High baseline lymphocyte count is a predictive biomarker of prolonged time to progression in patients with advanced solid tumors receiving checkpoint inhibitors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14532-e14532
Author(s):  
Mariangela Maltese ◽  
Stefano Panni ◽  
Silvia Lazzarelli ◽  
Matteo Brighenti ◽  
Federica Negri ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Lymphocyte Count ◽  
Checkpoint Inhibitors ◽  
Absolute Lymphocyte Count ◽  
Predictive Biomarker ◽  
Rank Test ◽  
Advanced Solid Tumors ◽  
Time To Progression ◽  
Neutrophil Lymphocyte Ratio ◽  
Kaplan Meier

e14532 Background: Biomarkers predicting response to checkpoint inhibitor are needed to better select patients most likely to benefit from treatment. We observed that baseline absolute lymphocyte count (ALC) can predict durable responses to anti-PD-1 antibodies in various malignancies. Methods: This is a retrospective analysis of patients with advanced solid tumors treated with anti-PD-1 antibodies. Pembrolizumab was given at 2 mg/kg every 3 weeks, Nivolumab at 3 mg/kg every 2 weeks. Peripheral ALC and absolute neutrophil count (ANC) from routine safety labs were collected at baseline, cycle 4 and cycle 8. Evaluation of response was based on irRECIST. Neutrophil lymphocyte ratio [NLR = ANC/ALC] was stratified by ≤4 or > 4. The lymphocyte count cutoff was 1000/mm3. Time to progression (TTP) and overall survival (OS) were estimated with the Kaplan-Meier method. Differences between groups were estimated with the log rank test. Results: We have retrospectively evaluated 40 patients with unresectable stage III/IV Non Small Cell Lung Cancer (squamous n. 17; 42.5%, adenocarcinoma n. 7; 17.5%), Malignant Melanoma (n.11; 27.5%), Renal Cell Carcinoma (n.5; 12.5%) treated with anti-PD-1 antibodies. 6 pts (15%) received treatment as 1st line, 14 pts (35%) as 2nd line, 20 pts (15%) as ≥ 3rd line. We observed a 29% partial response (PR), 31% stable disease (SD) and 40% progressive disease (PD). The overall response rate (ORR) was 29% [I.C. 95% 13-42]. Median TTP was 5.5 months [IC 95% 3.3-NR]. Median OS was not reached. Pts with baseline ALC ≥1000/mm3 had significantly longer TTP (median value not reached), compared with those who had ALC < 1000/mm3 (median TTP 2.8 months), p = 0.01. There was also a trend for longer TTP in patients with NLR < 4 vs ≥4 (4.9 vs 10.5 months, p 0.44). Conclusions: In our observation baseline ALC ≥1000/mm3 is a predictive biomarker of prolonged TTP in patients treated with anti-PD-1 antibodies. The potential predictive value of this test should be prospectively validated.

Abstract 13352: Decreased Absolute Lymphocyte Count and Increased Neutrophil Lymphocyte Ratio With Immune Checkpoint Inhibitors-associated Myocarditis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zsofia D Drobni ◽  
Amna Zafar ◽  
Leyre Zubiri ◽  
Daniel Zlotoff ◽  
Raza Alvi ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Lymphocyte Count ◽  
Checkpoint Inhibitors ◽  
Absolute Lymphocyte Count ◽  
Cardiac Events ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Adverse Cardiac Events ◽  
Lower Blood

Introduction: Myocarditis due to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune-related adverse event (irAE). Hypothesis: Limited data have suggested an association between baseline and on-treatment absolute lymphocyte count (ALC) and neutrophil lymphocyte ratio (NLR) and the development of other irAEs; there are no data characterizing the role of ALC and NLR in ICI-associated myocarditis. Methods: This was a case control study of 55 patients with ICI myocarditis and 55 controls without any post-ICI irAEs. We leveraged clinical testing where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events (MACE) was also tested. Results: In those who developed myocarditis, there was a decrease in ALC from baseline (1.6 K/μL, IQR 1.1-1.9) to admission (1.1 K/μL, IQR 0.7-1.3, p<0.001, Panel A). Similarly, among those who developed myocarditis, there was an increase in NLR from baseline (3.5, IQR 2.3-5.4) to admission (6.6, IQR 4.5-14.1, p<0.001, Panel B). There was no change in patients treated with an ICI who did not develop myocarditis. Among those who developed myocarditis, a greater decrease in ALC or increase in NLR was associated with a higher heart rate and a lower blood pressure at admission. In follow-up, there were 20 events; larger decreases in ALC or increases in NLR were associated with MACE (Panel C and D). Conclusions: A reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR were associated with subsequent MACE.

