Purpose Prior phase II studies of intravesical gemcitabine have shown it to be active and well tolerated, but durable responses in patients with nonmuscle invasive bladder cancer who have experienced ...recurrence after bacillus Calmette-Guérin treatment are uncommon. We performed a multi-institutional phase II study within the SWOG (Southwest Oncology Group) cooperative group to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting. Materials and Methods Eligible patients had recurrent nonmuscle invasive bladder cancer, stage Tis (carcinoma in situ), T1, Ta high grade or multifocal Ta low grade after at least 2 prior courses of bacillus Calmette-Guérin. Patients were treated with 2 gm gemcitabine in 100 cc normal saline intravesically weekly × 6 and then monthly to 12 months. Cystoscopy and cytology were performed every 3 months, with biopsy at 3 months and then as clinically indicated. Initial complete response was defined as negative cystoscopy, cytology and biopsy at 3 months. Results A total of 58 patients were enrolled in the study and 47 were evaluable for response. Median patient age was 70 years (range 50 to 88). Of the evaluable patients 42 (89%) had high risk disease, including high grade Ta in 12 (26%), high grade T1 in 2 (4%) and carcinoma in situ in 28 (60%) with or without papillary lesions. At the initial 3-month evaluation 47% of patients were free of disease. At 1 year disease had not recurred in 28% of the 47 patients, all except 2 from the high risk group, and at 2 years disease had not recurred in 21%. Conclusions Intravesical gemcitabine has activity in high risk nonmuscle invasive bladder cancer and offers an option for patients with recurrence after bacillus Calmette-Guérin who are not suitable for cystectomy. However, less than 30% of patients had a durable response at 12 months even with maintenance therapy.
Prostate cancer (PrCa) is the most common cancer found among men in the United States, and is the second-leading cause of death for these individuals. Although most patients with prostate cancer ...experience disease control after primary therapy, approximately 20% to 40% of these patients will eventually encounter recurrent disease. While androgen deprivation therapy may achieve temporary tumor control or regression in the majority of patients with advanced disease, virtually all patients with metastatic disease will experience progressive PrCa. Consequently, their disease may no longer respond to primary androgen blockade and may then spread to distant sites, most commonly to the bones and/or regional lymph nodes. This state of disease, termed castration-resistant prostate cancer (CRPC), is heterogeneous, has a variety of clinical symptoms which may include biochemical progression, progression in bone, or soft tissue, and may present with or without symptoms from cancer. While treatments were previously somewhat limited, there has been a substantial increase in the understanding of the biological and genetic basis for PrCa progression. The mechanisms of androgen independence in CRPC include, but are not limited to, autocrine production of androgen by the prostate cancer cell, as well as androgen receptor activity despite low testosterone levels, through a variety of different mechanisms. These findings have led to more targeted therapies for CRPC, improved clinical outcomes, and increased survival. Further understanding of the mechanisms that cause castration resistance potentially could improve therapeutic efficacy.
Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) with
mRNA ...overexpression. We assessed rogaratinib efficacy and safety versus chemotherapy in patients with
mRNA-positive advanced/metastatic UC previously treated with platinum chemotherapy.
FORT-1 (ClinicalTrials.gov identifier: NCT03410693) was a phase II/III, randomized, open-label trial. Patients with
/
mRNA-positive locally advanced or metastatic UC with ≥ 1 prior platinum-containing regimen were randomly assigned (1:1) to rogaratinib (800 mg orally twice daily, 3-week cycles; n = 87) or chemotherapy (docetaxel 75 mg/m
, paclitaxel 175 mg/m
, or vinflunine 320 mg/m
intravenously once every 3 weeks; n = 88). The primary end point was overall survival, with objective response rate (ORR) analysis planned following phase II accrual. Because of comparable efficacy between treatments, enrollment was stopped before progression to phase III; a full interim analysis of phase II was completed.
