scholarly journals Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI)

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2827 ◽  
Author(s):  
Andrea De Giglio ◽  
Laura Mezquita ◽  
Edouard Auclin ◽  
Félix Blanc-Durand ◽  
Mariona Riudavets ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Prognostic Impact ◽  
Steroid Use ◽  
Free Survival ◽  
Cancer Symptoms ◽  
Steroid Group ◽  
Poor Outcomes ◽  
Nsclc Patients

Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (≥10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. Results: 413 patients received ICI, 299 were steroids-naïve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1–12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p < 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9–1.5] and mOS [1.9 mo.; 95%CI, 1.5–2.4; p < 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2–5.6] and OS [HR 4.53; 95% CI, 1.8–11.1], both p < 0.0001. Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms.

Baseline systemic inflammatory immune index may predict overall survival and progression-free survival in patients with non-small cell lung cancer patients on immune checkpoint inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21202-e21202
Author(s):  
John P. Palmer ◽  
Yenong Cao ◽  
Samer Ibrahim ◽  
Natasha Dhawan ◽  
Muhammad Zubair Afzal ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
The Mean ◽  
Nsclc Patients

e21202 Background: Increased systemic inflammatory state and increased inflammation within tumor micro-environment (TME) have been associated with a worse prognosis and lower responsiveness to immune checkpoint inhibitors (ICI). Systemic inflammatory immune index (SII) reflects the changes in the systemic inflammatory matrix. Studies have shown the association of SII with cancer survival and treatment outcomes. We aim to study the effect of SII on treatment outcomes in non-small cell lung cancer (NSCLC) patients being treated with ICI. Methods: We conducted a retrospective analysis on 178 NSCLC patients treated with ICIs (pembrolizumab, nivolumab, ipilimumab/nivolumab or atezolizumab) alone or in combination with chemotherapy. SII is the product of platelets multiplied by neutrophils divided by lymphocytes. Baseline and 8-week SIIs were obtained. Radiographic response, duration of radiographic response (date of best response to radiographic progression), overall survival (OS), and progression-free survival (PFS) were evaluated. A high SII was defined as a value greater than the median SII. Cox regression univariate and multivariate analyses were performed. Logistic regression, t-test, and Chi-square tests were applied. Results: Overall, 81% patients had adenocarcinoma and 19% patients had squamous, adenosquamous or large cell carcinoma. The majority of the patients were female (56.2% vs. 43.8%). Median SII at baseline was 1335. The objective response rate (ORR) was 45.1%. The disease control rate was 75.8%. The ORR was 51% in patients receiving ICI first-line compared to 35% in those who received ICI as a second-line therapy. At baseline, there was no difference in the mean SII between responders and non-responders (2146.2 vs. 1917.5, P = 0.5); however at 8 weeks, the mean SII was significantly lower in responders compared to non-responders (1198.8 vs. 2880.2, P = 0.02). A total of 15 (10.9%) patients were found to have pseudoprogression or mixed response on follow-up imaging. Among these, 11(73.3%) patients had low SII at 8 weeks (P = 0.04). The median OS was significantly higher in patients with low SII at baseline (29.6 months vs. 10.1 months, P = 0.001 95% CI 10.6 – 22.1). Similarly, there was a significant difference in median PFS in patients with low SII (14.6 months vs. 6.7 months, P = 0.002, 95% CI 5.6 – 11.6). There was no correlation between high or low SII on the incidence of immune-related adverse events. Conclusions: SII may have significant impact on OS and PFS and could be serially monitored to assess the response to ICI. A low SII may help to differentiate pseudoprogression vs. true progression. Prospective studies are needed to validate these findings. Further, it will be interesting to see if SII could be incorporated into predictive models to determine the duration of cytotoxic therapy in selected patients.

scholarly journals The Prognostic Significance of the Continuous Administration of Anti-PD-1 Antibody via Continuation or Rechallenge After the Occurrence of Immune-Related Adverse Events

2021 ◽  
Vol 11 ◽  
Author(s):  
Toshiya Fujisaki ◽  
Satoshi Watanabe ◽  
Takeshi Ota ◽  
Kohei Kushiro ◽  
Yusuke Sato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Continuous Administration ◽  
Free Survival ◽  
Programmed Cell Death 1 ◽  
Third Line ◽  
Nsclc Patients

ObjectivesAlthough immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs.MethodsWe retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors.ResultsOf 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4–NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4–NE); p = 0.031].ConclusionThe current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

scholarly journals ctDNA-Profiling-Based UBL Biological Process Mutation Status as a Predictor of Atezolizumab Response Among TP53-Negative NSCLC Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Jun Lu ◽  
Yanwei Zhang ◽  
Yuqing Lou ◽  
Bo Yan ◽  
Benkun Zou ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Biological Process ◽  
Checkpoint Inhibitors ◽  
Clinical Information ◽  
Progression Free Survival ◽  
Predictive Values ◽  
Mutation Status ◽  
Free Survival ◽  
History Of ◽  
Nsclc Patients