Hyperprogressive disease (HPD) in head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint inhibitors (ICI).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6029-6029 ◽  
Author(s):  
Salvatore Alfieri ◽  
Roberto Ferrara ◽  
Giuseppina Calareso ◽  
Stefano Cavalieri ◽  
Francesca Platini ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Subsequent Treatment ◽  
Smoking History ◽  
Rank Test ◽  
Neutrophil Lymphocyte Ratio ◽  
Kaplan Meier ◽  
Hyperprogressive Disease ◽  
Definition Of ◽  
Ecog Ps

6029 Background: HPD was described in 9% of cancer patients (pts) treated in phase I trials, in 13.8% of advanced non-small cell lung cancer and 29% of 34 HNSCC pts upon ICI. A better definition of the hallmarks and survival outcomes of HPD pts in a larger cohort of HNSCC is still lacking. Methods: We retrospectively analyzed all advanced HNSCC pts treated with ICI at our Institution between October 2014 and December 2018. Three scans, performed before ICI, at baseline and at first evaluation during ICI, were assessed according to RECIST 1.1. Tumor Growth Kinetics (TGK) pre- (TGKpre) and post-baseline (TGKpost) were measured as previously reported (Saâda-Bouzid E, Ann Oncol 2017). Pts were defined HPD if they had progression at first radiological evaluation and TGKpost/TGKpre ≥2. Correlation between HPD and clinical characteristics was performed by Fisher or t-student test. Median overall survival (mOS) and progression free survival (mPFS) were estimated using the Kaplan-Meier method and compared between HPD and non-HPD using the log-rank test. Results: Ninety pts were eligible: 18% were female, 4% had ECOG PS ≥ 2, 73% smoking history, 37% oropharyngeal cancer (61% HPV+), 65% locoregional disease (89% previously irradiated), 54% received combined immunotherapy, 75% in ≥ 2nd line. Two out of 90 pts had TGKpre = 0 and were not evaluable for TGK ratio. HPD was observed in 7.9% (7/88) of pts. HPD pts were significantly younger compared to non-HPD pts (median age 53 ± 3.7 vs 63.3 ± 0.9 years, p = 0.002) and had a significantly higher median neutrophil-lymphocyte ratio (NLR) (11.5 ± 3.5 vs 6.4 ± 0.4, p = 0.004). Overall, mOS and mPFS were 7.5 (95% CI: 4.2-10.8) and 2.2 months (95% CI: 0.9-3.4), respectively. At a median follow-up of 20.9 months (95% CI: 19-22.8), HPD pts had a significantly worse mPFS compared to non-HPD pts [1.8 (95% CI: 1.5-2.2) vs 3.5 (95% CI: 2.2-4.8) months; p = 0.001]. HPD correlated with a not significant trend in lower mOS compared to non-HPD group [3.7 (95% CI: 2.4-5.1) vs 8.3 (95% CI: 4.1-12.5) months; p = 0.348]. Three (43%) out of 7 HPD pts early switched to chemotherapy after PD to ICI having a mOS of 8.1 months (range 3.7-25.3). Excluding these 3 pts, HPD correlated with a significantly worse mOS compared to non-HPD [2.6 (95% CI: 1.9-3.3) vs 8.3 (95% CI: 4.1-12.5) months; p = 0.006]. Conclusions: HPD was identified in 7.9% of HNSCC and correlated with younger age and higher NLR. HPD pts who did not receive a subsequent treatment had poorer mPFS and mOS. The assessment of HPD in a control cohort of advanced HNSCC upon standard chemotherapy is ongoing.

Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21032-e21032
Author(s):  
Xuanzong Li ◽  
Linlin Wang
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Rank Test ◽  
Wild Type ◽  
Exact Test ◽  
Entire Cohort ◽  
Kaplan Meier ◽  
Tumor Mutational Burden ◽  
The Difference ◽  
Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

