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  • 1
    In: JAMA Network Open, American Medical Association (AMA), Vol. 5, No. 1 ( 2022-01-04), p. e2142046-
    Type of Medium: Online Resource
    ISSN: 2574-3805
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
    detail.hit.zdb_id: 2931249-8
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 654-654
    Abstract: 654 Background: IO-based regimens have demonstrated substantial efficacy in the management of metastatic clear-cell RCC (mccRCC), where they currently represent the standard of care. ChRCC has a dismal prognosis in the metastatic setting. Recent clinical trials evaluating IO-based regimens across non-ccRCC subtypes identified a preliminary poor response in advanced ChRCC, but were limited by low sample sizes. We sought to comprehensively evaluate the outcomes of patients with ChRCC treated with IO-based regimens. Methods: Using real-world data from the International Metastatic RCC Database Consortium (IMDC), we conducted a retrospective analysis of patients with advanced ChRCC who received IO-based therapies, including dual IO therapy or IO + VEGF targeted therapy (VEGF-TT), in the first-line setting. The primary outcome was overall survival (OS). Secondary outcomes included time to treatment failure (TTF) and ORR. Cox proportional hazards models were used to adjust for age and IMDC risk groups as covariates. A logistic regression was used to determine the association between the odds of achieving a response and RCC subtype. Results: We identified 31 patients with advanced ChRCC and 856 patients with ccRCC treated with IO-based therapies in the first-line setting, with a median age of 61.5 years (IQR: 51.5-69.0). Compared to patients with ccRCC who received IO-based therapies as initial regimens, patients with ChRCC had a lower OS (median OS: 24.7 vs. 50.5 months, respectively; p 〈 0.001) and a lower TTF (median TTF: 4.5 vs. 11.0 months, respectively; p 〈 0.001). Among patients with an evaluable objective response, the ORR was lower among patients with advanced ChRCC, as opposed to those with ccRCC (ORR: 12.0 vs 47.1%, respectively; p 〈 0.001). When evaluating first-line treatment with VEGF-TT monotherapy (sunitinib or pazopanib), no difference in outcomes was found between patients with ChRCC (n=122) and ccRCC (n=6,379) in relation to the primary endpoint of OS, while TTF and ORR suggested better outcomes for ccRCC (Table). Conclusions: In this real-world study, patients with metastatic ChRCC appear to display poor clinical outcomes even with IO-based regimens, as compared to ccRCC. The molecular determinants of poor response require further investigations. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 6_suppl ( 2020-02-20), p. 740-740
    Abstract: 740 Background: Metastatic vRCC are aggressive tumors with poor prognosis. Our phase 2 trial of AB in vRCC showed a response rate of 33%. We investigated on-therapy changes in circulating immune cells and cytokines and their association with outcomes. Methods: Blood was collected at baseline (C1D1) and on-therapy (C3D1). Peripheral blood mononuclear cells were analyzed for cell type, expression of immune checkpoints, markers of activation, proliferation and function using flow cytometry; circulating cytokines by multiplex immunoassay. Relationship with progression-free (PFS) and overall survival (OS) was assessed by cox regression models. Results: Baseline and on-therapy samples were collected from all 60 patients. High baseline levels of immunosuppressive cytokines IL1α, IL6, CCL4 and IL13, as well as high baseline levels of CD4+ lymphocytes expressing CD69, were associated with inferior PFS and OS (Table). However, a decline in these markers on-therapy was not predictive of outcomes. On-therapy assessments showed an increase in the IFN-γ inducible cytokine CXCL10 (p 〈 0.0001) as well as an increase in VEGF-A (p 〈 0.0001) consistent with induction of antitumor immunity and inhibition of angiogenesis. A decrease in PD-L1 expression on circulating CD8+ lymphocytes was associated with shorter PFS and OS (Table), suggesting a potential resistance mechanism. Conclusions: High baseline levels of immunosuppressive cytokines and CD4+ CD69+ lymphocytes portended worse survival in patients treated with AB. Early changes in PD-L1 expression on circulating CD8+ lymphocytes may inform resistance to therapy. Correlation of circulating and tissue-based biomarkers is ongoing. Clinical trial information: NCT02724878. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 4
    In: JAMA Oncology, American Medical Association (AMA), Vol. 9, No. 1 ( 2023-01-01), p. 128-
    Abstract: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. Objective To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. Design, Setting, and Participants This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. Exposures Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). Main Outcomes and Measures The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. Results The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR] , 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). Conclusions and Relevance This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. Trial Registration ClinicalTrials.gov Identifier: NCT04354701
    Type of Medium: Online Resource
    ISSN: 2374-2437
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 5
    In: JAMA Oncology, American Medical Association (AMA)
    Abstract: Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking. Objective To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer. Design, Setting, and Participants This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022. Exposure Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs] , immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19. Main Outcomes and Measures Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up. Results Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR] , 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13). Conclusions and Relevance In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.
