Analysis of the Association Between Adverse Events and Outcome in Patients Receiving a Programmed Death Protein 1 or Programmed Death Ligand 1 Antibody

2019 ◽  
Vol 37 (30) ◽  
pp. 2730-2737 ◽  
Author(s):  
V. Ellen Maher ◽  
Laura L. Fernandes ◽  
Chana Weinstock ◽  
Shenghui Tang ◽  
Sundeep Agarwal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Urothelial Cancer ◽  
Locally Advanced ◽  
Study Drug ◽  
Data Sets ◽  
Systemic Corticosteroids ◽  
Programmed Death ◽  
Programmed Death Protein 1 ◽  
The Relationship

PURPOSE To assess the relationship among tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti–programmed death protein 1 or ligand 1 (anti–PD-1/L1) antibodies. PATIENTS AND METHODS We examined seven trials in 1,747 patients with metastatic or locally advanced urothelial cancer that led to approval of an anti–PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy, and two enrolled patients who were cisplatin ineligible. The data sets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the investigator. ImAEs were defined as AESIs treated with topical or systemic corticosteroids. RESULTS In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti–PD-1/L1 antibody, whereas a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared with those with no related AESIs (hazard ratio, 0.45; 95% CI, 0.39 to 0.52). Fifty-seven percent of responding patients with a related AESI reported the AESI before documentation of response. CONCLUSION Patients who responded to treatment with an anti–PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not seem to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.

An FDA analysis of the association between adverse events and outcome in patients with urothelial cancer receiving a programmed death protein 1 or programmed death ligand 1 (anti-PD-1/L1) antibody.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4549-4549
Author(s):  
Chana Weinstock ◽  
Virginia Ellen Maher ◽  
Laura L. Fernandes ◽  
Shenghui Tang ◽  
Sundeep Agrawal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Urothelial Cancer ◽  
Locally Advanced ◽  
Study Drug ◽  
Drug Approval ◽  
Systemic Corticosteroids ◽  
Immune Mediated ◽  
Programmed Death ◽  
The Relationship

4549 Background: To assess the relationship between tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. The datasets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the Investigator. Immune-mediated adverse events were defined as AESIs treated with topical or systemic corticosteroids. Results: In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti-PD-1/L1 antibody while a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared to those with no related AESI [hazard ratio (HR) 0.42; 95% CI: 0.37, 0.49]. Fifty-seven percent of responding patients with a related AESI reported a related AESI prior to documentation of response. Conclusions: Patients who responded to treatment with an anti-PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not appear to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.

Impact of antibiotic use on clinical outcomes in patients with urothelial cancer receiving a programmed death protein 1 or programmed death ligand 1 (anti-PD-1/L1) antibody.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4557-4557 ◽  
Author(s):  
Chana Weinstock ◽  
Virginia Ellen Maher ◽  
Laura L Fernandes ◽  
Shenghui Tang ◽  
Sundeep Agrawal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Outcomes ◽  
Urothelial Cancer ◽  
Controlled Trial ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Drug Approval ◽  
Antibiotic Use ◽  
Programmed Death ◽  
Programmed Death Protein 1

4557 Background: Previous data has suggested that patients treated with anti-PD-1/L1 antibodies who receive antibiotics during their therapy might have dramatically decreased progression-free and overall survival 1,2. This has clinical implications for management of patients with suspected bacterial infection while on treatment with these agents. We assessed the relationship between antibiotic use and tumor response rate, progression-free survival, and overall survival in a large dataset of patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. Six were single arm trials and one was a randomized controlled trial whose control arm is not included in these analyses. Concomitant medication datasets were searched for systemic antibiotic used by each patient while on treatment. Results: Overall, 51% of patients (n=892) were exposed to antibiotics (ABX+) and 49% (n=855) were not exposed (ABX-). In these exploratory analyses, small numeric differences in OS, PFS, and ORR were seen in ABX+ vs. ABX- patients. Median OS was 9.23 vs. 9.86 months, median PFS was 105 vs 101 days, and ORR was 20% vs. 21% in ABX+ vs. ABX- patients, respectively. Conclusions: Patients who were treated with antibiotics while on therapy with an anti-PD-1/L1 antibody for urothelial cancer had similar outcomes to those who were not treated with antibiotics. Numeric differences in outcomes were not significant and did not duplicate previous analysis demonstrating a median OS that was doubled in ABX- patients1. Our exploratory analyses do not appear to demonstrate a clear need for practitioners to avoid antibiotic use in patients treated with PD-1/L1 agents for fear of significantly impacting clinical outcomes. References: 1) Tinsley et. al., ASCO annual meeting 2018, abstract 3010 2) Routy et. al., Science 05 Jan 2018: Vol. 359, Issue 6371. [Table: see text]