Tissue tumor mutational burden (TMB) as a biomarker of efficacy with immune checkpoint inhibitors (ICI) in metastatic gastrointestinal (mGI) cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14559-e14559
Author(s):  
Robert William Lentz ◽  
Tyler Friedrich ◽  
Junxiao Hu ◽  
Alexis Diane Leal ◽  
Sunnie S. Kim ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Continuous Variable ◽  
Tumor Type ◽  
Logistic Regression Models ◽  
Kaplan Meier ◽  
Academic Center

e14559 Background: While TMB is very dependent on methodology, tissue TMB-H (≥10 mutations/megabase) may predict benefit with ICIs. Pembrolizumab received tissue-agnostic approval for TMB-H unresectable cancers in 2020, but little is known about TMB as a predictive biomarker in mGI cancers. We hypothesized that tissue TMB will correlate with efficacy of ICIs in mGI cancers. Methods: A retrospective chart review identified patients with mGI cancers who received an anti-PD-(L)1 drug and had known TMB at a single academic center from 2012 to 2020. The association of TMB with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was analyzed using the Fisher’s exact and Log-rank tests. Survival curves were generated using the Kaplan-Meier method. Cox proportional hazard and logistic regression models were used to adjust for microsatellite status. Significance was prespecified at 0.05. Results: 83 patients were identified and included. The most common cancer types were colorectal adenocarcinoma (AC, n = 29), esophageal/gastric AC (n = 21) and SCC (n = 4), cholangiocarcinoma (n = 11), anal SCC (n = 7), and pancreas AC (n = 7). Average age was 61, average number of lines of prior systemic therapy for advanced disease was 1.3 (range 0-4), and 37% of patients were treated on a clinical study. All patients received an anti-PD-(L)1 drug; 6%, 2%, and 36% also received ipilimumab, cytotoxic chemotherapy, and other combinations, respectively. Among those with esophageal/gastric cancer, 76% had known PD-L1 CPS (84% ≥1, 63% ≥5, 42% ≥10). TMB was primarily determined by Foundation One CDx (87%). TMB ranged from 0 to 54; n = 22 (27%) were TMB-H (of these, n = 10 were microsatellite instability-high (MSI-H)), and n = 61 were TMB-L ( < 10 mutations/megabase; of these, n = 2 were MSI-H). The prevalence of TMB-H and microsatellite stable (MSS) was 14.4%. TMB-L, compared to TMB-H, was associated with inferior ORR (3.5% vs 55.6%; odds ratio (OR) 0.045; p < 0.001) and PFS (median 12.7 vs 29.3 weeks; hazard ratio (HR) 2.70; p = 0.001), but not OS (HR 1.20; p = 0.60). In patients with MSS disease, TMB-L, compared to TMB-H, was associated with inferior ORR (OR 0.13; p = 0.04) but not PFS (HR 1.76; p = 0.07) or OS (HR 0.89; p = 0.79). In subgroup analyses, ORR was not significantly associated to tumor type in all or MSS patients. TMB as a continuous variable, in patients with MSS disease, was positively correlated with ORR (p = 0.02) and PFS (p = 0.04), but not OS (p = 0.59). Among all patients, PFS and OS data is immature (median follow-up 13 and 31 weeks). Conclusions: In a single center retrospective study of patients with mGI cancers treated with ICIs, TMB-H was associated with improved ORR and PFS compared to TMB-L. In patients with MSS disease, ORR remained significant. PFS and OS data are immature. TMB as a biomarker of efficacy with ICIs in mGI cancers warrants further study to guide clinical use.

Baseline neutrophil-to-lymphocyte ratio and absolute lymphocyte count in patients with HER2-negative breast cancer treated with eribulin may predict overall survival.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13005-e13005
Author(s):  
Shigeto Maeda ◽  
Keisei Anan ◽  
Kenichiro Koga ◽  
Sayaka Kuba ◽  
Hiroshi Yano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Overall Survival ◽  
Lymphocyte Count ◽  
Group Performance ◽  
Absolute Lymphocyte Count ◽  
Neutrophil To Lymphocyte Ratio ◽  
Rank Test ◽  
Lymphocyte Ratio ◽  
Log Rank Test

