Hyperprogressive disease during treatment with immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21664-e21664 ◽  
Author(s):  
Pablo Ayala de Miguel ◽  
Javier López Gallego ◽  
Itziar Gorospe García ◽  
Pablo René Rivera Vargas ◽  
Andrea Posada Restrepo ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Eastern Cooperative Oncology Group ◽  
Hyperprogressive Disease ◽  
Metastatic Sites

e21664 Background: Hyperprogressive disease (HPD) is a new pattern of progressión during immunotherapy and is described as an acceleration of tumor growth during treatment with immune checkpoint inhibitors (ICI). The rate of HPD in advanced solid tumors remains unknown, but it has been reported in 9% to 29% of patients in two recent series. Our aim was to study prognostic factors of HPD. Methods: We collected data of 104 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and December 2019. Several variables as clinical, tumour-related and therapeutical were included in the analysis. The variables were compared by chi-square and Fisher test, then we performed a multivariate logistic regression model to analyse the effects of the covariates, and finally we performed a Kaplan Meier survival analysis. We described HPD as disease progression at first evaluation with an increase in tumor growth rate exceeding 50%, according to Gustave Roussy criteria previously reported. Results: Cohort of 84 men and 20 women, median age of 67 years and 86% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 89% were active or ex-smokers and 11% had never smoked. 60% of patients had adenocarcinoma histology, 39% scamous and 1% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 37% M1a, 30% M1b and 30% M1c. 2 patients had driver mutations in EGFR gene. 41% of patients had unknown PDL1 status; 14% had no PDL1 expression, 14% low expression and 31% high expression. 78% of patients had progressed to prior line of treatment, while 22% were treatment-naive. Nine of 104 patients (8.7%) in our population developed HPD during treatment with ICI. HPD occured within the first two months of treatment in all 9 patients, and was associated with worse overall survival in the multivariate analysis by Cox regression (12.6 vs 2.6 months; HR 13.94, p < 0.001). The presence of 2 or more metastatic sites was related to the development of HPD in the multivariate analysis (HR 8.59, p = 0.026). Conclusions: The incidence of HPD in our population is concordant with previous report about this topic. As previously described by Ferrara et al, HPD was significantly associated with a high number of metastatic sites before start treatment with ICI and correlated with poor outcomes in patients with advanced NSCLC.

scholarly journals Redefine Hyperprogressive Disease During Treatment With Immune-Checkpoint Inhibitors in Patients With Gastrointestinal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhenghang Wang ◽  
Chang Liu ◽  
Yuezong Bai ◽  
Xiaochen Zhao ◽  
Longgang Cui ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Signaling Pathway ◽  
Growth Kinetics ◽  
Gastrointestinal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Hazard Ratio ◽  
Genomic Alterations ◽  
Hyperprogressive Disease

ObjectiveEmerging evidence showed that immune checkpoint inhibitors (ICIs) lead to hyperprogressive disease (HPD) in a small proportion of patients. There is no well-recognized standard for the evaluation of HPD. Comprehensive exploration of HPD definition system in gastrointestinal cancer treated with ICI is lacking to date.MethodsA total of 126 patients with advanced or metastatic gastrointestinal cancer treated with ICI monotherapy were analyzed. Seven definitions of HPD were defined with tumor growth kinetics (TGK) or tumor growth rate (TGR) by including new lesions or not, and with different cutoffs. Incidence and performance of different criteria were compared. Clinicopathologic characteristics and baseline genomic variations associated with HPD were also explored.ResultsTumor growth kinetics ratio of more than two fold that incorporated new lesions into calculation of HPD outperformed other definitions by successfully stratifying 14 patients (11.1%) with both accelerated disease progression (median PFS, 1.62 versus 1.93 months; hazard ratio, 1.85; 95% CI, 0.98 to 3.48; P = 0.059) and worse overall survival (median OS, 3.97 versus 10.23 months; hazard ratio, 2.30; 95% CI, 1.11 to 4.78; P = 0.021). Baseline genomic alterations in circulating tumor DNA, including SMARCA2, MSH6, APC signaling pathway, and Wnt signaling pathway, might be associated with the risk of HPD.ConclusionIncorporating new lesions emerging during the treatment was shown to be reliable for the assessment of TGK. TGK serves as a more convenient way to reflect tumor growth acceleration compared with TGR. Genomic alterations were suggested to be associated with the occurrence of HPD.