scholarly journals Henoch–Schönlein Purpura Associated with Lung Cancer: When Paraneoplastic Manifestations Impede Oncological Management

2021 ◽  
Vol 2021 ◽  
pp. 1-4
Author(s):  
Éloïse Philippe ◽  
Aude Barnier ◽  
Juliette Menguy ◽  
Gilles Robinet ◽  
Gilles Quéré ◽  
...  
Keyword(s):  
Lung Tumor ◽  
Locally Advanced ◽  
Lung Squamous Cell Carcinoma ◽  
Henoch Schonlein Purpura ◽  
Systemic Corticosteroids ◽  
Programmed Death ◽  
Programmed Death Protein 1 ◽  
Schonlein Purpura ◽  
Henoch Schönlein Purpura

Background. Henoch–Schönlein purpura (HSP) is an uncommon syndrome that mostly occurs in children, in whom it is frequently triggered by infections. In contrast, HSP in adults is more frequently of neoplastic origin. Case Presentation. We report HSP associated with a locally advanced lung squamous cell carcinoma that was considered a paraneoplastic syndrome. Systemic corticosteroids were given because a kidney biopsy revealed active glomerulonephritis. Concomitant chemoradiotherapy achieved a partial response of the lung tumor. Consolidation immunotherapy (programmed death protein-1-ligand-1 (PD-L1) inhibitor) was cancelled because HSP is known to be an autoimmune vasculitis, and long-term corticosteroid therapy was pursued. Conclusion. Further prospective studies are needed to evaluate the effect of anti-PD-(L) 1 immunotherapies on autoimmune manifestations.

Comparative effectiveness of proton therapy versus photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6521-6521 ◽  
Author(s):  
Brian Christopher Baumann ◽  
Nandita Mitra ◽  
Joanna Harton ◽  
Ying Xiao ◽  
Andrzej Wojcieszynski ◽  
...  
Keyword(s):  
Overall Survival ◽  
Propensity Score ◽  
Adverse Events ◽  
Comparative Effectiveness ◽  
Performance Status ◽  
Locally Advanced ◽  
Grade 3 ◽  
Unplanned Hospitalizations ◽  
Locally Advanced Cancer ◽  
Disease Free

