lenvatinib as another first-line treatment choice and regorafenib, cabozantinib, and ramucirumab as second-line therapeutic options. However, only patients with preserved liver function (Child-Pugh-Turcotte [CPT]-A) were enrolled in these studies and are consequently suitable for these drugs. After promising phase‑1 and phase-2 studies, subsequent phase‑3 trials evaluating the immune checkpoint inhibitors (ICIs) nivolumab and pembrolizumab have failed to demonstrate a significant improvement in patient survival. Ongoing trials are evaluating the combination of ICIs with tyrosine kinase inhibitors or vascular endothelial growth factor (VEGF) inhibitors. Recently, in a phase‑3 trial, the combination therapy atezolizumab and bevacizumab led to a significantly improved overall survival compared to sorafenib in the first-line setting. Further studies are needed to determine how best to select between the growing number of therapeutic options.

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer.

Starting in 2014, large phase III clinical trials began to disclose the study results of using programmed death (PD)-1 immune checkpoint inhibitors (ICIs) (pembrolizumab, nivolumab) and PD-ligand (L)1 (atezolizumab, durvalumab, avelumab) ICIs immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). In the recurrent and metastatic (R/M), cisplatin-refractory setting, nivolumab achieved a 2.2-fold increase of the median 1-year overall survival as compared with investigators' choice of salvage chemotherapy (36.0 vs. 16.6%). A paradigm shift to the winning regimen, pembrolizumab combined with platinum and infusional fluorouracil, has outperformed the past gold standard of cetuximab-based platinum and fluorouracil combination in terms of overall survival (median, 13.6 vs. 10.1 mo) when administered as the first-line treatment for R/M HNSCC. Nevertheless, many patients still did not respond to the PD-1/PD-L1 checkpoint inhibitor treatment, indicating innate, adapted, or quickly acquired resistance to the immunotherapy. The mechanisms of resistance to ICIs targeting the PD-1/PD-L1 signaling pathway in the context of HNSCC are the focus of this review. The past 5 years have seen improved understanding of the mechanisms underlying checkpoint inhibition resistance in tumor cells, such as: tumor cell adaption with malfunction of the antigen-presenting machinery via class I human leukocyte antigen (HLA), reintroduction of cyclin D–cyclin-dependent kinase (CDK) 4 complex to cell cycles, enrichment of CD44+ cancer stem-like cells, or development of inactivating mutation in IKZF1 gene; impairment of T-cell functions and proliferation through mutations in the interferon-γ-regulating genes, suppression of the stimulator of interferon genes (STING) pathway, or resulted from constitutional nutritional iron deficiency state; metabolic reprogramming by cancer cells with changes in metabolites such as GTP cyclohydrolase 1, tetrahydrobiopterin, kynurenine, indoleamine 2,3-dioxygenase, and arginase 1; defective dendritic cells, CD-69 sufficient state; and the upregulation or activation of the alternative immune checkpoints, including lymphocyte activation gene-3 (LAG3), T-cell immunoglobulin and ITIM domain (TIGIT)/CD155 pathway, T-cell immunoglobulin mucin-3 (TIM-3), and V domain-containing Ig suppressor of T-cell activation (VISTA). Several potential biomarkers or biosignatures, which could predict the response or resistance to the PD-1/PD-L1 checkpoint immunotherapy, are also discussed.

Selective modulation of immune transcripts in extracellular vesicles from plasma of renal cell carcinoma patients receiving nivolumab.

719 Background: Patients (pts) displaying a full-fledged immune response show high levels of circulating extracellular vesicles (EVs) containing immune transcripts that might be transferred to neighboring cells to amplify immune responses, as in autoimmunity and transplantation. We hypothesized EV immune transcripts could reflect immune activation in cancer pts receiving immunotherapy with immune checkpoint inhibitors (ICI). These RNA-containing EVs may surrogate immune functionality and represent a plasma transcriptional signature of adaptive immunity that can be readily detected by liquid biopsy. Methods: Blood samples from metastatic renal cell cancer pts,treated with ICI nivolumab (n=8) or tyrosine kinase inhibitor cabozantinib (n=9) were collected at baseline, week 4 and 12. EV-RNA was isolated from plasma with membrane affinity spin columns and evaluated for CD274(PD-L1), IFNG, PDCD1 (PD-1), CD3 and GZMB (granzyme B) transcripts by qRT-PCR. Results: All pts showed a statistically significant increase of CD3, IFNG, GZMB, PD-1 and PD-L1 immune transcripts in plasma EVs, evidenced at 4 and 12 weeks of therapy. Treatment subgroup analysis revealed an upregulation of CD3, IFNG, GZMB and PD-1 transcripts only in plasma EVs of patients receiving nivolumab that was more evident in those showing clinical benefit (4/8), while PD-L1 increased significantly during cabozantinib treatment. Upon comparing transcripts with soluble proteins, PD-L1 displayed similar kinetics, while PD-1 increased only as transcript but not as protein, given its potential sequestration by the anti-PD-1 antibody. This effect was detectable only in nivolumab but not in cabozantinib treated pts. Conclusions: Monitoring immune transcripts carried by plasma EVs holds promise as potential tool to assess the entity of the ongoing immune activation during immunotherapy. Plasma EVs may be exploited as indicators of immune response and help to predict clinical efficacy at early on-treatment time points. This approach based on plasma EVs might represent a starting point for the development of a novel strategy to study immune responses in clinical setting.

