Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received ...prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti-PD-1 pathway-targeted therapy.
Patients with metastatic RCC who received prior anti-PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed.
Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients.
Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.
Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for
-mutant lung cancer, yet resistance inevitably develops in ...patients. We modeled acquired resistance to osimertinib in transgenic mouse models of
-induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in
-either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in
. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance
. SIGNIFICANCE: This study provides insight into the biological and molecular properties of osimertinib resistance
mutations and evaluates therapeutic strategies to overcome resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/2017/F1.large.jpg.
Background
Population‐based studies demonstrate that Black men in the United States have an increased risk of death from prostate cancer. Determinants of racial disparities are multifactorial, ...including socioeconomic and biologic factors.
Methods
The authors conducted a pooled analysis of patients derived from 152 centers within the Veterans Health Administration. The cohort included men who had nonmetastatic prostate diagnosed between 2001 and 2015 and received definitive radiation therapy. The primary endpoint was prostate cancer‐specific mortality (PCSM). Secondary endpoints included all‐cause mortality (ACM) and the time from a prostate‐specific antigen level ≥4 ng/mL to biopsy and radiation therapy. A Cox regression model was performed to adjust for differences between clinical parameters.
Results
Among the 31,131 patients included in the cohort, 9584 (30.8%) were Black. The 10‐year cumulative incidence of death from prostate cancer was lower in Black men compared with White men (4.0% vs 4.8%; P = .004). In a competing risk model, Black race was associated with a decreased risk of PCSM (subdistribution hazard ratio, 0.79; 95% CI, 0.69‐0.92; P = .002). Similarly, the 10‐year cumulative incidence of death from any cause was lower in Black men (27.6% vs 31.8%; P < .001). In multivariable analysis, Black men had a 10% decreased risk of ACM (hazard ratio, 0.90; 95% CI, 0.85‐0.95; P < .001).
Conclusions
The current results indicate relatively lower PCSM and ACM among Black men who were included in a large Veterans Health Administration cohort and received radiation therapy as primary treatment for nonmetastatic prostate cancer. There is an ongoing need to continue to understand and mitigate the factors associated with disparities in health care outcomes.
In this pooled analysis from multiple Veterans Health Administration medical centers, an association is observed between race and both prostate cancer‐specific and all‐cause mortality in men who receive curative‐intent radiation therapy. However, when care is delivered in a system with improved access, mortality decreases among Black men with prostate cancer who receive radiation therapy.
Abstract
Background
Despite higher risks associated with prostate cancer, young African American men are poorly represented in prostate-specific antigen (PSA) trials, which limits proper ...evidence-based guidance. We evaluated the impact of PSA screening, alongside primary care provider utilization, on prostate cancer outcomes for these patients.
Methods
We identified African American men aged 40-55 years, diagnosed with prostate cancer between 2004 and 2017 within the Veterans Health Administration. Inverse probability of treatment-weighted propensity scores were used in multivariable models to assess PSA screening on PSA levels higher than 20, Gleason score of 8 or higher, and metastatic disease at diagnosis. Lead-time adjusted Fine-Gray regression evaluated PSA screening on prostate cancer–specific mortality (PCSM), with noncancer death as competing events. All statistical tests were 2-sided.
Results
The cohort included 4726 patients. Mean age was 51.8 years, with 84-month median follow-up. There were 1057 (22.4%) with no PSA screening prior to diagnosis. Compared with no screening, PSA screening was associated with statistically significantly reduced odds of PSA levels higher than 20 (odds ratio OR = 0.56, 95% confidence interval CI = 0.49 to 0.63; P < .001), Gleason score of 8 or higher (OR = 0.78, 95% CI = 0.69 to 0.88; P < .001), and metastatic disease at diagnosis (OR = 0.50, 95% CI = 0.39 to 0.64; P < .001), and decreased PCSM (subdistribution hazard ratio = 0.52, 95% CI = 0.36 to 0.76; P < .001). Primary care provider visits displayed similar effects.
Conclusions
Among young African American men diagnosed with prostate cancer, PSA screening was associated with statistically significantly lower risk of PSA levels higher than 20, Gleason score of 8 or higher, and metastatic disease at diagnosis and statistically significantly reduced risk of PCSM. However, the retrospective design limits precise estimation of screening effects. Prospective studies are needed to validate these findings.
With the advent of new therapeutic modalities, management of metastatic castrate-sensitive prostate cancer (mCSPC) has been in flux. From androgen-deprivation therapy to docetaxel to androgen ...receptor-signaling inhibitors, each agent has heralded a new treatment paradigm. As such, the optimal first-line therapy for mCSPC remains incompletely defined. This review provides a narrative of recent advances to systemic therapy within the mCSPC treatment space, particularly with regard to expansion to triplet therapy.