6521 Background: Concurrent chemo-radiotherapy is standard-of-care curative treatment for many cancers, but is associated with substantial morbidity. Proton therapy may increase the tolerability or effectiveness of concurrent chemo-radiotherapy by reducing radiation to normal tissues. Methods: We conducted a comparative effectiveness study of adult non-metastatic cancer patients treated with curative intent with proton chemo-radiotherapy vs. photon chemo-radiotherapy from 2011-2016 at the University of Pennsylvania. Re-irradiation and disease sites treated with photon-only therapy were excluded. Data on adverse events and survival was gathered prospectively. Primary endpoint was 90-day adverse events associated with unplanned hospitalizations (CTCAEv4 grade ≥3 adverse events). Secondary endpoints included decline in ECOG performance status during treatment, 90-day grade ≥2 adverse events, disease-free survival (DFS) and overall survival (OS). Modified Poisson regression models with inverse propensity score weighting were fit for both outcomes. Propensity scores were estimated using an ensemble machine-learning approach. Results: 1,483 patients were included (391 proton/1,092 photon). Proton patients were significantly older (median 66 vs. 61), had less favorable Charlson-Deyo comorbidity scores (median 3.0 vs. 2.0), and had lower integral radiation dose to tissues outside the target (p < 0.05 for all). Baseline toxicity and performance status were similar (p > 0.05). In propensity score weighted-analyses, proton chemo-radiotherapy was associated with significantly lower relative risk (RR) of 90-day grade ≥3 adverse events [11.5%(95%CI 8.3-14.7%) for protons; 27.6%(95%CI 24.9-30.2%) for photons; RR 0.31, 95%CI 0.15-0.66, p < 0.01]; 90-day grade ≥2 adverse events (RR 0.78, 95%CI 0.65-0.93, p < 0.01); and decline in performance status during treatment (RR 0.51, 95%CI 0.37-0.71, p < 0.01). There was no difference in DFS or OS. Conclusions: In adults with locally advanced cancer, proton chemo-radiotherapy was associated with significantly reduced acute adverse events causing unplanned hospitalizations with similar disease-free and overall survival.

scholarly journals Kidney injury associated with antitumor therapy: focus on the adverse events of modern immuno-oncological drugs

2021 ◽  
Vol 93 (6) ◽  
pp. 649-660
Author(s):  
Elena S. Kamyshova ◽  
Irina N. Bobkova ◽  
Marina I. Sekacheva
Keyword(s):  
Adverse Events ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Inhibitory Effect ◽  
Immune System Activation ◽  
Programmed Death ◽  
Programmed Death Protein 1 ◽  
System Activation ◽  
New Generation

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) or its ligand (PD-L1), are a new generation of immuno-oncological drugs that to date have demonstrated efficacy in a number of malignancies. The mechanism of ICT inhibitors action consist in the potentiation of the immune response by eliminating the tumor cells inhibitory effect on the T-lymphocytes activation. However, excessive immune system activation can cause the development of a special class of immune-related adverse events (irAEs) involved a wide variety of organs and systems, including the kidneys. Despite the fact that immuno-mediated kidney injury caused by ICI therapy develops quite rarely, it can be serious and determine the patient's prognosis, which necessitates early diagnosis and timely start of treatment. In this regard, awareness of the manifestations of ICI-associated renal irAEs is particularly relevant not only for oncologists and for nephrologists, but for doctors of other specialties. In this review, we elucidated the main variants of immuno-mediated kidney injury caused by ICI therapy, discussed possible predictors and mechanisms of their development, and considers the general principles of diagnosis and management of patients according to the severity of irAEs.

scholarly journals PIVOT-10: Phase II study of bempegaldesleukin plus nivolumab in cisplatin-ineligible advanced urothelial cancer

2020 ◽  
Author(s):  
Robert A Huddart ◽  
Arlene O Siefker-Radtke ◽  
Arjun V Balar ◽  
Mehmet A Bilen ◽  
Thomas Powles ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Objective Response ◽  
Locally Advanced ◽  
Response Rates ◽  
Complete Response ◽  
First Line ◽  
First Line Therapy ◽  
Programmed Death ◽  
Metastatic Urothelial Cancer

The choice of first-line therapy for patients with metastatic urothelial cancer (mUC) is based on cisplatin-eligibility and programmed death-ligand 1 (PD-L1) status. For patients with mUC who are ineligible for cisplatin and with low PD-L1 expression, chemotherapy-based regimens are the only approved first-line option. In a Phase I/II trial of the chemotherapy-free regimen, bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab, patients with locally advanced or mUC experienced tumor responses regardless of baseline PD-L1 expression (objective response rates: 50 and 45% in patients with PD-L1-positive and -negative tumors, respectively). The Phase II PIVOT-10 study (NCT03785925), evaluates efficacy and safety of first-line BEMPEG plus nivolumab in cisplatin-ineligible patients with locally advanced or mUC. Most patients will have low PD-L1 expression. Primary end point: objective response rates (including complete response).