Atezolizumab, an immune checkpoint inhibitor, has been approved for use in clinical practice in non-small cell lung cancer (NSCLC) patients, but potential biomarkers for response stratification still need further screening. In the present study, a total of 399 patients with high-quality ctDNA profiling results were included. The mutation status of ubiquitin-like conjugation (UBL) biological process genes (including ABL1, APC, LRP6, FUBP1, KEAP1, and TOP2A) and clinical information were further integrated. The results suggested that the patients with the clinical characteristics of male or history of smoking had a higher frequency of UBL mutation positivity [UBL (+)]; the patients who were UBL (+) had shorter progression-free survival (PFS) (1.69 vs. 3.22 months, p = 0.0007) and overall survival (8.61 vs. 16.10 months, p &lt; 0.0001) than those patients with UBL mutation negativity [UBL (–)]; and more promising predictive values were shown in the smoker subgroup and ≤ 3 metastasis subgroup. More interestingly, we found the predictor has more performance in TP53-negative cohorts [training in an independent POPLAR and OAK cohorts (n = 200), and validation in an independent MSKCC cohort (n = 127)]. Overall, this study provides a predictor, UBL biological process gene mutation status, not only for identifying NSCLC patients who may respond to atezolizumab therapy but also for screening out the potential NSCLC responders who received other immune checkpoint inhibitors.

Co-occurring alteration of NOTCH and DDR pathways serve as novel predictor to efficacious immunotherapy in NSCLC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21106-e21106
Author(s):  
Zhimin Zhang ◽  
Yanyan Gu ◽  
Xiaona Su ◽  
Jing Bai ◽  
Wei Guan ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Checkpoint Inhibitors ◽  
Notch Pathway ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Expression Data ◽  
Free Survival ◽  
Future Clinical Practice ◽  
Cancer Genome Atlas ◽  
Nsclc Patients

e21106 Background: Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the majority produce an ultra-rapid progressive disease. Methods: Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. 106 NSCLC patients treated with immunotherapy were combined from Rizvi et. al and Hellman et. al studies (whole exon sequencing) as the discovery dataset. Two independent validation datasets were comprised of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. Results: In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [ 22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [ Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96 ; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1 ]. By analyzing TCGA cohort, we found patients with coexisting NOTCH and co-DDR pathway had a higher TMB, more infiltration of CD4+T cells. Conclusions: Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.

Overweight or obese patients may take longer to respond and be less responsive to immune checkpoint inhibitors in non-small cell lung cancer: A retrospective review.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21209-e21209
Author(s):  
John P. Palmer ◽  
Yenong Cao ◽  
Samer Ibrahim ◽  
Natasha Dhawan ◽  
Muhammad Zubair Afzal ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Normal Weight ◽  
Obese Patients ◽  
Small Cell Lung ◽  
Free Survival ◽  
Radiographic Response ◽  
Nsclc Patients

e21209 Background: Immune checkpoint inhibitors (ICI) are now the standard of care in the treatment of non-small cell lung cancer (NSCLC). ICIs may be used as monotherapy or in combination with chemotherapy. Increased recruitment of inflammatory cells in the tumor micro-environment is associated with a poor response to ICIs. Although obesity is a risk factor for many types of cancers, including lung cancer, it is associated with a low systemic inflammation state. This creates an effect known as the “obesity paradox,” resulting in better treatment-related outcomes in overweight and obese patients receiving ICIs. However, in obese patients, the neutralizing interleukin (IL) - 1β level is high, which can decrease the responsiveness to ICI. We aim to study the effect of increased weight on treatment-related outcomes in NSCLC patients receiving ICI. Methods: We conducted a retrospective analysis on 178 NSCLC patients treated with ICIs, such as pembrolizumab, nivolumab, ipilimumab/nivolumab or atezolizumab, alone or in combination with chemotherapy. Overweight was defined as having a BMI of 25 – 29.9 while obesity was defined as having a BMI of ≥ 30. Overall survival (OS), progression free survival (PFS), best radiographic response, and the time to achieve radiographic response were evaluated. Cox regression univariate and multivariate analyses were performed. Logistic regression and Chi-square tests were applied. Results: Of the 178 patients with NSCLC, 81% had adenocarcinoma, and 19% had squamous, adenosquamous, or large cell carcinoma. The majority of patients were female (56.2% vs. 43.8%). Overall, 48.6% patients were overweight or obese. The objective response rate (ORR) was 45.1% and the disease control rate (DCR) was 75.8%. The ORR was 37% in overweight/obese patients compared to 52% in patients with a normal weight (p = 0.06). The DCR was 76% vs. 73.9%, (p = 0.7). The median time to achieve the best radiographic response was 3.7 months in overweight/obese patients compared to 2.5 months in those of normal weight (p = 0.2). A considerably higher proportion of the patients progressed in overweight/obese category (80.7% vs. 69.3%, P = 0.08). However, there was no significant difference in median PFS between the two categories (7.4 vs. 8.1 months, P = 0.2). The overall survival was not significant different between both categories (15.9 vs. 16.8 months, P = 0.5). Conclusions: Our study suggests that obesity and overweight status can result in a low response rate to ICIs in NSCLC patients and can delay the time to achieve the best radiographic response per RECIST criteria. However, we did not observe any significant impact on the overall or progression-free survival. A large, population-based study will help to elucidate the impact of weight on the responsiveness to ICI.

