Second-line Immunotherapy Research Articles

Pharmacologic Treatment and Early Rehabilitation Outcomes in Pediatric Patients With Anti-NMDA Receptor Encephalitis

ObjectivesTo describe the immunotherapy and pharmacologic treatments administered to pediatric patients with N-methyl-D-aspartate receptor encephalitis (NMDARE) during inpatient rehabilitation as well as to examine clinical and demographic variables associated with early functional outcomes. DesignRetrospective chart review and post hoc analysis. SettingPediatric inpatient rehabilitation unit. ParticipantsPediatric patients (N=26; mean age, 10.79±5.17y) admitted to an inpatient rehabilitation unit with a confirmed diagnosis of NMDARE. InterventionsInpatient rehabilitation; pharmacologic treatments. Main Outcome MeasureFIM for Children (WeeFIM) Developmental Functional Quotient (DFQ). ResultsAll patients received first-line immunotherapies to treat NMDARE, and 69% also received second-line immunotherapies. Patients were prescribed an average of 8 medications for symptom management (range, 3-15 per patient), most often for the treatment of agitation (100%), psychiatric symptoms (92%), and seizures (65%). Sixty-five percent of patients demonstrated an improvement in Total WeeFIM DFQ over the course of inpatient rehabilitation, with 35% demonstrating limited to no change in Total WeeFIM DFQ (“unfavorable early outcome”). Those with unfavorable early outcome were significantly younger than those showing more favorable outcome. Pharmacologic treatment for seizures, movement disorders, and decreased arousal or level of consciousness were each associated with unfavorable early outcome independent of age differences. ConclusionFindings highlight the symptomatic heterogeneity and polypharmacy involved in the care and treatment of patients with NMDARE, with patients receiving a variety of immunotherapies and medications for symptom management. The presence of (and treatment for) seizures, movement disorders, and deteriorated neurologic status may each be associated with poor early outcomes in this population. Further investigation is needed to better classify presentations and treatments for this disease and to determine how differences are associated with long-term outcomes.

Clinical outcomes of pediatric Anti-NMDA receptor encephalitis.

To investigate the clinical features and long-term outcomes of pediatric Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Thirty-two anti-NMDAR encephalitis patients with positive anti-NMDAR antibody test results were recruited. Clinical outcomes were evaluated using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) and the modified Rankin Scale (mRS). The median age of onset was 9.0 years (range, 0.7-17.2 years). Twenty-four patients (75.0%) were female. All patients received first-line immunotherapy including intravenous immunoglobulin and/or steroid therapy. The second-line immunotherapy was administered to 22 patients (68.8%). Clinical outcomes were evaluated in 27 patients who were followed for longer than 6 months after onset, among whom the median follow-up duration was 31.2 months (range, 6.3-82.9 months). The proportion of patients with ≤2 points on the mRS at their 12-month follow-up was 79.2% (19/24). The CASE scores of these 19 patients ranged from 0 to 5, with language and memory deficits accounting for most of these disabilities. When the outcome was assessed according to onset age (<12 years or 12-18 years), the younger group tended to show a slower recovery over their clinical course. Despite overall favorable clinical outcomes, mild cognitive problems, including language and memory, may persist in pediatric anti-NMDAR encephalitis patients. A specific outcome measure, such as CASE, should be adopted to delineate clinical outcomes and aid the development of individualized treatment plans.

Risk of Developing Checkpoint Immune Pneumonitis and Its Effect on Overall Survival in Non-small Cell Lung Cancer Patients Previously Treated With Radiotherapy.

IntroductionImmune checkpoint inhibitor-related pneumonitis (ICIP) is a potentially life threatening immune-related adverse event (irAE), especially in non-small cell lung cancer (NSCLC) patients. Currently, the potential for increased irAE in patients who receive radiotherapy is scarcely known, although a connection between antitumor immune responses and irAEs has been suggested. In this study, we evaluated the development of ICIP in non-small cell lung cancer patients with prior radiotherapy, treated with immunotherapy in the second-line.MethodsIn this retrospective trial, we included patients treated with second-line immunotherapy at the National Cancer Institute in Mexico City from February 2015 to February 2018. Clinical, radiological and treatment variables were evaluated according to the presence of ICIP as defined by the Common Terminology Criteria for Adverse Events (4.0) in patients with or without a previous (≥months) history of radiotherapy.ResultsAmong 101 NSCLC patients who received treatment with ICIs, 22 patients (21.8%) were diagnosed with ICIP, of which 73% (16/22) had a history of radiotherapy (OR 6.04, 95% CI 2.03−18.0, p < 0.001). Median progression free survival and overall survival were similar in patients who developed ICIP compared with those who did not, however, patients who presented grade ≥ 2 ICIP had an increased risk of mortality (HR 2.54, 95% CI 1.20−5.34, p = 0.014).ConclusionIn this real-world cohort of NSCLC patients treated with ICI, the history of prior radiotherapy was associated with increased risk for ICIP development. Unlike other irAEs, grade ≥ 2 ICIP is an independent prognostic factor for decreased survival in NSCLC patients.