    Type of Medium: Online Resource
    ISSN: 2374-2437
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 6
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 11, No. 8 ( 2023-08-03), p. 1114-1124
    Abstract: Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an “inflammatory module” that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49–0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39–0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2732517-9
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  • 7
    In: Journal of Thrombosis and Haemostasis, Elsevier BV, Vol. 19, No. 10 ( 2021-10), p. 2522-2532
    Type of Medium: Online Resource
    ISSN: 1538-7836
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2099291-9
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 5077-5077
    Abstract: 5077 Background: Several ICIs are used in first and subsequent lines of therapy for mRCC, either alone or in combination with another ICI or targeted therapy (TT). There are no data on the efficacy and safety of using an ICI in patients who have already received an ICI in a prior line of therapy. Methods: We reviewed patients with mRCC at 8 institutions who received 2 separate lines of ICI therapy (ICI-1, ICI-2), including as a single-agent and/or combination with other agents. The primary outcomes were overall response rate (ORR) and time to progression (TTP) with ICI-1 and ICI-2. Immune-related adverse events (irAEs) were graded using CTCAEv5.0. Results: 65 patients were included. Median age at diagnosis of mRCC was 60 years (range 30-86) and the majority had clear cell RCC (n=56, 86%). Median follow-up was 3.5 years (95% CI 2.9-4.4). Median lines at which ICI-1 and ICI-2 were received were 1 (1-6) and 3 (2-8) respectively. Reasons for discontinuing ICI-1 were disease progression (n=47, 72%), toxicity (n=15, 23%) or other (n=3, 5%). Therapies received at ICI-2 were single-agent ICI (n=26, 40%), or combinations of ICI with another ICI (n=20, 31%), TT (n=11, 17%) or other agent (n=8, 12%). Responses to ICI-1 and ICI-2 are shown in the Table; ORR to ICI-2 was significantly lower than to ICI-1 (23% vs. 36%, p=0.044). Amongst those who responded to ICI-2 (n=14), 7 (50%) received single-agent ICI, and the remainder received ICI in combination with another ICI (n=4, 29%) or TT (n=3, 21%); 7 patients (50%) had previously responded to ICI-1. The ORR to ICI-2 was higher in responders to ICI-1 (32%) compared to those with SD (17%) or PD (15%) to ICI-1. Median TTP (mTTP) at ICI-2 was shorter compared to ICI-1 (5.3 months vs. 8.5 months, Wilcoxon p=0.024). 29 patients (45%) experienced an irAE with ICI-2; 8 (12%) and 3 (5%) had a grade 3 or 4 irAE respectively, with 3 (30%) of these patients having previously had ≥grade 3 irAE to ICI-1. There were no treatment-related deaths. Conclusions: The ORR to ICI-2 was 23%, which is comparable to that seen with ICI after prior TT. Responses were seen even amongst those receiving single-agent ICI at ICI-2 and the likelihood of response to ICI-2 was higher if a patient had previously responded to ICI-1. No increase in toxicity with ICI-2 was apparent. Additional data from prospective studies are needed to determine whether sequential ICI has a role in treatment of mRCC. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e18766-e18766
    Abstract: e18766 Background: Patients (pts) with thoracic cancers have a high rate of hospitalization and death from COVID-19. Smoking has been associated with increased risk for severe COVID-19. However, there is limited data evaluating the impact of smoking recency on COVID-19 severity in pts with cancer. We aimed to characterize the clinical outcomes of COVID-19 based on the recency of smoking in pts with thoracic cancers (TC) and all other cancers (OC). Methods: Adult pts with cancer and lab-confirmed SARS-CoV-2 and smoking history recorded in the CCC19 registry (NCT0435470) were included. Pts were stratified by cancer type (TC or OC) and further stratified into subgroups based on the recency of smoking cessation: current smoker; former smokers who quit 〈 1 yr. ago; 1-5 yr. ago; 6-10 yr. ago; quit 〉 10 yr. ago; and never smoker. 