e13005 Background: In Japan, eribulin has been approved for inoperative or recurrent breast cancer, following treatment with an anthracyclines and a taxanes. We reported the efficacy and safety of eribulin as a first-line to third-line treatment in patients with advanced/metastatic breast cancer (MBC) previously treated with anthracylinsanthracyclines and taxanes (Breast 2017). Briefly, the main inclusion criteria were as follows: no history of eribulin administration; an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2,; human epidermal growth factor receptor 2 (HER2)-negative,; 20–75 years; ≥4 weeks from the last dose of chemotherapy, or ≥2 weeks from the last dosing of endocrine or radiation therapy; measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1; sufficient organ function; life expectancy of ≥3 months; and no significant abnormalities on electrocardiogram. Patients in this clinical trial were enrolled between December 1, 2011, and November 30, 2013. Eribulin was administered intravenously at a dose of 1.4 mg/m2 during a 2-5 min infusion on days 1 and 8 every 3 weeks. In contrast, baseline neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) were reported to predict progression-free survival (PFS) or overall survival (OS). However, these reports were mainly retrospective analysis. Therefore, retrospective evaluation of NLR/ALC in a prospective clinical trial is important to understand the association between NLR/ALC and OS/PFS. Methods: Of 47 prospectively enrolled patients in a previous trial, 45 patients were retrospectively evaluated for baseline NLR/ACL and at the time of 3 cycles of eribulin. The association between NLR/ALC and OS/PFS was also were analyzed for association with OS/PFS. The Kaplan-Meier method was used to estimate the OS/PFS distribution. The cut-off values for baseline NLR and ALC were set at 3 and 1500 /ul, respectively. Results: The median OS of patients with a baseline NLR < 3 was significantly longer than that of patients with a baseline NLR ≥ ≧3 (769 days vs. 409 days; log-rank test p = 0.0333). The median OS of patients with a baseline ALC ≥ ≧1500 was also significantly longer than that of patients with a baseline ALC < 1500 (964 days vs.vs 427 days; log-rank test p = 0.0425). Association between baseline NLR/ALC and PFS were not seen, and also association between at the time of 3 cycles of NLR/ALC and OS/PFS were not seen neither. Conclusions: Baseline NLR and ALC in the patients with HER2- negative breast cancer who plan to treat eribulin may predict overall survival. Clinical trial information: UMIN000007121.

scholarly journals Electrolytes supplementation can decrease the risk of nephrotoxicity in patients with solid tumors undergoing chemotherapy with cisplatin

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Omary M. S. Minzi ◽  
Tatu E. Lyimo ◽  
Francis F. Furia ◽  
Alphonce I. Marealle ◽  
Manase Kilonzi ◽  
...  
Keyword(s):  
Treatment Group ◽  
Serum Creatinine ◽  
Solid Tumors ◽  
Normal Saline ◽  
Controlled Trial ◽  
Kidney Injury ◽  
Rank Test ◽  
Control Group ◽  
Relative Risks ◽  
Kaplan Meier

Abstract Background Cisplatin is an important drug in the treatment of various Cancers. However, this drug causes nephrotoxicity that is linked to electrolyte derangement. The aim of this study was to evaluate the effect of electrolyte supplementation in reducing kidney injury in patients receiving cisplatin-based regimen. Methods This was non-randomized interventional study conducted at Ocean Road Cancer Institute (ORCI) among patients with confirmed solid tumors. Patients who received cisplatin-based chemotherapy at a dose of ≥50 mg with intravenous normal saline supplemented with Magnesium, Calcium and Potassium (triple electrolyte supplementation) were compared with those who received cisplatin-based chemotherapy with normal saline alone. The patients were followed up for 4 weeks and serum creatinine was measured at every visit. Nephrotoxicity was defined as serum creatinine elevation > 1.5 times that at baseline. Results A total of 99 patients were recruited, whereby 49 patients (49.5%) received electrolyte supplementation (treatment group) and 50 patients (51.5%) did not receive electrolyte supplementation (control group). The incidence risk of nephrotoxicity was 20.41% (n = 10) in the treatment group and 54% (n = 27) in the control group. Patients in the control group were 2.6 times more likely to experience nephrotoxicity as compared to treatment group [Relative Risks (RR); 2.6, 95%CI; 1.5–4.9, P < 0.0001]. The most common malignancy was cervical cancer, n = 43 (87.8%) in treatment group and n = 45 (90.0%) in the control group (P = 0.590). The Kaplan-Meier analysis and the log-rank test revealed that electrolytes supplementation was associated with extended survival with less nephrotoxicity incidences [P = 0.0004; Hazard ratio (HR) 0.3149; 95% CI 0.165 to 0.6011]. Conclusions Electrolytes supplementation decreases the risk of nephrotoxicity after chemotherapy with cisplatin. A randomized controlled trial with a larger sample size is recommended to evaluate the robustness of these findings.