scholarly journals Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

2021 ◽  
Vol 22 (10) ◽  
pp. 5207
Author(s):  
Chi Yan ◽  
Jinming Yang ◽  
Nabil Saleh ◽  
Sheau-Chiann Chen ◽  
Gregory D. Ayers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mtor Pathway ◽  
Complete Regression ◽  
Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

scholarly journals Plasma Biomarkers Screening by Multiplex ELISA Assay in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 97
Author(s):  
Adrien Costantini ◽  
Paul Takam Kamga ◽  
Catherine Julie ◽  
Alexandre Corjon ◽  
Coraline Dumenil ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Elisa Assay ◽  
Small Cell Lung ◽  
Plasma Biomarkers

Immune checkpoint inhibitors (ICIs) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). An unmet need remains for new biomarkers associated with ICIs. In this study, consecutive patients with advanced NSCLC treated with nivolumab or pembrolizumab were included. Plasma at ICIs initiation was prospectively collected and a multiplex ELISA assay testing 48 cytokines and growth factors was performed. Exploratory endpoints were the association between plasma biomarkers with outcome and grade III–IV immune related adverse events (irAEs). Thirty-five patients were included. Patients without clinical benefit (n = 22) had higher pre-ICI soluble Hepatocyte Growth Factor (sHGF) (210.9 vs. 155.8 pg/mL, p = 0.010), lower pre-ICI soluble Fibroblast Growth Factor (sFGF) (4.0 vs. 4.8 pg/mL, p = 0.043) and lower pre-ICI interleukine-12 (IL-12) (1.3 vs. 2.2 pg/mL, p = 0.043) concentrations. Patients with early progression (n = 23) had higher pre-ICIs sHGF (206.2 vs. 155.8 pg/mL, p = 0.025) concentrations. Patients with low sHGF levels at ICIs initiation had longer progression-free survival and overall survival than those with high sHGF levels: respectively 2.5 vs. 8.0 months (p = 0.002), and 5.5 vs. 35.0 months (p = 0.001). TNF-α, IL-16, IL-12p40 and MCP3 were associated with high grade irAEs. This study shows the potential association between several plasma biomarkers with outcome and grade 3–4 IrAEs in advanced NSCLC treated with ICIs.

scholarly journals 363 Vactosertib and durvalumab as second or later line treatment for PD-L1 positive non-small cell lung cancer: interim result

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A388-A388
Author(s):  
Byoung Chul Cho ◽  
Ki Hyeong Lee ◽  
Ji-Youn Han ◽  
Byoung Yong Shim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Objective Response Rate ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Anti Tumor Activity

BackgroundTargeting transforming growth factor-β (TGF-β) is reported to augment the efficacy of immune checkpoint inhibitors (ICIs) through either enhanced anti-tumor immunity or the correction of tumor microenvironment (TME). Therefore, the combination of vactosertib, a highly selective TGF-β RI kinase inhibitor, and durvalumab is anticipated to improve anti-tumor activity of the ICI. A phase 1b/2a study was conducted to evaluate the combination of vactosertib and durvalumab in patients with advanced NSCLC who progressed after platinum-based chemotherapy.MethodsPatients were treated with vactosertib at a dose of 200 mg twice daily (five days on and two days off) and durvalumab at a dose of 1500 mg every four weeks. Eligible patients were ≥19 years old with good performance status (ECOG 0–1) and have no prior exposure to immune checkpoint inhibitors or other TGF- β R1 kinase inhibitors. The objectives of this analysis were to evaluate the safety, antitumor activity including objective response rate (ORR), duration of response (DOR), and time to response (TTR) as well as circulating pharmacodynamic biomarkers related to TGF-β signaling. Response was assessed per RECIST (v1.1).ResultsBy August 4 2020, twenty-six PD-L1 positive (SP263 assay) patients were analyzed. Median age was 61.5 years (range 48–83), 69.2% were male, median number of previous lines of chemotherapy was 1 (range 1–4), and all patients were PD-L1 positive (15 patients with PD-L1≥25% and 11 patients with PD-L1 1–24%). The most frequently reported treatment-related adverse events (TRAE) were itching (38.5%) and skin rash (34.6%), but no Gr≥3 itching and rash were observed. Each case of the following was reported as Grade 3 TRAEs: adrenal insufficiency, anemia, and pneumonitis; Grade 4 TRAE, CPK increase, was observed in one patient. Objective response rate was 30.8% and 40.0% in patients with PD-L1≥1% and ≥25% respectively. Circulating PAI-1 and CTGF evaluated in 15 patients decreased significantly on Cycle 1 day 5. Ongoing biomarker results will be presented.ConclusionsThe combination of vactosertib and durvalumab has demonstrated a manageable safety profile and encouraging anti-tumor activity as a potential therapeutic strategy in patients with advanced NSCLC. The efficacy outcomes of this combination in a larger number of patients with advanced NSCLC will be followed.Trial RegistrationNCT03732274Ethics ApprovalThe study was approved by Ethics Board of Severance Hospital (4-2018-0892), National Cancer Center (NCC2019-0057), St. Vincent’s Hospital (VC19MDDF0205), and Chungbuk National University Hospital (2019-08-015).

