Background
Previous studies have shown that men with HIV and germ cell cancer (HIV‐GCC) have inferior overall survival (OS) in comparison with their HIV‐negative counterparts. However, little ...information is available on treatments and outcomes of HIV‐GCC in the era of combination antiretroviral therapy (cART).
Methods
This study examined men living with HIV who were 18 years old or older and had a diagnosis of histologically proven germ cell cancer (GCC). The primary outcomes were OS and progression‐free survival (PFS).
Results
Data for 89 men with a total of 92 HIV‐GCCs (2 synchronous GCCs and 1 metachronous bilateral GCC) were analyzed; among them were 64 seminomas (70%) and 28 nonseminomas (30%). The median age was 36 years, the median CD4 T‐cell count at GCC diagnosis was 420 cells/µL, and 77% of the patients on cART had an HIV RNA load < 500 copies/mL. Stage I disease was found in 44 of 79 gonadal GCCs (56%). Among 45 cases with primary disseminated GCC, 78%, 18%, and 4% were assigned to the good‐, intermediate‐, and poor‐prognosis groups, respectively, of the International Germ Cell Cancer Collaborative Group. Relapses occurred in 14 patients. Overall, 12 of 89 patients (13%) died. The causes of death were refractory GCC (n = 5), an AIDS‐defining illness (n = 3), and other causes (n = 4). After a median follow‐up of 6.5 years, the 5‐ and 10‐year PFS rates were 81% and 73%, respectively, and the 5‐ and 10‐year OS rates were 91% and 85%, respectively.
Conclusions
The 5‐ and 10‐year PFS and OS rates of men with HIV‐GCC were similar to those reported for men with HIV‐negative GCC. Patients with HIV‐GCC should be managed identically to HIV‐negative patients.
Lay Summary
Men living with HIV are at increased risk for germ cell cancer (GCC).
Previous studies have shown that the survival of men with HIV‐associated germ cell cancer (HIV‐GCC) is poorer than the survival of their HIV‐negative counterparts.
This study examined the characteristics, treatments, and outcomes of 89 men with HIV‐GCC in the era of effective combination antiretroviral therapies.
The long‐term outcomes of men with HIV‐GCC were similar to those reported for men with HIV‐negative GCC.
Patients with HIV‐GCC should be managed identically to HIV‐negative patients.
In this study of 89 men with HIV and germ cell cancer, the 5‐year progression‐free and overall survival rates are 81% and 91%, respectively. The long‐term outcomes of men with HIV‐associated germ cell cancer are similar to those reported for men with HIV‐negative germ cell cancer.
Abstract Updated information published up to 2016 regarding major advances in renal cancer, bladder cancer, and prostate cancer is here presented. Based on an ever better understanding of the genetic ...and molecular alterations that govern the initial pathogenic mechanisms of tumor oncogenesis, an improvement in the characterization and treatment of urologic tumors has been achieved in the past year. According to the Cancer Genome Atlas (ATLAS) project, alterations in the MET pathway are characteristics of type 1 papillary renal cell carcinomas, and activation of NRF2-ARE pathway is associated with the biologically distinct type 2. While sunitinib and pazopanib continue to be the standard first-line treatment in metastatic renal cell carcinoma of clear cell histology, nivolumab and and cabozantinib are now the agents of choice in the second-line setting. In relation to urothelial bladder carcinoma, new potential molecular targets such as FGFR3 , PI3 K/AKT , RTK/RAS , CDKN2A , ARIDIA , ERBB2 have been identified. Response to adjuvant cisplatin-based chemotherapy appears to be related to basal, luminal, and p53-like intrinsic subtypes. A phase II study with eribulin and a maintenance phase II trial with vinflunine have shown promising results. Similarly, the use of the check point inhibitors in advanced disease is likely to revolutionize the management of patients who have progressed after cisplatin-based chemotherapy. In prostate cancer, seven mutually exclusive molecular subtypes have been identified by the TCGA project. Chemotherapy has been consolidated as a key treatment for castration-sensitive metastatic prostate cancer, and abiraterone, enzalutamide, cabazitaxel, and radium-223 remain standard therapeutic options for men with metastatic castration-resistant prostate cancer. All this progress will undoubtedly contribute to the development of new treatments and therapeutic strategies that will improve the survival and quality of life of our patients.
Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved ...therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting.
In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms.
The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%).
EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.
Improved understanding of renal cell carcinomas (RCC) and recent contributions in the field of RCC biology led to the development of a novel class of drugs, i.e. multiple-kinase inhibitors, targeting ...growth factor receptors (e.g. sorafenib). Sorafenib has proven significant benefit in terms of progression-free survival in a phase II trial in RCC patients. A subsequent randomized phase III study (Treatment Approaches in Renal Cancer Global Evaluation Trial) confirmed the significantly prolonged progression-free survival and improvement in the quality of life compared to patients receiving placebo. In the USA and Europe, sorafenib has been approved for the treatment of advanced RCC.