Recomendaciones de oncólogos que trabajan en el ISSSTE para el tratamiento sistémico del cáncer de pulmón avanzado 2020

Based on the GRADE system, a group of specialists in Medical Oncology from ISSSTE produced a set of recommendations for the systemic treatment of advanced lung cancer —specifically non-small cell lung cancer and small-cell lung cancer— with immunotherapy, chemotherapy with or without antiangiogenic agents. Regarding the diagnosis, extension studies and lung grades are analyzed. Likewise, basic pathology, molecular biology, and imaging features are described to determine the treatment protocols for advanced lung cancer with actionable mutations or biomarkers related to domains such as actionable mutations, anaplastic lymphoma kinase, and reactive oxygen species (ROS1). The recommendations comprise the most important clinical issues: immunotherapy in lung cancer, first-line treatment for non-small cell lung cancer, non-squamous (wild-type) metastatic cancer, second-line immunotherapy regimes, chemotherapy without first-line immunotherapy for adenocarcinoma, firstline chemotherapy with antiangiogenic agents, as well as the characteristics a patient should present to be a candidate to receive immunotherapy. Dosages are stated in the different treatment protocols; the chemotherapy regimes for unresectable, locally-advanced lung cancer are being reviewed, as well as for ECOG 0-1 until ECOG 2, limited and extended stages. Even though there is no consensus on certain topics, this document includes clear guidelines whose aim is standardizing the criteria, and that will be subject to be reviewed and updated.

Immune Checkpoint Inhibitors versus VEGF Targeted Therapy as Second Line Regimen in Advanced Hepatocellular Carcinoma (HCC): A Retrospective Study.

Several targeted agents including multi-tyrosine kinase inhibitors (mTKIs) and immunotherapy (IO) agents have been approved for use beyond the frontline setting in patients with advanced hepatocellular carcinoma (HCC). Due to lack of prospective head-to-head comparative trials, there is no standardized way for alternating those agents beyond frontline. Therefore, we performed a retrospective review of the Kansas University (KU) cancer registry to determine whether IO may be superior to non-IO therapy. Patients with advanced HCC were divided into two groups based on the second-line systemic regimen received (IO vs. non-IO). Progression-free survival (PFS) and overall survival (OS) were calculated under the Kaplan–Meier and Cox proportional hazards models. No statistically significant differences in PFS and OS were found, although a non-significant delayed separation in the survival curve favoring IO was identified (median PFS 3.9 months vs. 3 months; median OS 10 months vs. 10 months respectively for IO vs. non-IO). This retrospective analysis is one of the earliest and largest studies comparing second-line IO and non-IO therapies thus far reported. Future studies should aim to define specific biomarkers for response prediction and treatment optimization based on individual patient and tumor characteristics. Furthermore, combinatorial therapeutic strategies is an evolving approach showing early promising signal.

Anti-gamma-aminobutyric acid receptor type A encephalitis: a review.

To systematically review the clinical features, diagnosis, and management of anti-gamma-aminobutyric acid receptor Type A (GABAA) autoimmune encephalitis with a focus on recent data. In a review of published reports, we identified 50 cases of anti-GABAA receptor encephalitis with clinical features reported. The median age at presentation was 47 years old (range, 2.5 months-88 years old), 64% were adults, 36% were children and it occurred in both males and females. Eight-two percent (41/50) presented with seizures, 72% (36/50) with encephalopathy, and 58% (29/50) with both. Of those presenting with seizures, 42% developed status epilepticus during their disease course. Ninety-six percent (48/50) had MRI results reported, with 83% of these cases having abnormal findings, most commonly multifocal/diffuse cortical and subcortical T2/FLAIR hyperintense lesions without associated gadolinium enhancement. Almost one-third, 28% (14/50), had an associated malignancy detected by the time of diagnosis, 64% (9/14) of which was thymoma. Of 44 patients with outcomes reported, 80% had partial or complete recovery, whereas 20% had poor outcomes including 11% (5/44) who died. Of the 42 patients with type of treatment(s) and outcomes reported, 54% (23/42) received only first-line immunotherapy and 31% (13/42) received first-line and second-line immunotherapy. Receiving a combination of first-line and second-line immunotherapy may be associated with higher likelihood of complete recovery. When follow-up MRIs were reported, all showed improvement, and sometimes complete resolution, of T2/FLAIR hyperintensities. Anti-GABAA receptor encephalitis can present across the age spectrum and should be considered in patients who present with rapidly progressive encephalopathy and/or seizures. Brain MRI often shows a distinctive pattern of multifocal cortical and subcortical T2/FLAIR hyperintense lesions, generally not typical of other known central nervous system autoantibody associated encephalitis syndromes. High clinical suspicion and early diagnosis are important given the potential for clinical improvement with immunotherapy.