30-day all-cause mortality was the primary endpoint. Secondary endpoints were any hospitalization; hospitalization with supplemental O2; ICU admission; and mechanical ventilation. Results: From January 2020 to December 2021, 752 pts from TC group and 8,291 pts from OC group met the inclusion criteria. 78% of patients in TC group ever smoked compared to 36% patients in the OC group. In both groups, the majority of never-smokers were females (70% and 60% in TC and OC respectively). The burden of smoking and the rate of pulmonary comorbidities (PC) was higher in the TC group (PC 22-69%) compared to OC group (PC 12-26%) across all smoking strata. Overall, 30-day all-cause mortality was 21% and 11% in pts with TC and OC respectively. Former smokers who quit 〈 1 year ago in TC group had the highest rate of mortality and severe COVID-19 outcomes. However, in the OC group, there was no consistent trend of higher mortality or severe COVID-19 outcomes in specific subgroups based on smoking recency. Conclusions: To our knowledge this is the largest study evaluating the effect of granular phenotypes of smoking recency on COVID-19 outcomes in pts with cancer. Recent smokers who quit 〈 1 year ago in TC group had the highest rate of mortality and severe COVID-19. Further analysis exploring the factors (e.g., smoking pack years) associated with severe outcomes in this subgroup is planned.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4519-4519
    Abstract: 4519 Background: Patients with advanced RCC with S/R components exhibit poor clinical outcomes. IO-based combination therapies demonstrated substantial efficacy among patients with metastatic S/R ccRCC, compared to VEGF targeted therapy (VEGF-TT). Recent trials showed promising activity of IO-based regimens in patients with advanced nccRCC. We sought to assess the efficacy of IO regimens among patients with S/R nccRCC. Methods: Patients with advanced nccRCC treated with 1L IO regimens (IO/IO or IO/VEGF-TT) or 1L VEGF-TT monotherapy (sunitinib or pazopanib) were included. Cases were categorized as S/R or non-S/R. The primary outcomes were overall survival (OS) and time to treatment failure (TTF) in patients with S/R nccRCC receiving 1L IO or VEGF-TT. Overall response rate (ORR) was a secondary outcome. OS and TTF were compared between groups (IO vs. VEGF-TT) using Cox regression models adjusted for age, IMDC risk groups, and nccRCC subtype. ORR was compared between groups (IO vs. VEGF-TT) using a logistic regression adjusted for the same confounders. Results: Overall, 103 patients with S/R nccRCC were included, of whom 33 (32%) received 1L IO regimens. Median follow-up was 31 months. After adjustment for confounding factors, patients with S/R nccRCC treated with IO regimens presented with significantly improved survival outcomes as compared to those receiving VEGF-TT (median OS [mOS]: NR vs. 7.1 and mTTF: 9.4 vs. 2.9 mos for IO regimens and VEGF-TT, respectively). Similarly, a higher ORR was seen in patients with S/R nccRCC receiving IO regimens versus VEGF-TT (34.1 vs. 10.9%, respectively). Among 430 patients with non-S/R nccRCC (IO regimens: n=44), no significant differences in survival outcomes between regimen classes were seen (mOS: 24.4 vs. 14.8 and mTTF: 4.2 vs. 5.0 mos for IO regimens and VEGF-TT, respectively). Conclusions: To our knowledge, this represents the largest effort to characterize the outcomes of patients with S/R nccRCC treated with IO regimens. Patients with S/R nccRCC appear to derive a substantial and selective benefit from IO regimens (vs. VEGF-TT). These data support the use of IO-based regimens in patients with S/R nccRCC. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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