Immune-related adverse events correlate with improved survival in patients with advanced mucosal melanoma treated with nivolumab: A single-center retrospective study in Japan.

Immune-related adverse events (irAE) were reported to be associated with better outcomes in various cancers treated with the immune checkpoint inhibitor nivolumab. Considering that their development depends on host immune activation, irAE may reflect antitumor response in mucosal melanoma (MM). This single-center retrospective study including patients with advanced MM receiving nivolumab monotherapy between August 2014 and September 2018 investigated whether the development of irAE was associated with clinical efficacy. The study patients were divided into those with and without irAE, and treatment efficacy and safety were evaluated. The study cohort of 27 patients included 20 (74%), six (22%) and one (4%) patient with primary MM in the head and neck, genitourinary and anorectal regions, respectively. The irAE onset was not significantly associated with the objective response rate in patients while it was significantly associated with the disease control rate. The median progression-free survival in patients with and without irAE was 301 and 63days, respectively. The median overall survival (OS) in patients with and without irAE was 723 and 199days, respectively. According to the timing of irAE onset, the OS was better in seven patients who developed irAE after 180days than in nine patients who developed irAE within 180days. Although 16 patients (59%) experienced any grade irAE, including three (11%) with grade 3 or more irAE, there were no treatment-related deaths. These results indicated that the development of irAE may correlate with improved survival in patients with MM treated with nivolumab monotherapy. Further studies are necessary to confirm these findings.

Harnessing big 'omics' data and AI for drug discovery in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary adult liver cancer. After nearly a decade with sorafenib as the only approved treatment, multiple new agentshave demonstrated efficacy in clinical trials, including the targeted therapies regorafenib, lenvatinib and cabozantinib, the anti-angiogenic antibody ramucirumab, and the immune checkpoint inhibitors nivolumab and pembrolizumab. Although these agents offer new promise to patients with HCC, the optimal choice and sequence of therapies remains unknown and without established biomarkers, and many patients do not respond to treatment. The advances and the decreasing costs of molecular measurement technologies enable profiling of HCC molecular features (such as genome, transcriptome, proteome and metabolome) at different levels, including bulk tissues, animal models and single cells. The release of such data sets to the public enhances the ability to search for information from these legacy studies and provides theopportunity to leverage them to understand HCC mechanisms, rationally develop new therapeutics and identify candidate biomarkers of treatment response. Here, we provide a comprehensive review of public data sets related to HCC and discuss how emerging artificial intelligence methods can be applied to identify new targets and drugs as well as to guide therapeutic choices for improved HCC treatment.

A case of small bowel adenocarcinoma wherein nivolumab conferred temporary benefit in disease control

Small bowel adenocarcinomas are rare. There is no definite consensus as to whether they should be treated in a manner similar to gastric or to colon cancer. We report the case of a young woman with a primary jejunal adenocarcinoma, bilateral ovary metastases, and peritoneal dissemination. First- and second-line chemotherapy for the gastric cancer failed. She was then treated with the immune checkpoint inhibitor nivolumab and had temporary improvement in her condition. To the best of our knowledge, this is the first case wherein nivolumab has been used to treat small bowel adenocarcinoma.

466P - Cancer immunotherapy efficacy and patients’ age: A systematic review and meta-analysis

BackgroundCheckpoint inhibitors have been regarded as an alternative to docetaxel as the new standard second-line therapy or even first-line therapy in advanced non-small cell lung carcinoma (NSCLC), nevertheless, little is known about the effect of patients’ age on the efficiency of immune checkpoint inhibitors as cancer treatments. Thus, we did a systematic review and meta-analysis to assess the immune checkpoint inhibitor vs docetaxel efficacy in subgroups defined by patients’ age. MethodsA comprehensive search of online databases was performed. The main purpose was to evaluate the difference in efficacy of immune checkpoint inhibitors between patients above age 65 and under 65, measured in terms of the difference in overall survival log(HR) reported in study participants above and under 65. A random-effects model was used to calculate the pooled overall survival HR and 95% CI in patients above and under 65. ResultsA total of 19 eligible randomized controlled trials of immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab, or pembrolizumab) that reported overall survival according to patients’ age were recruited. Overall, the pooled overall survival HR was 0.75 (95% CI 0.67–0.85) (p<0.001) while the pooled progression-free survival HR was 0.72 (95% CI 0.55–0.93) (p = 0.011) in patients under age 65 treated with immune checkpoint inhibitors, compared with patients treated in control groups. In patients above age 65 treated with immune checkpoint inhibitors, the pooled overall survival HR compared with control groups was 0.80 (95% CI 0.74–0.87) (p<0.001) and the pooled progression-free survival HR was 0.81 (95% CI 0.67–0.97) (p = 0.223). The difference in efficacy between patients above and under 65 treated with immune checkpoint inhibitors was significant in overall survival. Nevertheless, there were no significant differences in progression-free survival between groups. ConclusionsImmune checkpoint inhibitors can improve overall survival for patients with advanced cancers such as non-small-cell lung cancer. However, the magnitude of benefit is age-dependent. Future research should guarantee greater inclusion of patients under age 65 in trials and focus on improving the effectiveness of immunotherapies in patients under age 65. Legal entity responsible for the studyDepartment of Thoracic Surgery and Oncology. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.