Background
Immune checkpoint inhibitors (ICIs) represent an appealing treatment for patients with advanced urothelial cancer (aUC) and a poor performance status (PS). However, the benefit of ICIs for ...patients with a poor PS remains unknown. It was hypothesized that a poor Eastern Cooperative Oncology Group (ECOG) PS (≥2 vs 0‐1) would correlate with shorter overall survival (OS) in patients receiving ICIs.
Methods
In this retrospective cohort study, clinicopathologic, treatment, and outcome data were collected for patients with aUC who were treated with ICIs at 18 institutions (2013‐2019). The overall response rate (ORR) and OS were compared for patients with an ECOG PS of 0 to 1 and patients with an ECOG PS ≥ 2 at ICI initiation. The association between a new ICI in the last 30 and 90 days of life (DOL) and death location was also tested.
Results
Of the 519 patients treated with ICIs, 395 and 384 were included in OS and ORR analyses, respectively, with 26% and 24% having a PS ≥ 2. OS was higher in those with a PS of 0 to 1 than those with a PS ≥ 2 who were treated in the first line (median, 15.2 vs 7.2 months; hazard ratio HR, 0.62; P = .01) but not in subsequent lines (median, 9.8 vs 8.2 months; HR, 0.78; P = .27). ORRs were similar for patients with a PS of 0 to 1 and patients with a PS ≥ 2 in both lines. Of the 288 patients who died, 10% and 32% started ICIs in the last 30 and 90 DOL, respectively. ICI initiation in the last 30 DOL was associated with increased odds of death in a hospital (odds ratio, 2.89; P = .04).
Conclusions
Despite comparable ORRs, ICIs may not overcome the negative prognostic role of a poor PS, particularly in the first‐line setting, and the initiation of ICIs in the last 30 DOL was associated with hospital death location.
This multi‐institution, retrospective cohort study shows that patients with an Eastern Cooperative Oncology Group performance status ≥2 (versus a performance status of 0‐1) have a comparable overall response rate but worse overall survival with treatment with an immune checkpoint inhibitor as first‐line therapy, whereas treatment initiation in the last 30 days of life is associated with increased odds of hospital death.
Background
In the non‐ETS fusion of prostate cancer (PCa) pathway, SPOP mutations emerge as a distinct oncogenic driver subclass. Both SPOP downregulation and mutation can lead to SPOP target ...stabilization promoting dysregulation of key regulatory pathways. CHD1 gene is commonly deleted in PCa. CHD1 loss significantly co‐occurs with SPOP mutations, resulting in a PCa subclass with increased AR transcriptional activity and with a specific epigenetic pattern.
Methods
In this study, SPOP alterations at mutational and protein levels and CHD1 copy number alterations have been analyzed and correlated with ERG and PTEN protein expression and with the clinical pathological features of the patients.
Results
SPOP protein loss has been detected in 42.9% of the cases, and it has been strongly associated with PTEN protein loss (p < .001). CHD1 gene loss has been detected in 24.5% and SPOP mutations in 5.9% of the cases. Loss of CHD1 has been strongly associated with SPOP mutations (p = .003) and has shown a trend to be associated with ERG wt cancers (p = .08).
The loss of SPOP protein (p = .01) and the combination of PTEN and SPOP protein loss (p = .002) were both statistically more common in grade group 5 cancers, with a prevalence of 60% and 37.5%, respectively. Furthermore, SPOP loss/PTEN loss and SPOP wt/PTEN loss phenotypes were strongly associated with extraprostatic perineural infiltration (p = .007). Strong CHD1 loss was associated with a shorter time to PSA recurrence in the univariate (p = .04), and showed a trend to be associated with the PSA recurrence risk in the multivariate analysis (p = .058).
Conclusions
The results of the present study suggest that the loss of SPOP protein expression, either alone or in combination with loss of PTEN and, on the other hand, a marked loss of the CHD1 gene are very promising prognostic biomarkers in PCa.
