Urothelial carcinoma remains a devastating disease with a poor prognosis. Though immune therapy with Bacillus Calmette–Guérin (BCG) has been used for localized bladder cancer for years, only ...immune-checkpoint blockade with antiprogrammed cell-death 1 (anti-PD-1) and antiprogrammed cell-death ligand 1 (anti-PD-L1) inhibitors have demonstrated improvement in survival of patients with metastatic disease. Anti-PD-L1 antibody, avelumab, was recently given United States Food and Drug Administration (FDA) accelerated approval for the treatment of recurrent/metastatic urothelial carcinoma after failure of first-line chemotherapy, marking the fifth immune checkpoint inhibitor to be given FDA approval for the treatment of metastatic urothelial cancer. The following manuscript will review avelumab, its pharmacology, and the clinical experience that has led to its approval, as well as future plans for clinical development of avelumab for the treatment or urothelial cancer.
Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)-enzalutamide and abiraterone-have been ...the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, responses to the second NAA are infrequent (25-30%) and short-lasting (median PFS ~3 months). With the growing adoption of NAA therapy in pre-metastatic castration-resistant settings, finding better treatment options for first-line mCRPC has become an urgent clinical need. The regulatory approval of two PARP inhibitors in 2020-rucaparib and olaparib-has provided the first targeted therapy option for patients harboring defects in selected DNA damage response and repair (DDR) pathway genes. However, a growing body of preclinical and clinical data shows that co-inhibition of AR and PARP induces synthetic lethality and could be a promising therapy for patients without any DDR alterations. In this review article, we will investigate the limitations of NAA monotherapy, the mechanistic rationale for synthetic lethality induced by co-inhibition of AR and PARP, the clinical data that have led to the global development of a number of these AR and PARP combination therapies, and how this may impact patient care in the next 2-10 years.
Purpose
Telehealth may remain an integral part of cancer survivorship care after the SARS-CoV-2 pandemic. While telehealth may reduce travel/waiting times and costs for many patients, it may also ...create new barriers that could exacerbate care disparities in historically underserved populations, manifesting as differences in overall care participation, and in differential video versus phone use for telehealth.
Methods
We reviewed visits by cancer survivors between January and December 2020 at a designated cancer center in Minnesota. We used descriptive statistics, data visualization, and generalized estimating equation logistic regression models to compare visit modalities and trends over time by age, urban/rural status, and race/ethnicity.
Results
Among 159,301 visits, including 33,242 telehealth visits, older and rural-dwelling individuals were underrepresented in telehealth compared with in-person care. Non-Hispanic White individuals, those aged 18–69 years, and urban residents used video for > 50% of their telehealth visits. In contrast, those aged ≥ 70 years, rural residents, and most patient groups of color used video for only 33–43% of their telehealth visits. Video use increased with time for everyone, but relative differences in telehealth modalities persisted. Visits of Black/African American patients temporarily fell in spring/summer 2020.
Conclusions
Our findings underscore reduced uptake of telehealth, especially video, among potentially vulnerable patient populations. Future research should evaluate reasons for differential telehealth utilization and whether visit modality (in-person versus video versus phone) affects cancer outcomes.
Implications for Cancer Survivors
A long-term cancer care model with integrated telehealth elements needs to account for specific barriers for vulnerable populations.
We improved the bispecific antibody platform that primarily engages natural killer (NK) cells to kill cancer cells through antibody-dependent cellular cytotoxicity (ADCC) by adding IL-15 as a ...crosslinker that expands and self-sustains the effector NK cell population. The overall goal was to target B7-H3, an established marker predominantly expressed on cancer cells and minimally expressed on normal cells, and prove that it could target cancer cells in vitro and inhibit tumor growth in vivo. The tri-specific killer engager (TriKE
) was assembled by DNA shuffling and ligation using DNA encoding a camelid anti-CD16 antibody fragment, a wild-type IL-15 moiety, and an anti-B7-H3 scFv (clone 376.96). The expressed and purified cam1615B7H3 protein was tested for in vitro NK cell activity against a variety of tumors and in vivo against a tagged human MA-148 ovarian cancer cell line grafted in NSG mice. cam1615B7H3 showed specific NK cell expansion, high killing activity across a range of B7-H3+ carcinomas, and the ability to mediate growth inhibition of aggressive ovarian cancer in vivo. cam1615B7H3 TriKE improves NK cell function, expansion, targeted cytotoxicity against various types of B7-H3-positive human cancer cell lines, and delivers an anti-cancer effect in vivo in a solid tumor setting.