Background
Black patients with laryngeal squamous cell carcinoma (LSCC) historically have inferior outcomes in comparison with White patients. The authors investigated these racial disparities within ...the Veterans Health Administration (VHA), an equal‐access system, and within the Surveillance, Epidemiology, and End Results (SEER) program, which is representative of the US hybrid‐payer system.
Methods
Patients with invasive (T1 or greater) LSCC were included from SEER (2004‐2015) and the VHA (2000‐2017). The primary outcomes of overall survival (OS) and larynx cancer–specific survival (LCS) were evaluated in Cox and Fine‐Gray models.
Results
In the SEER cohort (7122 patients: 82.6% White and 17.4% Black), Black patients were more likely to present with advanced disease and had inferior OS (hazard ratio HR, 1.37; 95% CI, 1.26‐1.50; P < .0001) in a multivariable analysis. Black LCS was worse in a univariable analysis (HR, 1.42; 95% CI, 1.27‐1.58; P < .0001), but this effect was attenuated by 83% when the authors controlled for the TNM category and was found to be insignificant in a multivariable analysis (HR, 1.05; 95% CI, 0.93‐1.18; P = .42). In the VHA cohort (9248 patients: 79.7% White and 20.3% Black), the 2 racial cohorts presented with similar tumor characteristics and similar OS (HR, 0.95; 95% CI, 0.89‐1.02; P = .14). Black LCS was similar in univariable (HR, 1.10; 95% CI, 1.00‐1.22; P = .05) and multivariable analyses (HR, 1.02; 95% CI, 0.92‐1.14; P = .67).
Conclusions
Black patients with LSCC had a tumor burden at diagnosis and survival outcomes comparable to those of White patients within the VHA; this was counter to what was observed in the SEER analysis and prior national trends. This study's findings point toward the notable role of health care access in contributing to racial health disparities in the realm of larynx cancer.
Within the “equal‐access” veterans' health system, Black and White patients with larynx cancer have similar disease burdens at diagnosis and similar larynx cancer survival outcomes. These observations, in contrast to Surveillance, Epidemiology, and End Results data, suggest that health care access may be a significant mediator of race‐based larynx cancer survival disparities.
•In this study the authors present 20 years of National Cancer Institute data on clinical trial enrollment for Kidney and Bladder cancer.•The authors found that compared to cancer incidence, Black, ...Hispanic and Female patients were underrepresented in Bladder and Kidney Cancer trials.•Lastly, Black and female patient participation was consistently unchanged throughout the 20 year period.
To determine the representation of women, minorities, and the elderly groups in clinical trials and whether participation has changed over time.
Retrospective study in the National Cancer Institute (NCI) Clinical Data Update System and Center for Disease Control and Prevention United States Cancer Statistics 2000 to 2019. We compared cancer incidence proportion to proportion of patients enrolled in an NCI trial when stratified by race/ethnicity, sex, and age. We performed multivariable analysis to determine the odds of participating in a clinical trial in 2015 to 2019 when compared to 2000 to 2004.
This study included 14,094 patients, 12,169 (86.3%) non-Hispanic White patients, 662 (4.7%) Black patients, and 660 (4.7%) Hispanic patients. There were 3,701 (26.3%) female patients and 10,393 (73.7%) male patients. For bladder cancer clinical trials, Black patients and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (odds ratio OR 0.71, 95% confidence interval CI 0.57–0.88, P = 0.002) and (OR 0.69, 95%CI 0.54–0.88, P = 0.003), respectively. For kidney cancer trials, Black and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (OR 0.42, OR 0.33–0.54, P < 0.001) and (OR 0.68, 95% CI 0.55–0.83, P < 0.001), respectively. Women were underrepresented in kidney cancer trials compared to men (OR 0.80, 95% CI 0.72–0.89) and similarly for bladder cancer trials (OR 0.72, 95% CI 0.64–0.81, P < 0.001). For bladder cancer trials, the participation of Black patients over time (OR 1.04, P = 0.814) and female patients over time (OR 1.03, P = 0.741) were unchanged. For kidney cancer trials, the participation of Black patients over time (OR 1.17, P = 0.293) and female patients over time (OR 1.03, P = 0.663) participation was also unchanged.
In this study of clinical trials in bladder and kidney cancer, we identified that Blacks, Hispanics, and females were underrepresented. Additionally, Black and female participation was unchanged over the span of 20 years.
Background
The safety of active surveillance (AS) for African American men compared with non‐Hispanic White (White) men with intermediate‐risk prostate cancer is unclear.
Methods
The authors ...identified patients with modified National Comprehensive Cancer Network favorable (“low‐intermediate”) and unfavorable (“high‐intermediate”) intermediate‐risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration database. They analyzed definitive treatment, disease progression, metastases, prostate cancer–specific mortality (PCSM), and all‐cause mortality by using cumulative incidences and multivariable competing‐risks (disease progression, metastasis, and PCSM) or Cox (all‐cause mortality) regression.