Contactin-1 autoimmunity: Serologic, neurologic, and pathologic correlates.

ObjectiveTo determine serologic characteristics, frequency, phenotype, paraneoplastic associations, and electrodiagnostic and histopathologic features accompanying contactin-1 autoimmunity.MethodsArchived sera known to produce synaptic tissue-based immunofluorescence patterns were reevaluated, and contactin-1 specificity was confirmed by recombinant protein assays. Screening of 233 chronic/relapsing demyelinating neuropathies for additional cases was performed.ResultsWe identified 10 contactin-1 IgG seropositive cases. Frequency of contactin-1 immunoglobulin (Ig) G among tested Mayo Clinic chronic/relapsing demyelinating neuropathies was 2%. Sensory predominant presentations (n = 9, 90%), neuropathic pain (n = 6, 60%), and subacute progression (n = 5, 50%) were commonly encountered among contactin-1 neuropathies. Two patients had chronic immune sensory polyradiculopathy-like phenotype at presentation. Electrodiagnostic studies were consistent with demyelination (slowed conduction velocities and/or prolonged distal latencies) without conduction block. Markedly elevated CSF protein (median 222 mg/dL, range 69–960 mg/dL), thickening/gadolinium enhancement of nerve roots (4/5), and subperineural edema on nerve biopsy (4/4) were other characteristic features. Three cases were diagnosed with paraneoplastic demyelinating neuropathies (thymoma, n = 1; breast cancer, n = 1; plasmacytoma, n = 1). Four of the 9 patients treated with IV immunoglobulin demonstrated initial clinical improvement, but the favorable response was sustained in only 1 case (median follow-up, 60 months). Sustained clinical stabilization or improvement was observed among 3 of the 6 cases in whom second-line therapies (rituximab, cyclophosphamide, and azathioprine) were used.ConclusionContactin-1 IgG has a distinct sensory predominant presentation commonly associated with neuropathic pain, with demyelinating changes on electrophysiologic studies. A paraneoplastic cause should be considered. Testing of contactin-1 IgG among cases with similar presentations may guide immunotherapy selection, especially second-line immunotherapy consideration.

Effect of genomic and transcriptional alterations in first-line chemotherapy on subsequent immunotherapy in non-small cell lung cancer (NSCLC) patients.

9614 Background: Recent studies have demonstrated that first-line immunotherapy has better therapeutic response than second-line immunotherapy in NSCLC patients. However, the mechanism behind this observation has not been elucidated. The aim of this study is to investigate the mechanism of unfavorable influence that the first-line chemotherapy exerts on subsequent immunotherapy. Methods: 29 NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET) mutations were enrolled in this study. Paired cancer tissues before and after chemotherapy were collected, and NGS-based WES and mRNA sequencing were performed. Sequencing data were analyzed with R packages and statistics analysis was performed with SPSS 20 software. P ≤ 0.05 was regarded as statistically significant. Results: We found that the total number of SNV/INDEL mutations and the tumor mutational burden (TMB) decreased significantly following chemotherapy. The decrease of mutation burden correlated well with therapeutic response: patients with partial response (PR) exhibited significant decrease while patients with stable disease (SD) or progression of disease (PD) did not. Meanwhile, a sharp decrease in common mutations before and after chemotherapy was observed in PR and PD patients, but not SD patients, suggesting that mutational change reflected the therapeutic response. The change in copy number variations (CNVs) exhibited similar trends and correlation with therapeutic response. Subsequent analysis on mRNA levels revealed a sharp decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant to immunotherapy response. Pathway enrichment analysis showed that the genes with decreased expression mainly represented immune-related signaling pathways or biological processes. Conclusions: Our study revealed a possible mechanism underlying unsatisfactory multiple-line immunotherapy following chemotherapy, and indicated that first-line chemotherapy may influence the tumor microenvironment to exert unfavorable influence on subsequent immunotherapy.

Activity and safety of third-line BRAF-targeted therapy (TT) following first-line TT and second-line immunotherapy (IT) in advanced melanoma.

10049 Background: Patients with advanced melanoma who progress on 1st line TT and 2nd line IT have limited treatment options. We explored the safety and efficacy of re-treatment with 3rd line TT. Methods: was pooled from 6 centers in Australia from 2009-2018. Eligible patients with BRAF V600 mutant melanoma had 1st line therapy with a BRAF/MEK inhibitor, 2nd line IO and were re-challenged with a BRAF/MEK inhibitor. Results: 90 patients were included; median age 61 years, 78% BRAF V600E, 89% ECOG 0-1 at baseline. 1st line TT was combination BRAF/MEK inhibitors in 80%, predominately dabrafenib/trametinib. Response to 1st line therapy was CR 20%, PR 41%, SD 17% and PD 13% and median duration of therapy was 7.2 months (0-33 months). 70% stopped for progressive disease, 9% toxicity and 16% had a planned switch to immunotherapy. For 2nd line IT, 49% had PD-1 alone, 33% had PD-1+CTLA-4, 14% had CTLA-4 alone. Only median duration on IT was 67 days (0-23 months), 81% ceased for PD, 14% for toxicity. Of patients who had a planned switch to IO before 1st line TT progression, one patient responded to second line IO with SD as BORR, there were no other responses to 2nd line IO in the planned switch group. At 3rd line TT re-challenge, 54% were AJCC stage IVd, 34% IVc, 51% had elevated LDH, 59% ECOG 0-1. 47% were re-challenged with dabrafenib/trametinib, 33% vemurafenib/cobimetinib, 11% encorafenib/binimetinib. BORR was 28%, with median duration on 3rd line TT 81 days. The OS was 1.7 years, with 34% alive at time of analysis. Conclusions: Despite progression on 1st line TT and 2nd line IT, patients may experience meaningful response and on re-challenge TT.