We have previously shown that the long non-coding (lnc)RNA
(
; formerly
) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene
(a ...homolog of the
gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the
/
regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression.
The reciprocal
and
gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of
and
to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence.
We consistently observed increased expression of
and decreased expression of
in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of
or
and time to disease recurrence, independent of tumor grades and stages.
We concluded that upregulation of the lncRNA
and targeted downregulation of the protein-coding
gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted.
We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).
The treatment landscape of metastatic prostate cancer (mPCa) has evolved considerably over the past 15 years with approvals of targeted therapies such as poly-ADP-ribose polymerase inhibitors (PARPi) ...in castration-resistant metastatic castration-resistant prostate cancer (mCRPC) setting and novel antiandrogens and docetaxel in hormone-sensitive metastatic hormone-sensitive prostate cancer (mHSPC) setting. A number of promising clinical trials are now evaluating therapeutic combinations rooted in an improving understanding of tumor biology. Despite a plethora of effective treatment options, decisions regarding choice of therapy remain challenging due to the lack of head-to-head trials and a substantial overlap in selection criteria used in these trials. We summarize the data from key trials that led to approval of commonly used mPCa therapies and provides an easy-to-use clinical decision-making framework that incorporates patient-specific and disease-specific factors to aid selection of the optimal therapy. We outline the evolving use-cases for biomarker-guided treatment selection and our approach to incorporating these therapies in clinical practice. Finally, we highlight the rapidly growing pipeline of therapies that are in advanced stages of clinical development, such as combinations of novel antiandrogen and PARPi, vascular endothelial growth factor (VEGF) inhibitor and immunotherapy, as well as prostate specific membrane antigen (PSMA)-targeted therapies, many of which are poised to transform the landscape in the coming decade.
Background.
Sorafenib is an orally active multikinase inhibitor, and bortezomib is a proteasome inhibitor that affects multiple signaling pathways. Sorafenib has clinical activity in renal cell ...carcinoma (RCC), whereas bortezomib has demonstrated activity against RCC cell lines in vitro, with in vitro studies showing synergism between the two agents in the induction of apoptosis in neoplastic cell lines. In this phase II study, we explored the efficacy and toxicity of this regimen.
Methods.
Adult patients with cytologically confirmed clear cell RCC with no prior chemotherapy, Zubrod performance status of 0–1, serum creatinine <1.5 mg/dL, and normal liver function tests were treated with sorafenib 200 mg orally b.i.d. with bortezomib 1 mg/m2 intravenously on days 1, 4, 8, and 11 every 21 days. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was median progression‐free survival (PFS) of at least 70 weeks.
Results.
Seventeen patients were enrolled between April 2011 and January 2013. Median age was 62 years (range: 44–75 years). Four of 17 patients had known brain metastasis on enrollment. Median number of cycles was 4 (range: 1 to ≥45). No patient had complete response, 1 had partial response, 12 had stable disease, and 4 had progressive disease (response rate of 6%; 95% confidence interval: 0%–29%) with treatment. Median PFS was 13.7 weeks, and median overall survival was 110 weeks. The study was halted for futility.
Conclusion.
The combination of sorafenib and bortezomib was well tolerated; however, response rate and PFS were comparable to sorafenib monotherapy. This regimen is not recommended for further development.
