Survival Benefit Of Immunotherapy Research Articles

Role of immunotherapy in stage IV non-small cell lung cancer with liver metastasis: A NCDB analysis.

9046 Background: Despite approvals of immune checkpoint inhibitors in stage IV non-small cell lung cancer (NSCLC), survival benefit of immunotherapy (IO) in those with liver metastasis is controversial. Randomized controlled trials demonstrated conflicting results. Methods: Using National Cancer Database (NCDB), Stage IV NSCLC cases diagnosed in 2016-2017 with at least 30-day follow up were analyzed. Clinical demographics included age (20-69 vs. 70+), sex (male vs. female), race (whites vs. others), institution (academic vs. others), Charlson-Deyo score (0-1 vs. 2-3), year of diagnosis (2016 vs. 2017), Histology (adenocarcinoma NOS vs. other), brain metastasis (Yes vs. No), bone metastasis (Yes vs. No), liver metastasis (Yes vs. No). They were divided into liver-metastasis positive (LM+) vs. negative (LM-). Information regarding cancer treatment was limited to the first course of therapy, including surgery for primary lesion (Yes vs. No), radiation (Yes vs. No), multi-agent chemotherapy (Yes vs. No), and IO (Yes vs. No). Overall Survival (OS) analysis was performed using Kaplan-Meier curves and Log-rank tests. Cox proportional hazard model was used for multivariate analyses. A two-sided p-value < 0.05 was considered as significant. Results: A total of 13,594 LM+ and 69,885 LM- cases met eligibility and further analyzed. 2,944 and 15,553 patients were treated with IO, respectively. No significant association between use of IO and status of liver metastasis was observed (p = 0.124). The median OS in LM+ cases was significantly shorter than that in LM- cases (5.0 vs 8.8 months, respectively, p < 0.0001). Use of IO was associated with improved OS in both LM+ and LM- cohorts with similar HRs/p-values (0.62/ < 0.0001 and 0.64/ < 0.0001, respectively). Multivariate analysis demonstrated that use of IO had a significantly improved OS in both LM+ (HR = 0.69, p < 0.0001) and LM- (HR = 0.64, p < 0.0001) cohorts. The OS benefit of IO in LM+ cohort remained with propensity score matching analysis (mOS 9.0 vs. 4.4 months, HR = 0.62, p < 0.0001). Further exploratory analysis focusing on those treated with multiagent chemotherapy showed that the addition of IO improved OS in both LM+ (HR = 0.77, p < 0.0001) and LM- (HR = 0.79, p < 0.0001) cohorts. Conclusions: This retrospective study using one of the largest cancer databases suggests that use of IO improves OS of NSCLC patients with LM regardless of chemotherapy status, and its magnitude of OS benefit is similar to that in LM- patients. [Table: see text]

Plasma GDF15 levels associated with circulating immune cells predict the efficacy of PD-1/PD-L1 inhibitor treatment and prognosis in patients with advanced non-small cell lung cancer

PurposeAlthough increased plasma growth differentiation factor-15 (GDF15) levels have been reported in patients with various cancers, the predictive role of PD-1/PD-L1 inhibitors in advanced cancers remains unknown. This study aimed to investigate GDF15 levels as a predictive marker in advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors and analyze their association with immune cell populations.MethodsThis study included 87 patients with advanced NSCLC receiving anti-PD-1/PD-L1 inhibitors between March 2018 and May 2020. Blood samples were obtained immediately before and months after PD-1/PD-L1 inhibitor administration.ResultsThe objective response rate (ORR) was significantly higher in the low GDF15 than in the high GDF15 group (39.2% vs. 15.3%, P = 0.013). The median progression-free survival (PFS) was significantly longer in the low GDF15 than in the high GDF15 group (13.2 [95% CI 7.6–18.9] vs. 7.2 [95% CI 4.8–9.6] months, P = 0.048). Moreover, plasma GDF15 levels negatively correlated with PD-1+/CD8+ T cells (r = − 0.399, P = 0.003) and positively with PD-1+/Treg cells (r = 0.507, P < 0.001) and PD-1+Treg/CD4+ T cells (r = 0.439, P < 0.001). The ORR was significantly higher in the group with decreased GDF15 from baseline than in the increased GDF15 group (37.2% vs. 10.0%, P = 0.026). The median PFS was significantly longer in the decreased GDF15 group (14.8 [95% CI 10.4–19.2] vs. 5.9 [95% CI 2.8–9.0] months, P = 0.002). Plasma GDF15 levels were associated with PD-1+CD8+ T cells and PD-1+ Treg cells.ConclusionPlasma GDF15 could be a potential biomarker for predicting the efficacy and survival benefit of immunotherapy in advanced NSCLC.