The role of targeted therapy (TKI) in the treatment of advanced hepatocellular carcinoma (aHCC) in the era of immunotherapy: Real-world data using AI analytics from an academic medical center.

e16623 Background: The management of aHCC has evolved dramatically in recent years, with new agents like immunotherapy receiving regulatory approval. As we begin incorporating these drugs into routine clinical practice, data on real-world sequencing of therapies and clinical outcomes are needed. Methods: We utilised the DISCOVERYAI platform, a virtual machine containing de-identified patient electronic health records to review HCC patients treated at the National University Health System, Singapore from January 2015 to December 2019. We then identified those who received systemic therapy and correlated their clinical outcomes. Results: In total, 395 HCC patients were identified; 75 received surgery, 174 received loco-regional therapy and 102 referred for consideration of systemic therapy. Of those considered for systemic therapy, median age was 65 years (range 23-87); 88% male (n = 90); hepatitis B/hepatitis C/non-hepatitis, 41(40.2%)/ 10(9.8%)/ 51(50.0%). 75.5% (n = 77) of them received systemic therapy with a TKI and/or immunotherapy. 39% (n = 30) of these received second-line treatment. Child-Pugh score at start of treatment was A5/A6/B7/B8, 38(49.3%)/ 32(41.6%)/ 5(6.5%)/ 2(2.6%) respectively. In the first-line, 66% (n = 51) received TKI and 34% (n = 26) received immunotherapy. Amongst those treated with first-line TKI, 45% (n = 23) received second-line therapy; 65% (n = 15) immunotherapy, 35% (n = 8) another TKI. Of those treated with first-line immunotherapy, 27% (n = 7) received second-line TKI. At a median follow-up of 35 months, first-line median progression-free survival (mPFS) for TKI vs immunotherapy was 3.7 vs 3.1 months (HR 0.73; 95% CI, 0.40-1.33; p = 0.31). mPFS for second-line immunotherapy vs TKI was 4.0 vs 2.9 months (HR 0.43; 95% CI, 0.19-0.96; p = 0.04). When comparing sequencing of therapies, the combined first and second mPFS for TKI-immunotherapy/TKI-TKI/immunotherapy-TKI is 9.5/7.6/7.6 months respectively (log-rank test, p = 0.71). Those patients that received both immunotherapy and TKI had significantly higher overall survival (OS) compared to those receiving only immunotherapy or only TKI or none (mOS NR vs 10.1 vs 13.2 vs 4.7 months; p &lt; 0.001). Conclusions: TKI remains an important pillar of treatment in aHCC in the era of immunotherapy. While immunotherapy provides long durable responses and benefit in a minority of patients, the majority appear to benefit from TKI. Biomarker studies are needed to discern treatment algorithms for aHCC.

The mutation profiles of HBV or HCV infected hepatocellular carcinoma patients underlie the varied responses to second-line immunotherapy.