scholarly journals Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhimin Zhang ◽  
Yanyan Gu ◽  
Xiaona Su ◽  
Jing Bai ◽  
Wei Guan ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Checkpoint Inhibitors ◽  
Notch Pathway ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Expression Data ◽  
Free Survival ◽  
Future Clinical Practice ◽  
Cancer Genome Atlas ◽  
Nsclc Patients

Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 vs 3.6 months, p &lt; 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2–0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31–0.96; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18–1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.

scholarly journals The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis

2021 ◽  
Author(s):  
Charissa A C Jessurun ◽  
Alexander F C Hulsbergen ◽  
Anouk E de Wit ◽  
Ishaan A Tewarie ◽  
Tom J Snijders ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Steroid Use ◽  
Random Effects Models ◽  
Steroid Group ◽  
Symptomatic Management ◽  
Stratified Analysis

Abstract Background Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI. Methods A systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies. Results After screening 1145 abstracts, fifteen observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9-10.2 months. In the non-steroid group, median OS ranged from 4.9-25.1 months. Pooled results demonstrated significantly worse OS (HR 1.84, 95% CI 1.22-2.77) and systemic progression free survival (PFS; HR 2.00, 95% CI 1.37-2.91) in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS (HR 1.31, 95% CI 0.42-4.07). Conclusions Administration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.

scholarly journals Beyond Abscopal Effect: A Meta-Analysis of Immune Checkpoint Inhibitors and Radiotherapy in Advanced Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2352
Author(s):  
Francesco Fiorica ◽  
Umberto Tebano ◽  
Milena Gabbani ◽  
Mariasole Perrone ◽  
Sonia Missiroli ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Metastatic Nsclc ◽  
Nsclc Patients

Background: Immune checkpoint inhibitors (ICI) plus radiotherapy (RT) have been suggested as an emerging combination in non-small cell lung cancer (NSCLC) patients. However, little is known about the magnitude of its benefits and potential clinical predictors. Objective: To assess the effects of this combination on the increase in overall and progression-free survival. Data sources: The MEDLINE and CANCERLIT (1970–2020) electronic databases were searched, and the reference lists of included studies were manually searched. Study selection: Studies were included if they were comparative studies between combination ICI-RT and ICI or RT alone in advanced or metastatic NSCLC patients. Overall survival (OS) was analyzed according to the treatment strategy. Data extraction: Data on population, intervention, and outcomes were extracted from each study, in accordance with the intention-to-treat method, by two independent observers and combined using the DerSimonian method and Laird method. Results: Compared to ICI or RT alone, ICI-RT significantly increased the 1-year and 3-year OS RR by 0.75 (95% CI 0.64–0.88; p = 0.0003) and 0.85 (95% CI 0.78–0.93; p = 0.0006), respectively. Furthermore, there was a statistically significant benefit on 1- and 3-year progression-free survival (RR 0.73 (95% CI, 0.61–0.87; p = 0.0005) and RR 0.82 (95% CI 0.67–0.99; p = 0.04), respectively). Conclusions: In patients with advanced or metastatic NSCLC, combination ICI-RT increases 1- and 3-year OS and progression-free survival compared to ICI or RT alone.

Systematic literature review of clinical outcomes in adults with metastatic or advanced synovial sarcoma

2020 ◽  
Vol 16 (35) ◽  
pp. 2997-3013
Author(s):  
Kentaro Kogushi ◽  
Michael LoPresti ◽  
Shunya Ikeda
Keyword(s):  
Synovial Sarcoma ◽  
High Frequency ◽  
Clinical Evidence ◽  
Systemic Treatment ◽  
Progression Free Survival ◽  
Treatment Modalities ◽  
Free Survival ◽  
New Treatment ◽  
Poor Outcomes

Background: Synovial sarcoma (SS) is a rare, aggressive soft tissue sarcoma with a poor prognosis after metastasis. The objective of this study was to conduct a systematic review of the clinical evidence for therapeutic options for adults with metastatic or advanced SS. Materials & methods: Relevant databases were searched with predefined keywords. Results: Thirty-nine publications reported clinical data for systemic treatment and other interventions. Data on survival outcomes varied but were generally poor (progression-free survival: 1.0–7.7 months; overall survival: 6.7–29.2 months) for adults with metastatic and advanced SS. A high frequency of neutropenia with systemic treatment and low quality of life post-progression were reported. Conclusion: Reported evidence suggests poor outcomes in adults with metastatic and advanced SS and the need for the development of new treatment modalities.

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