Pathological complete remission in ALK-positive lung cancer patient after multiple lines of conversion therapy.

Traditional therapeutic approaches for the treatment of advanced non-small-cell lung cancer (NSCLC) are based on chemotherapy. However, the discovery and understanding of oncogenic driver alterations has led to the development of targeted therapies that have substantially improved patient outcomes. Still, to date, there have been no reports of patients with advanced anaplastic lymphoma kinase (ALK)-positive lung cancer achieving clinical complete response (cCR) in the systemic lesion and pathological complete remission (pCR) in primary lung lesion after multiple lines of conversion therapy. In this case, a 55-year-old man was diagnosed with ALK-positive, stage IV lung adenocarcinoma using immunohistochemistry and next generation sequencing (NGS) tests. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, were used respectively as first-line, second-line, and third-line therapy. The patient received treatment with crizotinib and achieved partial response (PR), but 5 months later the efficacy was evaluated as progressive disease (PD). Ceritinib was used as the second-line treatment, but the disease progressed 6 months later. Alectinib was used as the third-line treatment, but the efficacy was evaluated as PD. From April 2019 to November 2019, the patient received 4 cycles of induction chemotherapy with pemetrexed/carboplatin/bevacizumab and then switched to pemetrexed/bevacizumab as the fourth-line treatment, and received the fifth line treatment, cetuximab/paclitaxel liposome/nedaplatin, for 1 cycle, but the disease still progressed. Then the patient received the sixth line of treatment, camrelizumab/lorlatinib, for 9 antitumor cycles, resulting in PR. The patient underwent surgery followed by maintenance treatment with lorlatinib and achieved cCR. To our knowledge, this is the first documented case of cCR in a patient with ALK-positive advanced lung adenocarcinoma treated with multiple lines of therapy followed by surgical treatment. This case reveals the possible survival benefit of immunotherapy after multiple line treatment in ALK-positive advanced lung adenocarcinoma, indicating that it is possible find new therapeutic targets based on NGS molecular detection and provide precise therapeutic strategies for clinical practice when drug resistance or progression occurs in cancer therapy.

EPID-21. INCORPORATING RECEIPT OF STANDARD-OF-CARE AS A KEY VARIABLE IN POPULATION-BASED STUDY OF GLIOBLASTOMA SURVIVAL

Abstract Object Populational database research with real-world settings offers epidemiologic insight at scales that cannot be easily recapitulated, especially for rare cancers such as glioblastoma. However, most survival studies were conducted without consideration for whether the patients received the standard of care (SOC). METHODS Survival analysis was performed using the National Cancer Database (NCDB) and stratified for Methyl-guanine-methyl transferase (MGMT) promotor methylation. Glioblastoma patients age &amp;lt; 40 were excluded to minimize the prognostic impact of isocitrate dehydrogenase (IDH) mutations. SOC was defined as the receipt of chemotherapy and radiation within 2-6 weeks of surgical biopsy or resection. Sensitivity analyses were performed allowing chemotherapy and radiation start date to differ by 0, 3, 5, and 10 days. RESULTS Within the NCDB (N = 11231), 54.7% of newly diagnosed glioblastoma patients did not receive SOC. The median survival time (MST) estimates were significantly shorter for all glioblastoma patients (10.9, IQR: 4.3-21.5, months) relative to SOC treated patients (15.3, IQR: 8.6-26.2, months; p &amp;lt; 0.001). The MST estimates remain stable in sensitivity analysis allowing for 0, 3, 5, and 10-day discrepancy between chemotherapy and radiation start date. These results were recapitulated using the SEER-Medicare database. The MST estimates for MGMT methylated and unmethylated glioblastoma patients after SOC in the NCDB were 21.0 and 14.5-mo, respectively. The overall and MGMT-specific survival estimates mirror those reported by the SOC arms of five recent randomized controlled studies. Analysis of all glioblastoma patients indicates survival benefit of immunotherapy (HR: 0.90, p = 0.020) while such benefit was absent in SOC treated patients (HR: 0.97, p = 0.644) - with the latter observation more reflective with trial results and clinical experiences. CONCLUSION Survival analysis in the populational database study can be misleading without information on the receipt of SOC.