Neoadjuvant vascular targeted photodynamic therapy in urothelial cancer: Preclinical data.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 321-321
Author(s):  
Barak Rosenzweig ◽  
Renato B Corradi ◽  
Sadna Budhu ◽  
Ricardo Alvim ◽  
Pedro Guiraldes Recabal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Photodynamic Therapy ◽  
Local Recurrence ◽  
Therapeutic Efficacy ◽  
Urothelial Cancer ◽  
Statistical Tests ◽  
Locally Advanced ◽  
Long Term Memory ◽  
Recurrence Rates ◽  
Targeted Photodynamic Therapy

321 Background: Recurrence and progression following surgical treatment of locally advanced urothelial cancer is high spurring a need to develop effective, well-tolerated neoadjuvant strategies. We examined the efficacy and immunotherapeutic mechanism of neoadjuvant sub-ablative vascular targeted photodynamic therapy (sbVTP) in urothelial cancer. Methods: Following urothelial tumor implantation, mice were randomized to receive neoadjuvant sbVTP (WST-11; TOOKAD Soluble, Steba Biotech, France) or sham treatment 17 days prior to surgical resection. Therapeutic efficacy was evaluated by local and systemic response and survival studies. Immunohistochemistry and flow cytometry were used to elucidate mechanism. Kaplan-Meier, Mann-Whitney and Fischer exact test were used to analyze the data. All statistical tests were two-sided. Results: On the day of surgery, tumor volume was 1222 mm3 (95% CI 976-1468 mm3) vs. 135 mm3 (95% CI 66-204 mm3, p < 0.0001) and systemic progression was 30% vs. 7% (p<0.05), for control vs. sbVTP treated animals, respectively. Median progression free survival and overall survival were 45 and 55 days respectively for surgery only group and significantly longer (50% not reached, p<0.05) for the sbVTP + surgery group. Local recurrence rates were significantly lower in neoadjuvant treated animals. Neoadjuvant sbVTP was associated with increase in early antigen presenting cells followed by long term memory, effectory and active T-cell increase in spleen, lungs and blood. Conclusions: Neoadjuvant sbVTP treatment demonstrates evidence of therapeutic efficacy through an immune mediated response in this murine urothelial cancer model by delaying local and systemic progression, prolonging progression free and overall survival, and reducing local recurrence. Evaluation of this form of therapy in clinical trials is warranted.

scholarly journals Antiphospholipid Antibody Induced by Nivolumab

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Ahmed Aburahma ◽  
Nour Aljariri Alhesan ◽  
Farah Elounais ◽  
Emad Abu Sitta
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Antiphospholipid Antibody ◽  
Gi Tract ◽  
The Third ◽  
Programmed Death ◽  
Prolonged Aptt ◽  
Programmed Death Protein 1

Nivolumab is a monoclonal antibody against the programmed death protein 1 and is used for patients with advanced melanoma. It is associated with potentially immune-related adverse events, including disorders of the skin, GI tract, and the thyroid; these disorders were successfully treated with prednisone and infliximab. Other immunotherapeutic agents were observed to induce the formation of antiphospholipid antibody (APA) including α-interferon and interleukin-2. We present a case of APA development after the third dose of nivolumab in a 71-year-old male with advanced melanoma. The APA was detected after finding a prolonged aPTT; the lupus anticoagulant assay tested positive. The patient was treated with prednisone but, unfortunately, he expired a few days later.

scholarly journals Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center

2015 ◽  
Vol 33 (28) ◽  
pp. 3193-3198 ◽  
Author(s):  
Troy Z. Horvat ◽  
Nelly G. Adel ◽  
Thu-Oanh Dang ◽  
Parisa Momtaz ◽  
Michael A. Postow ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Treatment Failure ◽  
Systemic Corticosteroid ◽  
Standard Dose ◽  
Corticosteroid Treatment ◽  
Cancer Center ◽  
Time To Treatment ◽  
Systemic Corticosteroids ◽  
Time To Treatment Failure