e16629 Background: HBV and HCV infections facilitate the development of hepatocellular carcinoma (HCC) via different mechanisms, given that the DNA sequence of HBV but not HCV can integrate into the host genome. However, it remains unclear that whether the altered genomic landscape of HCC patients caused by HBV or HCV infection may result in different responses to treatments. Methods: The MSK panel sequencing results and treatment data of 127 HCC patients were downloaded from the TCGA database (MSK, Clin Cancer Res 2018). Profiles of HBV positive and HCV positive patients were extracted. Based on the treatment received, those patients were classified to sorafenib treated groups and sorafenib + immunotherapy (IT) groups. The progression-free survival (PFS, months) and overall survival (OS, months) were compared, and the mutational profiles of patients were analyzed. Results: Among patients who received sorafenib treatment alone, the mean PFS of HBV positive patients (n = 12, 4.9 ±1.1) is similar to that of the HCV positive patients (n = 21, 5.1±1.8). However, the mean OS of HBV positive patients (n = 12, 18.3 ±6.6) was longer than the mean OS of HCV positive patients (n = 21, 10.0 ±1.9). Among the patients who received immunotherapy following sorafenib treatment, the mean IT PFS of HBV positive patients was (n = 5, 4.4 ±1.8), which was longer than the mean IT PFS of HCV positive patients (n = 5, 2.5 ±0.5). Consistently, the mean IT OS of HBV positive patients (n = 5, 10.9 ±4.4) was longer than the mean IO PFS of HCV positive patients (n = 5, 4.6 ±1.0). Overall it seems that the HBV positive patients responded better to second-line immunotherapy, despite the fact that these comparisons did not reach statistical difference due to the limited sample size. By comparing the MSK panel sequencing results, mutations exclusive to the HBV or HCV infected groups were identified. Enrichment analysis showed that 7/35 mutations exclusively found in the HBV positive group are responsible for lymphocyte activation (p &lt; 0.00001), which may underlie the better IT treatment outcome. Among the mutations restricted to the HCV infected group, 9/50 were involved in histone modification, 7/50 were involved in Hepatitis B pathways (p &lt; 0.0001), suggesting that HCV infection may interfere with diverse molecular processes. Conclusions: HBV and HCV infected HCC patients may respond differently to second-line immunotherapy. This difference is perhaps related to the altered genetic landscape of the patients resulted from virus infections by HBV or HCV.

PD51-12 COST-EFFECTIVENESS OF IMMUNOTHERAPIES IN METASTATIC BLADDER CANCER

INTRODUCTION AND OBJECTIVE: The development of immunotherapies (IOs) for the treatment of bladder cancer in first and second-line increased the economic burden of this disease. We aimed to use an economic model to compare the cost-effectiveness when IOs are included in the treatment algorithm of metastatic bladder cancer. METHODS: The model evaluated overall survival, progression-free survival and costs associated with each drug; adverse event (AE) treatment; monitoring; and post-progression (third-line treatment or best supportive care (BSC)). Efficacy, safety, and treatment duration were estimated from regimens’ pivotal clinical trials. The model included first-line gemcitabine-cisplatin (Gem-Cis), gemcitabine-carboplatin (Gem-Carb) or IOs in Cis-ineligible patients and high PD-L1 expression, and second-line IOs, Gem-Carb, paclitaxel or docetaxel. Cost of BSC and AEs was retrieved from published Canadian studies. Sensitivity analyses were conducted to take in consideration potential rebates to IOs in hospital. RESULTS: The cost of treating patients with Gem-Cis in first-line was estimated to be $16,339 with 53% of cost related to the management of adverse events. When treating patients in second-line setting, the incremental cost-effectiveness ratio (ICER) of Pembrolizumab, Atezolizumab and Durvalumab compared to Paclitaxel/Docetaxel were 166,430$/LYG (life-year gained), 180,795$/LYG and 74,141$/LYG, respectively. Managing adverse events represented less than 1 % for IOs and 10% for paclitaxel/docetaxel of their associated total costs. In Cis-ineligible patients, as first-line therapy, Atezolizumab had an ICER of 79,491$/LYG compared to Gem-Carb, while Pembrolizumab did not appear to increase patient survival. The willingness-to-pay (WTP) threshold in Canada for prolonging end-of-life therapy in cancer patients is usually cited to be below 100,000$/quality-adjusted life years, therefore only Durvalumab would be considered cost-effective in 2nd line and Atezolizumab in 1st line. CONCLUSIONS: In a Canadian setting, most IOs for metastatic bladder cancer had a positive ICER compared to chemotherapy, ranging from 75,000$/LYG to 180,000$/LYG. However, only Durvalumab in the 2nd line setting and Atezolizumab in the 1st line setting would be cost-effective given a WTP threshold of 100,000$. Finalized results from ongoing RCTs are needed to complete and confirm our results. Source of Funding: None

EPSILoN: A Prognostic Score Using Clinical and Blood Biomarkers in Advanced Non–Small-cell Lung Cancer Treated With Immunotherapy

BackgroundSecond-line immunotherapy (IO) has shown an overall survival benefit. However, only 18% to 20% of patients with advanced non–small-cell lung cancer (aNSCLC) will respond, with a median progression-free survival (PFS) of 2 to 4 months. Thus, biomarkers to select those patients most likely to benefit from IO are greatly needed. Patients and MethodsWe conducted a retrospective analysis of 154 patients with aNSCLC who had received anti–programmed cell death 1 therapy as second line or further treatment. We assessed the absolute neutrophil, lymphocyte, monocyte, and eosinophil counts at baseline (T0) and the second (T1) and third (T2) cycles. The neutrophil/lymphocyte ratio (NLR), derived-NLR (dNLR), lymphocyte/monocyte ratio (LMR), and their percentage of change at T1 and T2 compared with T0 were evaluated. The clinical characteristics and lactate dehydrogenase (LDH) level were also considered. Univariate and multivariate analyses were performed. Significant biomarkers for PFS on multivariate analysis were combined in a prognostic score. ResultsFor overall survival, the negative prognostic biomarkers were Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, NLR at T0, and dNLR at T1; the LMR at T0, T1, and T2 was identified as a positive prognostic biomarker. For PFS, the negative prognostic biomarkers were ECOG PS 2, liver metastases, NLR at T0, dNLR at T1 and T2, and ≥ 30% increase of NLR from T0 to T1; the positive prognostic biomarkers were heavy smoking, LDH, and LMR at T2. The ≥ 30% increase of LMR from T0 to T1 and T0 to T2 correlated with the overall response rate. A prognostic score (EPSILoN score; smoking, ECOG PS, liver metastases, LDH, NLR) identified 3 prognostic groups (median PFS, 10.2, 4.9, and 1.7 months, respectively; P < .001). ConclusionsThe EPSILoN score combines 5 baseline clinical and blood biomarkers and can help to identify patients with aNSCLC who will most likely benefit from second-line IO. Further studies are warranted.