Two RCC patients on chronic hemodialysis were treated with sorafenib.
Both patients responded to sorafenib treatment. Apart from high blood pressure, a major adverse effect of sorafenib treatment, treatment was well tolerated, in agreement with previous results.
The results of our study confirm the beneficial effect of sorafenib in the treatment of RCC in our 2 patients on dialysis.
The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell ...carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints.
In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334.
Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 95% CI 0·50–0·80). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 3% of 496 participants) and increased alanine aminotransferase (in 11 2%) in the pembrolizumab group, and hypertension (in 13 3% of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.
Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.
Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.
Intratumoral injection of ilixadencel, consisting of proinflammatory allogeneic dendritic cells, before nephrectomy, followed by sunitinib treatment after nephrectomy showed a trend for improved ...tumor response rate and overall survival, compared with sunitinib monotherapy.
The prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial.
To evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC.
A randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients).
The primary endpoints were 18-mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests.
The median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42–1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival.
The study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy.
We studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.
e17007
Background: Real-world evidence (RWE) on the epidemiology and management of localized/locally advanced prostate cancer (LPC) is lacking. Here we used EHRead, a natural language processing ...framework based on SNOMED CT terminology, to extract clinical information from electronic health records (EHRs) to perform a comprehensive description of a real-world cohort of LPC patients. Here we present a follow-up of the project already communicated at ESMO 2020. Methods: This is an observational, multicenter, retrospective study based on the secondary analysis of free-text and structured clinical information found in EHRs from all observed adult patients with LPC between January 2014 and December 2018 in 12 Spanish hospitals. A total of 375 variables were extracted using EHRead to assess patient clinical characteristics, treatment patterns and journey across different prostate cancer stages. Event-free survival (EFS) was analyzed in incident LPC patients with presence of Gleason or PSA and follow-up greater than 0 days. A multivariable Cox-proportional hazards model was applied to obtain adjusted hazard ratios (aHR). Results: We observed 19788 patients with LPC during a median of 3.5 (interquartile range 1.4-7.4) years of follow-up. 52% of patients had low- (LR), 21% intermediate- (IR) and 27% high-risk (HR) disease. 3938 (18%) patients transitioned to other disease stages, leading to castration-resistant prostate cancer (mCRPC) in 4%, 7%, 16% of patients with LR, IR, and HR LPC, respectively. 7884 (42%) patients received radiotherapy (RT), 7021 (38%) prostatectomy (PT), 6061 (31%) androgen deprivation therapy (ADT), and 1034 (6%) active surveillance. Local recurrence was observed in 3% and distant metastasis in 11% (57% bone, 37% visceral). Distant metastases were observed in 7%, 12% and 21% of HR, IR and LR; 8% vs. 9% of PT vs. RT; and 16% vs 6% of ADT vs. no ADT, respectively. EFS was assessed in 7465 (38%) patients, with a 4-year EFS rate of 18%. Median EFS was 22, 13, and 8 months for LR, IR, HR; 23 vs. 12 months for PT vs. RT; and 8 vs. 21 months for ADT vs. no ADT, respectively. A multivariable cox proportional hazards model is presented in the following Table. Conclusions: During the study period, 11% of all LPC patients developed metastatic disease, with only 18% remaining event-free at 4 years. Transition to mCRPC was 4- and 2-fold higher in HR vs. IR and LR disease, respectively. Disease risk, treatment with RT and/or addition of ADT were independently associated with shorter EFS. Our findings suggest that, despite adjuvant treatment, LPC local extension and histopathological characteristics at diagnosis remain critical determinants of patient prognosis. A more detailed analysis in patients with available Gleason and PSA is underway. Table: see text
5043