摘要
背景. 索拉非尼是口服的活性多激酶抑制剂，硼替佐米是可影响多个信号通路的蛋白酶体抑制剂。索拉非尼对肾细胞癌（RCC）具有临床活性，而硼替佐米则在体外RCC细胞系中被证实具有抗RCC活性，同时在体内研究提示这两个药物在诱导肿瘤细胞系凋亡方面具有协同作用。我们在本项II期研究中探索了这一方案的有效性和毒性特征。
方法. 患者入选标准如下：成年，经细胞学确诊为透明细胞型RCC，既往未接受过化疗，Zubrod体能状态0 ∼ 1，血清肌酐水平< 1.5 mg/dL，肝功能检验结果正常。治疗方案：索拉非尼200 mg口服，每天两次；硼替佐米于第1、4、8、11天1 mg/m2静脉输注，21天为一周期。治疗持续至疾病进展或发生不可接受的毒性事件。主要终点是中位无进展生存（PFS）至少达到70周。
结果. 2011年4月至2013年1月共纳入17例患者。中位年龄62岁（范围：44 ∼ 75岁）。4/17例患者在进入研究时已知发生脑转移。中位治疗周期为4个（范围：1 ∼ ≥ 45）。接受治疗的患者中，无人达到完全缓解，1例部分缓解，12例疾病稳定，4例发生疾病进展（缓解率为6%，95%可信区间：0 ∼ 29%）。中位PFS为13.7周，中位总生存为110周。研究因无获益而停止。
结论. 索拉非尼联合硼替佐米方案耐受良好，但缓解率和PFS与索拉非尼单药治疗相似。不建议对该方案进行进一步研究。The Oncologist 2015;20:370–371
Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune ...checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients.
We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0–1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants.
Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3–28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8–89·3) of 22 treatment-naive patients, seven (41·2%, 18·4–67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7–65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 21% of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia).
Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC.
Eisai and Merck Sharp & Dohme.
Advanced renal cell carcinoma (RCC) results in over 14,000 deaths each year in the United States alone. The therapeutic landscape for advanced RCC changed dramatically with the approval of tyrosine ...kinase inhibitors (TKI) between 2006 and 2012. A large-scale analysis of survival trends has not been performed in the TKI era to determine their impact on outcomes for advanced RCC patients.
The Surveillance, Epidemiology and End-Results (SEER) database was queried for adult patients with advanced RCC diagnosed between 2000 and 2013. Patients were divided into two cohorts based on the year of diagnosis-pre-TKI cohort 2000-2006 and TKI cohort 2007-2013. Kaplan-Meier survival and multivariate Cox proportional hazards analyses were performed.
A total of 14,976 patients were included in our study. Median age at diagnosis was 64 years (range, 18-89 years). Median (cancer-specific) overall survival was 10.0 months in the TKI cohort compared with 8.0 months in the pre-TKI cohort, corresponding to a 13% improvement in survival in the TKI area hazard ratio (HR) for death 0.87; 95% confidence interval (CI), 0.84-0.91, P<0.0001. Median survival was improved by 2 months for patients with clear-cell RCC histology HR for death 0.86; 95% CI, 0.84-0.91, P<0.0001. Patients with non-clear cell RCC had a 25% higher risk of mortality compared with those with clear-cell RCC. Additionally, median survival for non-clear cell RCC patients was not statistically different between the two cohorts (HR for death 0.98; 95% CI, 0.88-1.09, P=0.714). Subgroup analysis showed that elderly patients (age 71 years and above) had a 45% higher risk of death from advanced RCC compared with young patients (aged 18-50 years) HR for death 1.45; 95% CI, 1.36-1.54, P<0.0001. Gender and racial disparities in outcomes were also noted with women having a 10% higher risk of death compared with men (HR for death 1.10; 95% CI, 1.06-1.14, P<0.001) and Black patients having a 15% higher risk of death compared with White patients (HR for death 1.15; 95% CI, 1.08-1.23, P<0.0001).
Our study provides a largest registry-based analysis of survival outcomes in the TKI era. In majority of patients, the survival has improved significantly with the advent of TKIs as standard of care therapy. Survival for patients with non-clear cell RCC is clearly worse than clear-cell RCC and does not appear to have changed with TKIs. Elderly patients, women, and Black patients appear to have worse outcomes and these disparities merit further investigation.
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