Real-world outcomes in patients (pts) with metastatic urothelial carcinoma (mUC) who received first- or second-line immunotherapies (IO) in the United States (US).

457 Background: Benefit of IO (PD1 and PD-L1 inhibitors) for mUC was observed in clinical trials but real-world evidence for benefit and clinical outcomes is limited. Methods: This was a retrospective study of adult pts with mUC who initiated IO regardless of PD-L1 expression in the first- (1L cohort) or second-line (2L cohort) setting between 5/1/2016-1/31/2019 in the US Oncology Network (USON), a network of community oncology practices. Descriptive and Kaplan-Meier analyses to evaluate baseline characteristics, treatment patterns and clinical outcomes were conducted using data from USON’s electronic heath record. Results: Among 393 pts in the 1L cohort, median (range) age at IO initiation was 77 (42, 90+), 74% were male, 69% were White, and 19.1% and 4.1% had ECOG performance status (PS) 2 and 3/4, respectively. Among the 366 pts in the 2L cohort, median (range) age at IO initiation was 70 (29, 90+), 74% were male, 71% were White, and 19.7% and 1.4% had ECOG PS 2 and 3, respectively. Median (range) follow-up durations from IO initiation were 4.2 (0, 34.1; 1L cohort) and 4.1 (0, 31.3; 2L cohort) months (mo), during which time 43.1% (1L cohort) and 44.4% (2L cohort) of pts died. Median overall survival (OS) from IO initiation (95% confidence interval [CI]) was 10.6 (9.7, 13.2) mo for the 1L cohort and 9.4 (7.1, 11.5) mo for the 2L cohort; 1-year survival probabilities (95% CI) were 46.6% (40.1%, 52.8%; 1L cohort) and 43.4% (36.8%, 49.8%; 2L cohort). By the end of the follow-up, 48.1% of 1L pts and 47.8% of 2L pts were alive and did not advance to next line of therapy, and 13.5% of 1L and 13.4% of 2L cohort pts advanced to the next line of therapy. Median (95% CI) treatment durations were 2.6 (2.1, 2.9) and 2.8 (2.2, 3.5) mo for the 1L and 2L cohorts, respectively; 6-mo ongoing treatment probabilities (95% CI) were 26.6% (22.2%, 31.2%; 1L cohort) and 31.4% (26.4%, 36.4%; 2L cohort). Conclusions: OS of pts in the real world receiving 1L and 2L IO appears consistent with clinical trial results, although survival follow-up is limited. A minority of pts received post-IO therapy. Future research should examine influence of pt characteristics and PD-L1 expression on treatment choice and outcomes.

Association of immune microenvironment to response in treatment-naïve non-small cell lung cancer (NSCLC) samples with follow-up second-line immunotherapy data.

49 Background: Archival specimens collected months or years prior to starting immunotherapy are often used to identify patients for second line immune checkpoint inhibitor (ICI) treatment. PD-L1 expression and the immune microenvironment in these patients may have altered over time following multiple lines of failed standard of care (SOC) treatments. Methods: Formalin fixed paraffin embedded (FFPE) tumor samples, taken during resection performed as first line surgical treatment from a cohort of NSCLC patients (n = 18), were evaluated by Nanostring using the IO360 gene expression panel, and by immunohistochemistry (IHC) for CD3, CD8, PD-L1, CD68 and CD163. The resultant immune profiles were correlated with the clinical follow-up data for radiotherapy, SOC chemotherapy, and second line immunotherapy with the aim of understanding whether immune signatures predictive of response to ICI therapy may be identified in such samples. Results: Of the 18 cases, clinical follow-up data indicated objective response to ICI therapy for 4 patients, with the mean time from initial diagnosis to ICI treatment being 2.8 years (range: 0.4 to 8.5 years). Although pathologist PD-L1 IHC scores were not predictive of response, IHC image analysis data revealed significant increases in CD3 (2.3-fold) and CD8 (2.7-fold) T cell numbers in the responder population. In addition, although CD68+ macrophage frequencies did not differ significantly between responder and non-responder populations, reduced M2-like CD163+ macrophage/monocyte numbers were evident for responders. While the Tumor Inflammation Signature was not predictive of response, several gene expression signatures were significantly associated with response including increased abundance of CD8 T cells, cytotoxic cells, cytotoxicity, MHC class II antigen presentation and Melanoma-Associated Antigens (MAGE). Conclusions: Despite these patients having received various lines of radiotherapy and SOC chemotherapy prior to receiving immunotherapy, immune profiles associated with response to second line immunotherapy were detected in surgical first line resection samples.