1637P Impact of immune-related adverse events (irAEs) and survival (OS) in a cohort of MPM patients (p) treated with immunotherapy (IT)

Studies in solid tumors reported that p treated with IT who developed irAEs presented favorable OS. CheckMate-743 trial demonstrated survival benefit of IT over chemotherapy in 1st line. In a post-hoc analysis on 52 p who discontinued treatment due to irAEs, the survival benefit was not negatively impacted. We aimed to assess the impact of irAEs and survival outcomes in our series of p treated with IT.

First-line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non-small cell lung cancer with EGFR exon 20 insertions: Real-world evidence from China.

Currently, survival benefit of immunotherapy in advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins) is controversial, though it generally indicates poor response and activity. Compared with standard chemotherapy in combination with bevacizumab, first-line chemotherapy plus immune checkpoint inhibitor (ICI) in advanced NSCLC with EGFR ex20ins remains elusive and lacks real-world evidence. A retrospective real-world study was conducted to evaluate clinical outcomes of chemotherapy alone (C), chemotherapy plus ICI (C + I), or chemotherapy plus angiogenesis inhibitors (C + A) as first-line strategies for advanced NSCLC patients with EGFR ex20ins. Investigator-assessed response and survival outcomes were compared between subgroups. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to reveal concomitant alterations and explore the molecular landscape of ex20ins. A total of 164 patients were screened, identifying 35 kinds of ex20ins, and 122 cases treated with C, C + I, and C + A were finally included in the first-line analysis. C + A achieved much better objective response rate (ORR, 38.1% vs. 18.2%) and significant progression-free survival (PFS) benefit compared with C (median, 7.73 vs.5.93 months, HR=0.60, 95% CI: 0.40-0.90, p=0.014), and it showed similar ORR (38.1% vs. 40.0%), but higher disease control rate (DCR, 96.8% vs. 80.0%) and numerically longer median PFS (7.73 vs. 6.53 months, HR=0.83, 95% CI: 0.44-1.56, p=0.30) than C + I. There was no PFS difference between C + I and C, despite of PD-L1 expression or tumor mutational burden. KEGG analysis revealed concomitant upregulation of PI3K/AKT signaling might mediate intrinsic resistance to ICI in ex20ins. First-line chemotherapy plus angiogenesis inhibitors might yield more survival benefits than chemotherapy alone for NSCLC with EGFR ex20ins, whereas, it suggests that chemotherapy in combination with ICI might not obtain a better survival benefit for this subset of patients. Activation of PI3K/AKT signaling might mediate intrinsic immunosuppression in NSCLC with EGFR ex20ins.

The survival outcomes of the metastatic renal cell carcinoma with rhabdoid differentiation in immunotherapy era: Princess Margaret Cancer Center experience.