Results
The cohort included 1007 men (African Americans, 330 32.8%; Whites, 677 67.2%) followed for a median of 7.7 years; 773 (76.8%) had low‐intermediate‐risk disease, and 234 (23.2%) had high‐intermediate‐risk disease. The 10‐year cumulative incidences of definitive treatment were not significantly different (African Americans, 83.5%; 95% confidence interval CI, 78.5%‐88.7%; Whites, 80.6%; 95% CI, 76.6%‐84.4%; P = .17). Among those with low‐intermediate‐risk disease, there were no significant differences in the 10‐year cumulative incidences of disease progression (African Americans, 46.8%; 95% CI, 40.0%‐53.3%; Whites, 46.9%; 95% CI, 42.1%‐51.5%; P = .91), metastasis (African Americans, 7.1%; 95% CI, 3.7%‐11.8%; Whites, 10.8%; 95% CI, 7.6%‐14.6%; P = .17), or PCSM (African Americans, 3.8%; 95% CI, 1.6%‐7.5%; Whites, 3.8%; 95% CI, 2.0%‐6.3%; P = .69). In a multivariable regression including the entire cohort, African American race was not associated with increased risks of definitive treatment, disease progression, metastasis, PCSM, or all‐cause mortality (all P > .30).
Conclusions
Outcomes in the Veterans Affairs Health System were similar for African American and White men treated for low‐intermediate‐risk prostate cancer with AS.
The safety of active surveillance for African American men with intermediate‐risk prostate cancer is unclear. This study has measured similar clinical outcomes for African American men and non‐Hispanic White men treated for either modified National Comprehensive Cancer Network (NCCN) favorable (“low‐intermediate”) or unfavorable (“high‐intermediate”) intermediate‐risk prostate cancer with active surveillance, and it suggests that active surveillance may be an appropriate option for both African American men and non‐Hispanic White men with modified NCCN favorable (“low‐intermediate”) intermediate‐risk prostate cancer.
As the indications for the use of immunotherapy in genitourinary malignancies expand, its role in combination with standard or conventional therapies has become the subject of contemporary studies. ...Radiotherapy has multiple immunomodulating effects on anti-tumor immune response, which highlights potential synergistic role with immunotherapy agents. We sought to review the body of published data studying the combination of immunotherapy and radiotherapy as well as the rationale for combination therapy. Trial information and primary articles were obtained using the following terms "immunotherapy", "radiotherapy", "prostate cancer", and "bladder cancer." All articles and trials were screened to ensure they included combination radiotherapy and immunotherapy. The effects of radiation on the immune system, including both immunogenic and immunosuppressive effects, have been reported. There is a potential for combinatorial or synergistic effects between radiation therapy and immunotherapy in treating bladder and prostate cancers. However, results from ongoing and future clinical trials are needed to best integrate immunotherapy into current standard of care treatments for GU cancers.
Active surveillance (AS) is a safe treatment option for men with low-risk, localized prostate cancer. However, the safety of AS for patients with intermediate-risk prostate cancer remains unclear.
We ...identified men with NCCN-classified low-risk and favorable and unfavorable intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration. We analyzed progression to definitive treatment, metastasis, prostate cancer-specific mortality (PCSM), and all-cause mortality using cumulative incidences and multivariable competing-risks regression.
The cohort included 9,733 men, of whom 1,007 (10.3%) had intermediate-risk disease (773 76.8% favorable, 234 23.2% unfavorable), followed for a median of 7.6 years. The 10-year cumulative incidence of metastasis was significantly higher for patients with favorable (9.6%; 95% CI, 7.1%-12.5%; P<.001) and unfavorable intermediate-risk disease (19.2%; 95% CI, 13.4%-25.9%; P<.001) than for those with low-risk disease (1.5%; 95% CI, 1.2%-1.9%). The 10-year cumulative incidence of PCSM was also significantly higher for patients with favorable (3.7%; 95% CI, 2.3%-5.7%; P<.001) and unfavorable intermediate-risk disease (11.8%; 95% CI, 6.8%-18.4%; P<.001) than for those with low-risk disease (1.1%; 95% CI, 0.8%-1.4%). In multivariable competing-risks regression, favorable and unfavorable intermediate-risk patients had significantly increased risks of metastasis and PCSM compared with low-risk patients (all P<.001).
Compared with low-risk patients, those with favorable and unfavorable intermediate-risk prostate cancer managed with AS are at increased risk of metastasis and PCSM. AS may be an appropriate option for carefully selected patients with favorable intermediate-risk prostate cancer, though identification of appropriate candidates and AS protocols should be tested in future prospective studies.
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