Comparative efficacy of second-line treatments for advanced hepatocellular carcinoma: A network meta-analysis.

545 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and is often advanced at the time of diagnosis. This study conducted a network meta-analysis (NMA) to assess the comparative efficacy of second-line (2L) immunotherapy and tyrosine kinase inhibitors (TKIs) without biomarker selection for advanced HCC (aHCC), including nivolumab (NIVO) + ipilimumab (IPI), cabozantinib (CABO), regorafenib (REG), and placebo (PBO). Methods: Randomized trials for CABO and REG (CELESTIAL and RESORCE) were identified through a literature review and included in the NMA. NIVO (1mg/kg) + IPI (3mg/kg) (from CHECKMATE-040) was linked into the evidence network through a matching-adjusted indirect comparison (MAIC) vs. the PBO arm of the CELESTIAL trial. The CELESTIAL trial was chosen due to the similar study design and patient population as the CHECKMATE-040 trial. Clinically relevant characteristics were matched, which included age, sex, Barcelona clinic liver cancer stage, Eastern Cooperative Oncology Group status, α-fetoprotein level, and prior treatments. The NMA included CELESTIAL, RESORCE, and the MAIC results. Investigator-assessed ORR and hazard ratio (HR) of overall survival (OS) were compared in the NMA. Results: After matching the baseline characteristics in the MAIC, the ORR of NIVO+IPI was 30.4% and the HR vs. PBO was 0.35. In the NMA, NIVO+IPI had significantly higher ORR (31.2%) compared to TKIs and PBO (REG: 4.8%; CABO: 4.2%; PBO: 1.0%, differences are presented in Table). In addition, NIVO+IPI was associated with significantly prolonged OS vs. TKIs and PBO (HR: NIVO+IPI vs. REG: 0.56; NIVO+IPI vs. CABO: 0.46; NIVO+IPI vs. PBO: 0.35). Conclusions: The NMA showed that NIVO+IPI was associated with significantly higher ORR and prolonged OS compared to TKIs as 2L treatments for aHCC. [Table: see text]

Efficacy and predictive factors of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis.

Background:Immune checkpoint inhibitors (ICIs) have shown encouraging treatment efficacy for metastatic breast cancer in several clinical trials. However, response only occurred in a small population. Evidence predicting response and survival of patients with metastatic breast cancer following ICI treatment with existing biomarkers has not been well summarized. This review aimed to summarize the efficacy and predictive factors of immune checkpoint therapy in metastatic breast cancer, which is critical for clinical practice.Methods:PubMed, Embase, Cochrane Library, Web of Science, www.clinicaltrials.gov, and meeting abstracts were comprehensively searched to identify clinical trials. The outcomes were objective response rate (ORR), treatment-related adverse events (trAEs), immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS).Results:In this review, 27 studies with 1746 patients were included for quantitative synthesis. The pooled ORR was 19% [95% confidence interval (CI) = 12–27%]. Programmed death-ligand 1 (PD-L1)-positive patients had a higher response rate [odds ratio (OR) = 1.44, p = 0.01]. First-line immunotherapy had a better ORR than second-line immunotherapy (OR = 2.00, p = 0.02). Tumor-infiltrating lymphocytes (TILs) ⩾5% (OR = 2.53, p = 0.002) and high infiltrated CD8+ T-cell level (OR = 4.33, p = 0.006) were ideal predictors of immune checkpoint therapy response. Liver metastasis indicated poor response (OR = 0.19, p = 0.009). However, the difference was non-significant in ORR based on age, performance status score, lymph node metastasis, and lactate dehydrogenase (LDH) level. In addition, the PD-L1-positive subgroup had a better 1-year PFS (OR = 1.55, p = 0.04) and 2-year OS (OR = 2.28, p = 0.02) following ICI treatment. The pooled incidence during ICI therapy of grade 3–4 trAEs was 25% (95% CI = 16–34%), whereas for grade 3–4 irAEs it was 15% (95% CI = 11–19%).Conclusions:Metastatic breast cancer had modest response to ICI therapy. PD-L1-positive, first-line immunotherapy, non-liver metastasis, and high TIL and CD8+ T-cell infiltrating levels could predict better response to ICI treatment. Patients with PD-L1-positive tumor could gain more survival benefits from immune checkpoint therapy.