333 Background: Patients (pts) diagnosed with metastatic renal cell carcinoma (mRCC) with rhabdoid differentiation (RD) have a poor prognosis due to aggressive tumor behavior and inherent treatment resistance to targeted therapies. However, recent data has demonstrated the survival benefit of immunotherapy (IO) in mRCC. Here, we report survival outcomes of pts with mRCC with RD treated with targeted therapy and or IO. Methods: This retrospective survival analysis was performed in pts with mRCC and RD treated with targeted treatment and IO at Princess Margaret Cancer Centre (PM), Toronto. Demographics, disease characteristics and survival outcomes were collected. Overall survival (OS) was calculated using the Kaplan-Meier method (log-rank). OS hazard ratio (HR) were calculated using cox proportional hazards model. IBM SPSS Statistics v26 was used to conduct statistical analyses. Results: We identified 474 pts diagnosed with mRCC at PM between 2002 and 2019. A total of 57 (12%) pts diagnosed with mRCC had RD and were treated with targeted and or IO agents. Of these, 42 (73.7%) pts had pure RD and 15 (26.3%) pts had mixed RD and sarcomatoid features. Median age was 62 yrs (35-86yrs) and 42 (73.7%) were male. Overall, as per the IMDC score, 5(8.8%), 27(47.4%) and 25(43.8%) pts were categorized as good, intermediate, and poor risk, respectively. In total, 34 (59.6%) pts were treated with targeted therapy only during their first and second line treatment course and 23 (40.4%) pts received IO alone or in combination with targeted treatment in the first or second line. With a median follow up of 53.4 months (range, 38.3-68.4 months), the median OS for the whole mRCC with RD cohort was 23.1 months (95% CI: 14.6-31.5). The median OS in all pts treated with targeted therapy only vs IO receipt was 13.1 months (95%CI: 5.4-20.8 months) vs not reached; p = 0.026, respectively. HR for OS was 0.44 (95%CI: 0.22-0.93; p = 0.03) favoring IO receipt. Conclusions: While the number of pts included in our retrospective review was small, our analysis has suggested that pts with mRCC and RD have poor survival outcomes that may be improved with IO treatment. RD is a histopathological feature that could identify pts who may benefit from IO therapy. Further analysis is needed to explore the impact of RD on IO treatment response.

Survival outcomes of metastatic renal cell carcinoma (mRCC) with sarcomatoid differentiation (SD): A single-institutional experience and literature meta-analysis.

332 Background: Patients (pts) with mRCC with SD have unfavorable outcomes and poor prognosis due to aggressive tumor behavior. Chemotherapy and targeted treatment are often of little benefit. However, recent studies have shown a survival benefit of immunotherapy (IO). Here, we report survival outcomes of pts with mRCC with SD treated with first line IO or chemotherapy or targeted treatment. In addition we performed a meta-analysis of recent practice changing phase III, IO trials in mRCC. Methods: This retrospective survival analysis was performed in pts with mRCC with SD treated with IO or non-IO treatment at Princess Margaret Cancer Centre (PM), Toronto. Demographics, disease characteristics and survival outcomes were collected. Progression free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method (log-rank). PFS and OS hazard ratios (HR) were calculated using cox proportional hazards model. We identified the major, practice changing clinical trials that reported survival outcomes of mRCC with SD treated with IO and performed a random-effects meta-analysis of HR for PFS and OS. We compared these pooled results to our single institution experience. Results: We identified 474 pts diagnosed with mRCC at PM between 2002 and 2019. In total, 44 (9.3%) pts had mRCC with SD who were treated with IO or non-IO. Of these, 29 (65.9%) pts had pure SD and 15 (34.1%) pts had mixed rhabdoid and SD features. Median age was 59.6 years (36-78) and 33 (75%) were male. Overall, as per the IMDC score, 3(6.8%), 21(47.7%) and 20(45.5%) pts were categorized as good, intermediate, and poor risk, respectively. Eight (18.2%) pts were treated with IO as first line of treatment, and 36 (81.8%) pts received non-IO. With a median follow up of 64.8 months (range, 45.7-83.8 months), the median OS for the whole mRCC with SD cohort was 15.6 months (95% CI: 8.6-22.5). The median OS in all pts treated with IO vs non-IO was not reached vs 10.3 months (95%CI: 1.49-19.1 months; p = 0.005), respectively. The HR for OS was 0.1 (95%CI: 0.01-0.78; p = 0.023) favoring IO receipt. The median PFS in all pts treated with IO vs non-IO was 24 months (95%CI: non-estimable) vs 5.4 months (95%CI: 2.9-7.8 months; p = 0.021), respectively. The HR for PFS was 0.3 (95%CI: 0.11-0.89; p = 0.03) favoring IO receipt. We identified through meta-analysis five phase III clinical trials reporting PFS and OS in pts with mRCC with SD who received IO. The overall HR for OS and PFS for the total cohort were 0.55 (95%CI: 0.41-0.74), and 0.53 (95%CI: 0.42-0.67), respectively. Conclusions: Our meta-analysis has confirmed the benefit of IO agents in mRCC with SD. While the numbers included in this retrospective review were small, they have provided real world corroboration of the trial findings. Pts with mRCC and SD benefit from IO treatment, which should be considered the standard of care for these patients.

Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers

BackgroundThe gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims...

Efficacy of chemotherapy for malignant pleural mesothelioma according to histology in a real-world cohort

CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line in MPM with some differences in the efficacy of chemotherapy according to histology. The objective of this study is to characterize the impact of chemotherapy according to histology in patients diagnosed with MPM at our institution. Clinical records of all MPM patients diagnosed at Vall d’Hebron University Hospital between November 2002 and April 2020 were reviewed. Associations between clinical variables and outcomes were assessed with Cox regression models. Survival data were calculated by the Kaplan–Meier method. 189 patients were included with 76% of tumors classified as epithelioid subtype. First line chemotherapy was offered to 85% of patients. Median survival in overall population was 21.3 months (95% CI 17.2–24.3). We found that patients with epithelioid tumors had better overall survival (OS) and progression free survival (PFS). Median OS of epithelioid patients treated with first line chemotherapy was 26.7 months versus 15.0 months in non-epithelioid patients (HR 2.25 CI 95% 1.4–3.4; p < 0.001). Median PFS for patients with epithelioid tumors treated with chemotherapy was 4.8 months versus 3.6 months in non-epithelioid (HR 1.5 CI 95% 1.0–2.3; p = 0.03). The improvement of outcomes in patients with epithelioid histology was detected in patients treated with cisplatin or carboplatin. Histology was not a predictive factor for the platinum agent sensitivity (p of interaction PFS = 0.09, p of interaction OS = 0.65). In our series, patients with non-epithelioid tumors presented worse prognosis. Although epithelioid tumors exposed to cisplatin had higher PFS, histology was not a clear predictor of chemotherapy efficacy.

SY10-4 Clinical biomarkers to predict the efficacy of immune checkpoint inhibitors

The survival benefit of immunotherapy using the PD-1/PD-L1 inhibitors and/or anti-CTLA-4 antibody has been demonstrated across multiple cancer types. Furthermore, the combination of chemotherapy and immunotherapy has been emerged in our clinical practice. Immunotherapy has become an essential part of the current cancer therapy. The biomarkers to predict the efficacy of immunotherapy may help to identify the patients who can get the greatest therapeutic effects. PD-L1 expression and tumor mutation burden are the most promising predictive biomarkers in identifying who have achieved a response after being treatment with immunotherapy. However, the predictive value of these biomarkers remains insufficient. Recently, the variety of investigation for predictive biomarkers has been reported, such as neutrophil to lymphocyte ratio, microbiome, and occurrence of immune-related adverse events. I want to review these clinical biomarkers in JSMO 2021 meeting.

Analysis of chemotherapy efficacy according to histology in malignant pleural mesothelioma (MPM) patients (p).

e20563 Background: MPM is a highly aggressive pleural tumor associated with asbestos exposure and with limited survival despite systemic therapy. Histology is a prognostic factor and recently CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line with some differences in the efficacy of chemotherapy according to histology. However, randomized trials who led to the approval of antifolate in mesothelioma did not include analysis of outcomes by histology. The objective of this study is to characterize the impact of chemotherapy according to histology in p with MPM at our institution. Methods: We review 189 MPM p diagnosed at Vall d´Hebron University Hospital between November 2002 and April 2020. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: Patient’s characteristics: median age 68 years (y) (45-88 y), males: 70%, performance status (PS)1: 69%, asbestos exposure: 75%, epithelioid subtype: 76%. First line chemotherapy was offered to 85% of p (66% cisplatin-pemetrexed and 27% carboplatin-pemetrexed). Median overall survival (OS) in overall population was 21.3 m (95%CI17.2-24.3). Epithelioid histology, PS 0, neutrophil-lymphocyte ratio &lt;5 and treatment with cisplatin vs carboplatin were associated with significant improvements in OS (p&lt;0.001). When we analyzed the survival of patients who received first line chemotherapy according to histology, we found that patients with epithelioid tumors had better PFS and OS. Median PFS for p with epithelioid tumors treated with chemotherapy in first line was 4.8 m versus 3.6 months non-epithelioid (HR1.5 CI95% 1.1-2.3; p=0.03). OS of epithelioid p treated with first line chemotherapy was 26.7 m versus 15.0 m non-epithelioid patients (HR2.25 CI95% 1.4-3.4; p&lt;0.001). We analyzed if the differences in survival according to histology were due to type of systemic treatment received (Table). Conclusions: In our series, p with non-epithelioid tumors presented worse prognosis. We confirmed histology is a prognostic factor with better OS for p with epithelioid tumors. Moreover, we demonstrated better efficacy of chemotherapy in epithelioid tumors, although histology is not a predictive factor for the platinum agent sensitivity (p of interaction PFS=0.09, p of interaction OS= 0.65).[Table: see text]