scholarly journals Development of nomogram based on immune-related gene FGFR4 for advanced non-small cell lung cancer patients with sensitivity to immune checkpoint inhibitors

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Li Wang ◽  
Zhixuan Ren ◽  
Bentong Yu ◽  
Jian Tang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Cancer Genomics ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

Abstract Introduction Immune checkpoint inhibitors (ICIs) have become a frontier in the field of clinical technology for advanced non-small cell lung cancer (NSCLC). Currently, the predictive biomarker of ICIs mainly including the expression of PD-L1, TMB, TIICs, MMR and MSI-H. However, there are no official biomarkers to guide the treatment of ICIs and to determine the prognosis. Therefore, it is essential to explore a systematic nomogram to predict the prognosis of ICIs treatment in NSCLC Methods In this work, we obtained gene expression and clinical data of NSCLC patients from the TCGA database. Immune-related genes (IRGs) were downloaded from the ImmPort database. The detailed clinical annotation and response data of 240 advanced NSCLC patients who received ICIs treatment were obtained from the cBioPortal for Cancer Genomics. Kaplan–Meier survival analysis was used to perform survival analyses, and selected clinical variables to develop a novel nomogram. The prognostic significance of FGFR4 was validated by another cohort in cBioPortal for Cancer Genomics. Results 3% of the NSCLC patients harbored FGFR4 mutations. The mutation of FGFR4 were confirmed to be associated with PD-L1, and TMB. Patients harbored FGFR4 mutations were found to have a better prolonged progression-free survival (PFS) to ICIs treatment (FGFR4: P = 0.0209). Here, we built and verified a novel nomogram to predict the prognosis of ICIs treatment for NSCLC patients. Conclusion Our results showed that FGFR4 could serve as novel biomarkers to predict the prognosis of ICIs treatment of advanced NSCLC. Our systematic prognostic nomogram showed a great potential to predict the prognosis of ICIs for advanced NSCLC patients.

Effect of high-dose corticosteroid use on efficacy of immune checkpoint inhibitors in patients with renal cell carcinoma (RCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4583-4583
Author(s):  
Chris Labaki ◽  
Sarah Abou Alaiwi ◽  
Andrew Lachlan Schmidt ◽  
Talal El Zarif ◽  
Ziad Bakouny ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Univariate Analysis ◽  
High Dose ◽  
Line Of Therapy

4583 Background: The use of High-Dose Corticosteroids (HDC) has been linked to poor outcomes in patients with lung cancer treated with immune checkpoint inhibitors (ICIs) (Ricciuti B, JCO, 2019). There is no data on the effect of HDC on renal cell carcinoma patients (RCC) treated with immunotherapy. We hypothesized that HDC use would be associated with worse outcomes in RCC patients receiving ICIs. Methods: This study evaluated a retrospective cohort of patients with RCC at Dana-Farber Cancer Institute in Boston, MA. Clinical information including demographics, IMDC risk score, RCC histology, steroid administration, ICI regimen, line of therapy, time to treatment failure (TTF) and overall survival (OS) were collected. Patients were divided into those receiving HDC (prednisone ≥10 mg or equivalent for ≥ 1 week, HDC group) or not receiving HDC (No-HDC group). HDC administration was evaluated in relation to TTF and OS in a univariate analysis (Log-rank test) and a multivariate analysis (Cox regression). Results: 190 patients with RCC receiving ICIs were included, with a median age of 59 years. HDC were administered to 56 patients and 134 patients received no (N= 116) or only low-dose (N=18) steroids. In the HDC group, 40 patients received steroids for immune-related adverse events, 8 for other cancer-related indications, and 8 for non-oncological indications. There was no difference in TTF between the HDC and No-HDC groups (12-mo TTF rate: 34.8 vs. 32.3%, respectively; log-rank p=0.65). Similarly, there was no difference in OS between the HDC and No-HDC groups (36-mo OS rate: 56.7 vs. 62.4%, respectively; log-rank p=0.97). After adjusting for IMDC risk group, RCC histology, ICI regimen type, and line of therapy, TTF and OS did not differ in the HDC group as compared to No-HDC group (HR=1.14 [95%CI: 0.80-1.62], p=0.44 and HR=1.17 [95%CI: 0.65-2.11], p=0.59, respectively). Conclusions: In this retrospective study of patients with RCC treated with ICIs, administration of high-dose corticosteroids was not associated with worse outcomes.[Table: see text]

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