Anti-N-methyl-D-aspartate receptor encephalitis with accompanying ovarian teratoma in female patients from East China: Clinical features, treatment, and prognostic outcomes

PurposeThe association between anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDAR encephalitis) and teratoma is formally recognized. This study compared the clinical features, treatments and outcomes between female patients with or without accompanying teratomas and determined the potential influences of coexisting teratomas. MethodFifty-six female patients diagnosed with anti-NMDAR encephalitis were enrolled in two major tertiary hospitals in East China from January 2013 through March 2018 and were grouped as patients with or without teratoma. The clinical features were reviewed, and follow-up studies were performed. Comparisons were made between the two groups. ResultsPatients with teratoma reported fewer viral prodromes (p = 0.0085) and stronger positive intensity of anti-NMDAR antibodies in cerebrospinal fluid (CSF) (p = 0.0368), while nontumor patients tended to demonstrate lymphocytic pleocytosis in CSF (p = 0.0306). Seizure types varied between individuals, with complex partial seizures more common in teratoma patients (p = 0.0105). Nontumor patients frequently required combinations of first-line and second-line immunotherapy (p = 0.0014), which may be attributed to higher mRS scores at admission (p = 0.0300). Also, they had higher mean mRS scores since the 12-month follow-up and greater probability of relapse than did patients with teratomas (p = 0.0286). ConclusionsSymptomatology and auxiliary findings indicate that ovarian teratoma may be the immunologic trigger for anti-NMDAR encephalitis patients, while viral infection is likely to play a major part in pathogenesis for those without any detectable tumor. Overall, anti-NMDAR encephalitis patients with teratomas present with milder neurological symptoms and have better long-term outcomes after tumor removal.

Abstract A20: Gemcitabine primes the pancreatic tumor microenvironment for second-line immunotherapy

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6-12 months. As most patients present with disseminated disease, the majority are offered palliative chemotherapy. As there are no treatment strategies for patients who progress on chemotherapy, we explored the effects of long-term gemcitabine on the tumor microenvironment in order to identify potential therapeutic options in chemorefractory PDAC. Using a combination of mouse models and human-derived PDAC cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high-throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, gemcitabine led to large-scale alterations in the tumor secretome, namely by increasing the synthesis of CCL/CXCL chemokines and TGFβ-associated proteins. These secreted factors altered the composition of the tumor stroma, conferring drug resistance to cancer-associated fibroblasts in vitro. We therefore combined gemcitabine with anti-PD-1 in transgenic models of murine PDAC, which failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signal deficiency, gemcitabine and anti-PD-1 led to a robust CD8+ T cell-response and decrease in tumor burden. These results suggest that gemcitabine may prime PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation, but requires the inhibition of a TGFβ cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the management of gemcitabine-refractory PDAC. Citation Format: Daniel R. Principe, Matthew Narbutis, Sandeep Kumar, Alex Park, Navin Viswakarma, Matthew J. Dorman, Suneel D. Kamath, Hidayatullah G. Munshi, Ajay Rana. Gemcitabine primes the pancreatic tumor microenvironment for second-line immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A20.

EPSILoN: A Prognostic Score for Immunotherapy in Advanced Non-Small-Cell Lung Cancer: A Validation Cohort.

Background: Beyond programmed death ligand 1 (PD-L1), no other biomarkers for immunotherapy are used in daily practice. We previously created EPSILoN (Eastern Cooperative Oncology Group performance status (ECOG PS), smoking, liver metastases, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR)) score, a clinical/biochemical prognostic score, in 154 patients treated with second/further-line immunotherapy. This study’s aim was to validate EPSILoN score in a different population group. Methods: 193 patients were included at National Cancer Institute of Milan (second-line immunotherapy, 61%; further-line immunotherapy, 39%). Clinical/laboratory parameters such as neutrophil-to-lymphocyte ratio and lactate dehydrogenase levels were collected. Kaplan–Meier and Cox hazard methods were used for survival analysis. Results: Overall median progression-free survival and median overall survival were 2.3 and 7.6 months, respectively. Multivariate analyses for Progression-Free Survival (PFS) identified heavy smokers (hazard ratio (HR) 0.71, p = 0.036) and baseline LDH < 400 mg/dL (HR 0.66, p = 0.026) as independent positive factors and liver metastases (HR 1.48, p = 0.04) and NLR ≥ 4 (HR 1.49, p = 0.029) as negative prognostic factors. These five factors were included in the EPSILoN score which was able to stratify patients in three different prognostic groups, high, intermediate and low, with PFS of 6.0, 3.8 and 1.9 months, respectively (HR 1.94, p < 0.001); high, intermediate and low prognostic groups had overall survival (OS) of 24.5, 8.9 and 3.4 months, respectively (HR 2.40, p < 0.001). Conclusions: EPSILoN, combining five baseline clinical/blood parameters (ECOG PS, smoking, liver metastases, LDH, NLR), may help to identify advanced non-small-cell lung cancer (aNSCLC) patients who most likely benefit from immune checkpoint inhibitors (ICIs).