The intra-class heterogeneity of immunophenotyping and immune landscape in oesophageal cancer and clinical implications

Background The response rate and survival benefit of immunotherapy vary among patients, implying specific immune status of an individual could be associated with the effect of immunotherapy. However, in-depth studies of immune subtypes (ISs), immune landscape and tumour microenvironment of oesophageal cancer (ESCA) and their clinical implications are less reported. Methods We first accessed data from publicly available databases and preprocessed it based on a standard protocol. Then, ISs were identified by unsupervised learning. Thereafter, the association of these ISs and tumour mutation burden (TMB), biomarkers of chemotherapy-induced immune response, tumour markers were also assessed. In addition, the immune characteristics, immune landscape, co-expression network of immune genes, and clinical implications were visualized and analysed. Results We identified three immunoclusters based on immune-associated genes with intra-class heterogeneity and prognostic value. Cluster-specific associations with TMB, markers of chemotherapy-induced immune response, and tumour markers were revealed. A 4-gene signature (risk score= −0.16514291×BHLHE22−0.03964046×MXRA8−0.15242778×SLIT2−0.05553572×SPON1) based on co-expressed genes in the immunoclusters was developed and externally validated. Conclusions In summary, we identified clinically relevant immunoclusters in both adenocarcinoma and squamous cell carcinoma of oesophagus, revealing the necessity of assessing the complexity and diversity of immune microenvironment for cancer immunotherapy.

Efficacy and safety of immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma (HCC): A systematic review and meta-analysis of randomized clinical trials (RCTs).

e16631 Background: ICIs have ushered a new era in cancer therapy, but their efficacy in HCC is uncertain. Single-arm phase II studies with sorafenib-refractory patients have suggested clinical activity of nivolumab and pembrolizumab, which have become FDA-approved therapies. Nevertheless, the overall effect of ICIs compared with the standard of care (SOC) in unresectable HCC patients is still unknown. Methods: We systematically searched PubMed, Cochrane Library, Web of Science, LILACS, and ASCO and ESMO Meeting Proceedings in the last 10 years for RCTs that have compared the efficacy of ICIs versus the SOC in the systemic therapy of unresectable HCC. Outcomes of interest included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3-4 treatment-related adverse events (TRAEs). A summary hazard ratio (HR) of OS and PFS was calculated using 95% confidence intervals (CI) by fixed-effects model. The likelihood of ICIs being associated with ORR and TRAEs was expressed by odds ratio (OR) and 95% CI using a random-effects model (PROSPERO ID 162599). Results: Of the 2,334 studies yielded by the search, 3 studies were retained (KEYNOTE-240, CheckMate-459, and IMbrave150), totaling 1,657 patients (985 ICIs versus 672 SOC). Two studies compared ICIs versus sorafenib in 1st line setting, and one study compared with placebo in 2nd line. The ICIs studied were pembrolizumab, nivolumab, and atezolizumab. RCTs with anti-CTLA4 have not been reported. Two studies evaluated ICIs as monotherapy, and one study investigated the association with bevacizumab. Compared with the SOC (sorafenib in 1st line or placebo in 2nd line), ICIs significantly improved OS (HR: 0.78, 95% CI 0.68 – 0.89, p = 0.0002), PFS (HR: 0.79, 95% CI 0.71 – 0.89, p &lt; 0.0001), and ORR (OR: 2.82, 95% CI 2.02 – 3.93, p &lt; 0.0001). ICIs were associated with a lower probability of grade 3-4 TRAEs when compared to sorafenib (OR: 0.44, 95% CI 0.20 – 0.96, p = 0.04). No significant heterogeneity was found among studies when OS and ORR were analyzed, but it was found in the analysis of PFS and TRAEs. Conclusions: ICIs demonstrated superior efficacy and safety compared to the standard therapy of patients with unresectable HCC. The analysis of ICIs as monotherapy and combination therapy increased the heterogeneity among studies. The association of anti-angiogenic therapy with ICIs improved the survival benefit of immunotherapy and should become the new SOC in the 1st line systemic therapy of unresectable HCC.