Purpose Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF). Patients and Methods We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival. Results Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids. Conclusion IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.

scholarly journals Urothelial cancer: population-based analysis of the problem in Ukraine

2021 ◽  
Vol 4 (2) ◽  
pp. 4-10
Author(s):  
M.V. Pikul ◽  
E.O. Stakhovsky ◽  
O.A. Voylenko ◽  
O.E. Stakhovsky ◽  
Yu.V. Vitruk ◽  
...  
Keyword(s):  
Overall Survival ◽  
Urinary Tract ◽  
Urothelial Cancer ◽  
Locally Advanced ◽  
Upper Urinary Tract ◽  
Radical Nephroureterectomy ◽  
Chi Square ◽  
Urothelial Tumors ◽  
Organ Sparing ◽  
Locally Advanced Tumors

The aim of this work was to conduct a population analysis on the basis of the National Cancer Registry with the primary goal: to determine the effectiveness of urothelial cancer treatment in Ukraine; and the secondary goal: to identify the main trends and approaches to therapy with an assessment of their impact on overall survival. Materials and methods. The design of the study was retrospective observational. The analysis was conducted based on the data of the National Cancer Registry from 2008 to 2020. A total of 12,698 patients with urothelial tumors of the upper urinary tract and bladder who underwent surgical treatment were analyzed. Statistical sampling was performed based on the creation of the most homogeneous groups of patients with bladder cancer (BC) and the upper urinary tract carcinoma (UUTc) who had the required number of notified parameters for further analysis. The primary objectives of the analysis were to determine: the average age of primary detection of the studied nosologies, level of detection depending on gender, frequency of diagnosis verification before surgery, extent of surgery, frequency of postoperative complications based on data on 30-day rehospitalization, the level of deviation of the principles for prophylactic medical patients’ examination from generally accepted recommendations. The secondary objective was to assess the cumulative survival of patients with urothelial tumors depending on the localization of the primary tumor and the type of surgery (organ-sparing or radical). Results. Organ-sparing treatment was more typical for BC, while radical treatment was performed in 15 % of patients with carcinomas. Organ-sparing treatment was more typical for UUTc (40 %). It should be noted that in this nosology it is accep­table for invasive forms of urothelial cancer. The level of 30-day hospita­lization was low in both pathologies, with a slightly greater advantage of UUTc. The level of complications is grade III according to the Clavien-Dindo classification, averaging 0.2 % for the entire pool of patients. For BC, the overall survival rates by stages were: I — 73 %, II — 49 %, III — 18 % and IV — 11 % (chi-square = 1,807.207; p = 0.000001). For UUTc, the levels of 5-year overall survival correspond to the literature data, but there is a significant negative tendency to decrease the latter after a ­10-year period for all stages (chi-square = 146.298; p = 0.000003). In Ukraine, organ-sparing treatment for UUTc was not inferior to radical nephroureterectomy in the context of 5-year survival (51.3 vs. 51 %; log-rank test). The obtained data testify in favor of the 15% advantage of the total survival of patients who underwent radical nephroureterectomy at the premises of the National Cancer Institute (high volume center), compared to other regions of Ukraine. Levels of 5- and ­10-year survival in both nosologies were characterized by a statistically non-significant advantage of UUTc over BC of 7 %. Conclusions. Superficial and locally advanced tumors are the most complex ones in the treatment of urothelial cancer of the bladder and upper urinary tract in Ukraine. Superficial tumors require the most radical surgeries and subsequent effective local treatment. Locally advanced tumors require a comprehensive approach to treatment, adequate systemic therapy influences the final indicators of overall survival. In cases of surgical resectability and preservation of renal function, UUTc requires organ-sparing treatment; this approach aims to increase creatinine clearance in patients before systemic chemotherapy and to reduce the likelihood of progression of comorbidities and associated mortality.

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