Role of nutritional and inflammatory status in the prognosis of advanced gastric cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 35-35
Author(s):  
Antía Cousillas ◽  
Elena Gallardo ◽  
Iria Carou ◽  
Ángeles Rodriguez ◽  
Víctor Sacristán ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Laboratory ◽  
Prognostic Nutritional Index ◽  
Metastatic Gastric Cancer ◽  
Good Prognosis ◽  
Rank Test ◽  
Albumin Concentration ◽  
Neutrophil Lymphocyte Ratio ◽  
Inflammatory Status ◽  
Kaplan Meier

35 Background: This study explores the prognosis impact of nutritional and immune status in metastatic gastric cancer (GC). Recently research has been focused on a proinflammatory status and the relevance of inmune system of the patient in GC. Neutrophil-lymphocyte ratio (NLR) and prognostic nutritional index (PNI) has showed prognostic value in local disease. Our study was assesed in metastatic disease. Methods: One hundred and twenty patients with metastatic gastric adenocarcinoma were retrospectively evaluated between 2011 and 2015. 67.2% were metastatic at diagnosis and 32.8% had a recurrence of disease. Clinical, laboratory and histopathological characteristics were selected as risk factors. The optimal cut-off levels were defined as NLR = 3, PNI (10 x albumin concentration +0.005 x total lymphocyte count) = 43.8, albumin = 3.5 g/dL, body mass index (BMI) = 25. Patients with high NLR and hypoalbuminemia were defined as 2, patients who presented only one abnormally were defined as 1 and those with neither abnormality were defined as 0. Lab data levels were related with survival by Kaplan-Meier and compared by long-rank test. Results: Among 120 patients, mean age was 69 years old, 35% female and 72.5% had no comorbidity. NLR > 3 (6.7 vs 12.5months, p = 0.001), low PNI (7.7 vs 13.1months, p = 0.01) and low albumin (6.2 vs 11.2 months, p = 0.002) were correlated with OS. Significantly, patients with an BMI < 25 had a worse prognosis compared with patients with BMI ≥ 25 (7.4 vs 12.4months, p = 0.02). Obesity in metastatic GC was related with good prognosis in our review. In the group of patients with hypoalbuminemia and h-NLR (27.6%) OS was much worse than patients with normal albumin and low-NLR, 33.6% (4.4months vs. 12.8 months, p < 0.001) Conclusions: High NLR ( > 3) and low PNI ( < 43.8), albumin ( < 3.5g/dL) were correlated with worse outcomes. Moreover, the association in a score of NLR plus albumin showed eight months OS diference. As a recent data in other cancer sites, obesity was related with good prognosis in mGC in our review.

Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2554-2554 ◽  
Author(s):  
Jermaine Coward ◽  
Vinod Ganju ◽  
Ramin Behzadigohar ◽  
Kenneth Kwong ◽  
June Xu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Human Study ◽  
Safety Data ◽  
Advanced Solid Tumors ◽  
Duration Of Treatment ◽  
Efficacy Evaluation

2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.

Effect of concurrent beta-blocker use in patients receiving immune checkpoint inhibitors for advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15068-e15068
Author(s):  
Vaibhav G. Patel ◽  
Qian Qin ◽  
Bo Wang ◽  
Mahalya Gogerly-Moragoda ◽  
George Mellgard ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Model Systems ◽  
Beta Blockade ◽  
Clinical Activity ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Adrenergic Signaling

e15068 Background: Stress-induced adrenergic signaling suppresses the immune system. In animal model systems, pharmacological beta-blockade stimulated CD8+ T-cell activity, and further, it improved clinical activity of immune checkpoint inhibitors (ICI) in inhibiting tumor growth. Herein, we investigate the effect of beta blockers (BB) on clinical outcomes of patients receiving ICI in advanced solid tumors. Methods: We retrospectively evaluated patients with solid tumors treated with at least 2 doses of ICI at our institution from December 2010 to April 2017. The primary outcome was disease control rate (DCR), as defined by radiographic complete response, partial response, or stable disease, by RECIST 1.1 criteria. The primary predictor was use of BB (β1-selective BB vs. no BB; non-selective BB vs no BB). The primary predictive variable was analyzed using multivariate logistic regression model controlling for several parameters including patient demographics, co-morbidities, ECOG performance status, and tumor type and location of metastases. All tests were two-sided at the significant level of 0.05. Results: We identified 298 evaluable patients with median age of 66.5 (31-95). Of these patients, 200 (67%) did not use BB, 75 (25%) used β1-selective BB, and 23 (8%) used non-selective BB. In multivariate analysis, use of β1-selective BB was significantly associated with improved DCR compared to no BB (ORR 2.43, 95% CI 1.31-4.51, P = 0.005), while use of non-selective BB was not associated with improved DCR (ORR 1.71, 95% CI 0.65-1.47, P = 0.27). Conclusions: The concurrent use of BB may enhance the clinical activity of ICI, particularly β1-selective BB. Our findings warrant further investigation to understand the interaction of β1- and β2-adrenergic signaling and antitumor immune activity, and potentially explore a combination strategy of ICI and BB.

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