Analysis of Heterogeneity in Survival Benefit of Immunotherapy in Oncology According to Patient Demographics and Performance Status: A Systematic Review and Meta-Analysis of Overall Survival Data.

Immunotherapy (IO) has become standard of care (SOC) for many advanced malignancies, although identifying patients likely to benefit remains difficult. We sought to assess whether demographic factors are associated with response to IO, compared with SOC systemic therapy, using stratified meta-analysis. A systematic review of MEDLINE, PubMed, Embase, and Scopus from inception to October 2, 2018. Randomized controlled trials comparing IO to SOC in patients with advanced solid organ malignancies were included if results were stratified by age, performance status (PS), or race, assessing overall survival (OS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each group using random-effects models independently. We identified 21 eligible randomized controlled trials, including 20 stratified by age, 17 by PS, and 4 by race. Patients with PS 0 (HR, 0.74; 95% CI, 0.63-0.86) and PS≥1 (HR, 0.75; 95% CI, 0.68-0.83) had similar OS benefits from IO compared with SOC (P=0.80). There was no difference on the basis of patient race (white vs. nonwhite) (P=0.46). IO demonstrated an OS benefit for younger (below 65 y: HR, 0.73; 95% CI, 0.65-0.82) and older (65 y and above: HR, 0.79; 95% CI, 0.71-0.88) patients with no difference between age groups (P=0.27). Among prespecified subgroup analyses, there was significant effect modification in 2 subgroups: younger patients in the first-line setting (P=0.03) and those receiving anti-CTLA-4 drugs (P=0.05). When examining OS using stratified meta-analysis, we did not demonstrate significant differences in IO efficacy according to patient age, PS or race, though data on race were sparse.

Improved Survival with Immunotherapy but Lack of Synergistic Effect with Radiation for Stage IV Melanoma of the Head and Neck

Prospective randomized studies have demonstrated a survival benefit of immunotherapy in stage IV cutaneous melanoma. Some retrospective studies have hypothesized a synergistic effect of radiation and immunotherapy. Our objective was to identify whether there is a survival benefit for patients treated with radiation and immunotherapy in stage IV cutaneous melanoma of the head and neck (CMHN). The National Cancer Database was used to identify patients with stage IV CMHN between 2012 and 2014. These patients were stratified based on receipt of radiation and immunotherapy. Adjusted Cox regression was used to analyze overall survival. A total of 542 patients were identified with stage IV CMHN, of whom 153 (28%) patients received immunotherapy. Receipt of immunotherapy (hazard ratio [HR] 0.69, P = 0.02) and negative LNs (HR 0.50, P = 0.002) were independently associated with improved survival, whereas radiation conferred no survival benefit (HR 1.17, P = 0.26). Patients who received immunotherapy without radiation were associated with significantly improved survival compared with those who received immunotherapy with radiation (P < 0.0001). However, of patients who received radiation, the addition of immunotherapy did not seem to improve survival (P = 0.979). In stage IV CMHN, immunotherapy confers a 32 per cent survival benefit. The use of immunotherapy in patients who require radiation, however, is not associated with improved survival.

Association Between Smoking and Survival Benefit of Immunotherapy in Advanced Malignancies: A Systematic Review and Meta-Analysis.

Smoking is associated with an increased tumor mutational burden. As tumor mutational burden has been shown to correlate with response to immunotherapy (IO), we hypothesized that a history of smoking may be associated with better response to IO. We utilized a systematic review with stratified meta-analysis of randomized clinical trials of IO versus standard of care in patients with advanced solid organ malignancies. Among 9 relevant studies, we found no significant difference in the benefit of IO, compared with other systemic therapies, between ever smokers (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.58-1.04; P=0.09) and never smokers (HR, 0.75; 95% CI, 0.67-0.86; P<0.0001) (test for difference P=0.83). We also observed no significant difference between current (HR, 0.92; 95% CI, 0.63-1.34; P=0.66; I=67%) and never smokers (HR, 0.74; 95% CI, 0.59-0.93; P=0.01; I=46%) (test for difference P=0.35). Stratified meta-analysis demonstrates that smoking status is not significantly associated with the response to IO in the treatment of advanced solid organ malignancies.

Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers

Sex-associated differences in immune response are known, but a meta-analysis suggested men, compared with women, derive greater value from immunotherapy for advanced solid-organ malignant neoplasms. However, methodologic concerns and subsequent trials have placed these results in doubt. To perform an updated, comprehensive meta-analysis that assesses the efficacy of immunotherapy in advanced cancers according to patient sex. A systematic review of studies (n = 23) indexed in MEDLINE (PubMed), Embase, and Scopus from inception of these databases to October 2, 2018, was conducted. Randomized clinical trials that compared immunotherapy with standard of care in the treatment of advanced solid-organ malignant neoplasms were included if overall survival was reported as an outcome and if data stratified by patient sex were available. Observational studies, editorials, commentaries, review articles, non-peer-reviewed publications, studies that compared various immunotherapy regimens, studies that reported other measures of oncologic response, and studies that reported subgroup analyses for 1 sex only were excluded. Overall survival, with a test for heterogeneity between women and men, to assess the null hypothesis that no difference in the survival advantage of immunotherapy exists by patient sex. This meta-analysis included 23 randomized clinical trials that reported on 9322 men (67.9%) and 4399 women (32.1%); the age of most patients was in the 70s. An overall survival benefit of immunotherapy was found for both men (hazard ratio [HR], 0.75; 95% CI, 0.69-0.81; P < .001) and women (HR, 0.77; 95% CI, 0.67-0.88; P = .002). Random-effects meta-analysis of study-level differences in response to immunotherapy demonstrated no statistically significant difference between the sexes (I2 = 38%; P = .60). Subgroup analyses according to disease site, line of therapy, class of immunotherapy, study methodology, and representation of women recapitulated these findings. Stratified analyses demonstrated no statistically significant association of patient sex with the efficacy of immunotherapy in the treatment of advanced cancers using overall survival as the outcome.

Nonconventional responses and survival benefit of immunotherapy in advanced lung cancer.

e14572 Background: Objective response rates (ORR) utilizing RECIST or WHO criteria have been traditionally used as clinical endpoints to assess efficacy of cytotoxic chemotherapy. However in the era of immunotherapeutic agents, response rate assessment can be misleading due to nonconventional responses resulting in premature discontinuation of treatment. Wolchok et al proposed immune-related response criteria (irRC) to assess immune responses in melanoma. He also noted that stable disease which is not indicative of antitumor activity could be a potential surrogate marker of better clinical outcome. Brahmer et al reported nonconventional pattern of responses with Nivolumab in lung cancer. Methods: A retrospective chart review was done to assess differences in responses utilizing both RECIST v1.1 and irRC criteria in lung cancer patients treated with Nivolumab. Patients who received minimum of 4 cycles of Nivolumab were included in the study. The CT scans were reviewed by a senior radiologist. We reviewed 64 patients treated with Nivolumab between 4/30/2015 to 6/21/2016 and 30 patients were found eligible. Results: Patient characteristics. Male 53%; median age 61 years; squamous 47%; adeno 40%; small cell 13%; Median cycles of Nivolumab 6. Response rates utilizing both criteria was essentially similar with only 2 patients showing dis-concordant responses (6.6%). We utilized RECIST responses criteria for further analysis. Partial response (PR) 2/30; stable disease (SD) 12/30; progressive disease (PD) 15/30 and not evaluable (NE) 1/30. ORR 6.6%. Kaplan–Meier curve was used to analyze difference in survival between patients with PR+SD and PD. The median survival for PD was 9 months and PR+SD was not reached at median follow up of 1 year. Overall survival at 1 year for PD 33% and PR+SD 60% (p = 0.048). Hazard ratio for PD was 3.060 (p = 0.60). Conclusions: Patients with stable disease had a better survival and should be considered as responders though traditionally not included in the ORR. However irRC did not help in differentiating nonconventional immune responses in lung cancer patients. [Table: see text]