Background: PSqCC is a rare tumor with poor prognosis. The standard of care for advanced disease (AD) has been palliative platinum-based chemotherapy (CT). Most PSqCC patients (pts) have high ...levels of programmed death-ligand 1 (PD-L1). ORPHEUS has evaluated the efficacy and safety of Rf –a PD-1 antagonist– in pts with unresectable locally advanced or metastatic PSqCC. Methods: ORPHEUS (NCT04231981) is an international, multicenter, open-label, single-arm phase II trial. The study enrolled pts aged ≥18 years with locally advanced or metastatic PSqCC who had not received any previous treatment with PD-1 or PD-L1/2 agents. Pts received Rf 500 mg intravenously on day 1 of each 28-day cycle until progressive disease, unacceptable toxicity, discontinuation or death. The primary endpoint was investigator-assessed objective response rate (ORR) as per RECIST v.1.1. Secondary endpoints included clinical benefit rate, progression-free survival (PFS), duration of response (DoR), time to response (TTR), disease control rate (DCR), overall survival (OS) and safety evaluated as per NCI-CTCAE 5.0. The design was planned to attain an 80% power at 5% one-sided α level (H0: ORR≤5%; HA: ORR≥25%). Results: Between Jul 7, 2020, and Aug 26, 2021, 18 men were enrolled at 8 sites from Italy and Spain. Median age was 64.2 years (range 42-81),13 (72.2%) pts had an AD at first diagnosis, 15 (83.3%) had a previous surgical procedure for penile cancer (lymphadenectomy in 7 pts), 10 (55.6%) had previously received platinum-based CT (TPF/TIP in 8 pts) and 7 (38.9%) were naïve to AD treatment. At data cutoff (Aug 26, 2022), with a median follow-up of 7.2 months, no pts remained on therapy. ORR (3 partial responses) was 16.7% (95% CI 5.8%-39.2%) with a median DoR and TTR of 3.3 (range 1.8-8.5) and 1.9 (range 1.7-2.4) months, respectively. DCR was (33.3%) (1 stable disease ≥ 6 months). Median PFS was 2.0 months (95% CI 1.6-3.3) and median OS with 17 events was 7.2 months (95% CI 3.0-9.8). Most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were fatigue (27.8%; 5.6% G≥3), cellulitis, groin infection and Pseudomonas infection (11.1%; 5.6% G≥3), respectively. Treatment related (TR) TEAEs were fatigue (22.2%; 5.6% G≥3), rash (5.6%; 0% G≥3) and decreased appetite (5.6% G≥3). Anemia (11.1%; 0% G≥3) was the most frequent hematological TEAE. Serious unrelated TEAEs occurred in 5 pts (27.8%). Two (11.1%) pts discontinued treatment due to unrelated non-hematological TEAEs; 1 case of infected lymphocele (G3) and 1 case of skin neoplasm bleeding (G3). No TR deaths were reported. Conclusions: Rf in monotherapy showed signals of clinical activity in advanced or metastatic PSqCC pts. Safety profile was consistent with previous data. These results along with identification of suitable biomarkers could help to develop novel immunotherapy combination strategies in this orphan genitourinary tumor. Clinical trial information: NCT04231981 .
463
Background: Real-world evidence on la/mUC management in Europe is limited. This study describes patient (pt) characteristics, treatment patterns, survival, and HCRU for pts with la/mUC in Spain. ...Methods: A retrospective chart review was conducted using electronic medical records from 9 university hospitals in Spain. The study population included all pts aged ≥18 y with a first diagnosis/record of la/mUC from 1/1/2015–12/31/2020 (study period). Date of first la/mUC record/diagnosis during the study period was the index date. Pts with urachus carcinoma or other nonurothelial cancers were excluded. Pt characteristics are described for the full study population. Treatment patterns, survival, and la/mUC-associated HCRU are described for the follow-up cohort: a subset of the study cohort with a first la/mUC diagnosis/record from 1/1/2015–6/30/2020 (ie, to allow for ≥6 mo follow-up). Pts were followed from index date to death, loss to follow-up, or end of study. Median overall survival (OS) and progression-free survival (PFS; evaluated in a real-world setting) were determined using Kaplan–Meier curves. Time to progression, excluding pts who died and were censored at death, was also estimated. HCRU included inpatient admissions, outpatient visits, and emergency visits. Results: Overall, 903 pts were included. Median age at la/mUC diagnosis was 70 y; 79.6% were men. Most (71.0%) had ≥1 comorbidity, most commonly cardiovascular disease (54.2%). Primary tumor sites were the bladder (83.7%), urethra (7.0%), and upper tract (6.6%). De novo la/mUC (41.9%) was the most common initial UC diagnosis. In the follow-up cohort (n = 829), median follow-up was 12.7 mo. Most (84.7% n = 702) pts received first-line (1L) systemic treatment; of these, 46.9% (n = 329) received second-line (2L) and 16.6% (n = 116) received third-line (3L) therapy. Chemotherapy was the most common treatment (1L: 77.8% n = 546; 2L: 49.8% n = 164; 3L: 74.1% n = 86), followed by PD-1/L1 inhibitors (1L: 28.3% n = 199; 2L: 47.7% n = 157; 3L: 19.0% n = 22). From index la/mUC diagnosis, estimated median (95% CI) OS was 18.8 (17.5–21.5), PFS was 9.9 (8.9–10.5), and time to progression was 12.7 (11.3–14.6) mo. From the start of 1L, 2L and 3L therapy, estimated median (95% CI) OS were 16.9 (14.3–18.9), 11.6 (9.6–14.3), and 9.9 (7.9–12.6) mo. For HCRU, 71.8% (n = 595) of pts had ≥1 outpatient visit (mean: 2.2/mo), 56.6% (n = 469) had ≥1 inpatient admission (0.4/mo; median duration: 8.0 d), and 56.5% (n = 468) had ≥1 emergency visit (0.4/mo). Conclusions: This retrospective study of university hospital data describes pt characteristics and real-world treatment patterns, survival, and HCRU for pts with la/mUC in Spain. Advances in immunotherapy are shifting the treatment landscape for targeted groups of pts with la/mUC, but a need remains for innovative treatments that could improve pt outcomes.
PDF