Tiragolumab is a first‐in‐class, fully human IgG1/kappa anti‐TIGIT monoclonal antibody that blocks the binding of TIGIT to CD155 (the poliovirus receptor). We summarize the pharmacokinetics (PK) data ...from the phase 1a/1b GO30103 study of Q3W (every 3 weeks) sequential dosing of tiragolumab (2, 8, 30, 100, 400, 600, or 1200 mg) followed by atezolizumab (1200 mg), Q4W (every 4 weeks) sequential dosing (tiragolumab 840 mg followed by atezolizumab 1680 mg), and Q4W co‐infusion (tiragolumab 840 mg plus atezolizumab 1680 mg). Serum samples were collected at multiple time points following tiragolumab and atezolizumab intravenous infusion in patients with solid tumors for PK and immunogenicity assessment. The serum PK profile of tiragolumab appeared to be biphasic, with a rapid distribution phase followed by a slower elimination phase when administered alone or in combination with atezolizumab. In phase 1a, across doses of tiragolumab ranging from 2 to 1200 mg (cycle 1), the geometric mean (GM), coefficient of variation (CV%), serum tiragolumab Cmax ranged from 0.682 to 270 µg/mL (18.6% to 36.5%) and Cmin ranged from 0.0125 to 75.3 µg/mL (0.0% to 24.2%). The GM systemic exposure (area under the plasma drug concentration‐time curve, AUC0‐21) ranged from 310 to 2670 µg day/mL (20.5% to 27.0%); interindividual variability in AUC0‐21 ranged from 20.5% to 43.9%. Tiragolumab exposure increased in an approximately dose‐proportional manner when administered alone or with atezolizumab at doses ≥100 mg. Postbaseline, 4/207 patients (1.9%) were positive for treatment‐emergent antidrug antibodies (ADA) against tiragolumab, each at a single time point. Tiragolumab combined with atezolizumab demonstrated desirable PK properties, with no drug‐drug interactions or immunogenicity liability. There were no meaningful differences in tiragolumab or atezolizumab exposure between the Q4W co‐infusion and sequential dosing cohorts.
ClinicalTrials.gov: NCT02794571 (date of registration June 6, 2016).
Background
ERG fusion‐related prostate cancer (PrCa) is the most prevalent oncogenic driver subclass. SPOP, FOXA1, and IDH1 mutations are other three main oncogenic driver subclasses in ...non–ETS‐fusion PrCa. ERG protein levels seem to be increased in SPOP‐mutated cases, and different studies reported that SPOP mutations and ERG fusions are mutually exclusive. The aim of this study has been to analyze the alterations in non–ETS‐oncogenic drivers in PrCa.
Methods
SPOP, FOXA1, and IDH mutations were investigated by polymerase chain reaction (PCR) and Sanger direct sequencing. ERG, SPOP, and TMPRSS2‐ERG messenger RNA expression was assessed by quantitative real‐time PCR from complementary DNA, and the presence of the fusion was also analyzed by nonquantitative PCR. The clinical pathological features were retrieved from the charts of the 111 patients included in the study (MARBiobanc, Barcelona, Spain).
Results
Loss of SPOP expression (25.2%) was associated with ERG overexpression (P = 0.0036). SPOP mutations were found in 5.4% cases, all with wild‐type (wt) ERG (P = 0.007). FOXA1 mutations were found in 8.2% cases, most of them ERG wt (P = 0.06). No IDH1 mutations were found. SPOP or FOXA1 mutations were found in 1.7% of ERG‐rearranged, and 34.2% of non–ERG‐rearranged cases (P < 0.0001). SPOP or FOXA1 alterations (mutations or expression loss) were significantly more common in GG5, while isolated ERG overexpression was more common in GG1 tumors (P = 0.042). SPOP‐or FOXA1‐mutated cases were associated with a shorter time to prostate‐specific antigen (PSA) recurrence in the univariate (P = 0.0009), and with the PSA recurrence risk in the multivariate (P = 0.023) analysis.
Conclusions
In conclusion, SPOP and FOXA1 mutations may have prognostic value in ERG wt tumors. Interestingly, in absence of SPOP mutations, downregulation of this gene is a feature of many ERG‐rearranged prostate tumors.
TMPRSS2‐ERG expression in blood has been correlated with low docetaxel benefit in metastatic castration‐resistant prostate cancer (mCRPC). This multicenter study aimed to prospectively asses its role ...as a taxane‐resistance biomarker in blood and retrospectively in tumors, exploring also the impact of prior abiraterone/enzalutamide (A/E) in patients and in vitro. TMPRSS2‐ERG was tested by quantitative reverse‐transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2‐ERG expression was correlated with prostate‐specific antigen (PSA)‐progression‐free survival (PFS), radiological‐PFS (RX‐PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. In vitro ERG knockdown and combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Prior A/E (HR 1.8, 95% CI 1.2–2.8) and blood TMPRSS2‐ERG detection (HR 2, 95% CI 1.1–3.7) were independently associated to lower PSA‐PFS. In patients without prior A/E, blood and tumor TMPRSS2‐ERG independently predicted lower PSA‐PFS (HR 3.3, 95% CI 1.4–7.9 and HR 1.8, 95% CI 1.02–3.3, respectively) to taxanes. When prior A/E was administered, TMPRSS2‐ERG was not associated with outcome. There was a significant interaction between blood TMPRSS2‐ERG and prior A/E related to PSA‐PFS (p = 0.032) and RX‐PFS (p = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced the expression of neuroendocrine markers and reduced that of E‐cadherin. We conclude that prior hormone‐therapy may influence taxanes response and TMPRSS2‐ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow‐up evaluation.
What's new?
Despite known resistance mechanisms, no molecular biomarkers to predict taxane resistance are clinically available. TMPRSS2‐ERG rearrangement is a prostate cancerspecific genetic alteration known to impair taxane sensitivity in preclinical models. This study shows that blood and tumour TMPRSS2‐ERG expression independently predicted lower prostate‐specific antigen progression‐free survival in metastatic castration‐resistant prostate cancer (mCRPC) patients following taxanes. When prior abiraterone/ enzalutamide therapy was administered, TMPRSS2‐ERG was not associated with outcome. Prior hormone‐therapy may influence taxane response and TMPRSS2‐ERG prognostic value, suggesting the need for multiple and sequential biomarkers in mCRPC follow‐up evaluation.
Objectives
To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint ...inhibitors (ICIs).
Patients and Methods
We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression‐free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni‐ and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line).
Results
Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio aOR 0.73, 95% confidence interval CI 0.43–1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio aHR 0.93, 95% CI 0.73–1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81–1.27). Patients with mixed‐histology UTUC had a significantly lower ORR and shorter PFS vs mixed‐histology LTUC (aOR 0.20, 95% CI 0.05–0.91 and aHR 1.66, 95% CI 1.06–2.59), respectively).
Conclusion
Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed‐histology UTUC had a lower ORR and shorter PFS compared to mixed‐histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy.
Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers
. Biomarkers may facilitate identification of these ...responding tumors
. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer
. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
Objective
To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first‐line metastatic renal cell ...carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti‐VEGFR therapy in mRCC.
Patients and Methods
SUNRISES, a randomised open‐label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment‐naïve patients with clear‐cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression‐free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety.
Results
Accrual was low due to the advent of new‐generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1‐year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm.
Conclusions
The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.
Objective
To investigate causes of death in a UK cohort of patients with prostate cancer.
Patients and Methods
We examined causes of death in a UK cohort of 50 066 men with prostate cancer diagnosed ...between 1997 and 2006 reported to the Thames Cancer Registry (TCR) and followed‐up to the end of 2007.
The underlying cause of death was taken from the death certificate.
Uptake of PSA screening was low in the UK during the period studied.
We examined the relationship between cause of death and patient characteristics at diagnosis including age, cancer stage, and treatment (≤6 months of diagnosis).
Results
In all, 20 181 deaths occurred during the period; 49.8% recorded as being due to prostate cancer, 17·8% to cardiovascular disease, 11·6% to other cancers, and 20·7% to other causes.
Irrespective of age, cancer stage, or treatment ≤6 months of diagnosis, prostate cancer was an important cause of death ranging from 31·6% to 74·3% of all deaths in different subgroups.
Conclusion
For men with prostate cancer diagnosed in a setting where uptake of PSA screening is low, our findings challenge the belief that prostate cancer is not an important cause of death.
Objectives
To compare clinical outcomes with programmed‐death ligand‐1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical ...surgery (RS) or radiation therapy (RT) prior to developing metastatic disease.
Patients and Methods
We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate ORR, progression‐free survival PFS, overall survival OS) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first‐line and second‐line or greater second‐plus line). Logistic regression was used to compare ORR, while Kaplan–Meier analysis and Cox regression were used for PFS and OS. Multivariable models were adjusted for known prognostic factors.
Results
We included 562 patients (first‐line: 342 and second‐plus line: 220). There was no difference in outcomes based on prior locoregional treatment among those treated with first‐line ICIs. In the second‐plus‐line setting, prior RS was associated with higher ORR (adjusted odds ratio 2.61, 95% confidence interval CI1.19–5.74), longer OS (adjusted hazard ratio aHR 0.61, 95% CI 0.42–0.88) and PFS (aHR 0.63, 95% CI 0.45–0.89) vs no prior RS. This association remained significant when type of prior locoregional treatment (RS and RT) was modelled separately.
Conclusion
Prior RS before developing advanced disease was associated with better outcomes in patients with aUC treated with ICIs in the second‐plus‐line but not in the first‐line setting. While further validation is needed, our findings could have implications for prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include the study’s retrospective nature, lack of randomization, and possible selection and confounding biases.
PDF