ORRs were 20.7% (rogaratinib, 18/87; 95% CI, 12.7 to 30.7) and 19.3% (chemotherapy, 17/88; 95% CI, 11.7 to 29.1). Median overall survival was 8.3 months (95% CI, 6.5 to not estimable) and 9.8 months (95% CI, 6.8 to not estimable; hazard ratio, 1.11; 95% CI, 0.71 to 1.72;
= .67). Grade 3/4 events occurred in 37 (43.0%)/4 (4.7%) patients and 32 (39.0%)/15 (18.3%), respectively. No rogaratinib-related deaths occurred. Exploratory analysis of patients with
DNA alterations showed ORRs of 52.4% (11/21; 95% CI, 29.8 to 74.3) for rogaratinib and 26.7% (4/15; 95% CI, 7.8 to 55.1) for chemotherapy.
To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with
-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested
DNA alterations in association with
/
mRNA overexpression may be better predictors of rogaratinib response.
Prostate cancer is the second most common cause of cancer-related death in men. Although the overall survival of patients with metastatic prostate cancer has improved with the addition of ...second-generation hormone therapy, most men will develop progressive disease, eventually leading to death. Novel therapeutic mechanisms are needed to improve treatments and outcomes in patients with metastatic prostate cancer. Biomarker-driven treatments such as targeted therapies and immuno-oncologic agents are currently under investigation, and may lead to less toxicity and better outcomes for these patients. Here, we review the current use and future direction of these novel therapeutic targets.
Background: The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials ...in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial. Methods: Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%–90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice's criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided. Results: Three-month PSA level declines of 20%–40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio HR= 0.43, 95% confidence interval CI = 0.34 to 0.55; P<.001), and the increased risk of death for men treated with M/P compared with D/E (HR = 1.24, 95% CI = 1.02 to 1.51; P = .032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy. Conclusions: Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.
MEDI3726 is an antibody-drug conjugate targeting the prostate-specific membrane antigen and carrying a pyrrolobenzodiazepine warhead. This phase I study evaluated MEDI3726 monotherapy in patients ...with metastatic castration-resistant prostate cancer after disease progression on abiraterone and/or enzalutamide and taxane-based chemotherapy.
MEDI3726 was administered at 0.015-0.3 mg/kg intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary objective was to assess safety, dose-limiting toxicities (DLT), and MTD/maximum administered dose (MAD). Secondary objectives included assessment of antitumor activity, pharmacokinetics, and immunogenicity. The main efficacy endpoint was composite response, defined as confirmed response by RECIST v1.1, and/or PSA decrease of ≥50% after ≥12 weeks, and/or decrease from ≥5 to <5 circulating tumor cells/7.5 mL blood.
Between February 1, 2017 and November 13, 2019, 33 patients received MEDI3726. By the data cutoff (January 17, 2020), treatment-related adverse events (TRAE) occurred in 30 patients (90.9%), primarily skin toxicities and effusions. Grade 3/4 TRAEs occurred in 15 patients (45.5%). Eleven patients (33.3%) discontinued because of TRAEs. There were no treatment-related deaths. One patient receiving 0.3 mg/kg had a DLT of grade 3 thrombocytopenia. The MTD was not identified; the MAD was 0.3 mg/kg. The composite response rate was 4/33 (12.1%). MEDI3726 had nonlinear pharmacokinetics with a short half-life (0.3-1.8 days). The prevalence of antidrug antibodies was 3/32 (9.4%), and the incidence was 13/32 (40.6%).
Following dose escalation, no MTD was identified. Clinical responses occurred at higher doses, but were not durable as patients had to discontinue treatment due to TRAEs.
Prostate-specific antigen progression (PSA-P) is an indicator of progression in hormone-sensitive (HS) and castration-resistant (CR) prostate cancer (PC). We evaluated different definitions of PSA-P ...as predictors of overall survival (OS).
A total of 1,078 patients with HSPC who were on hormones (Southwest Oncology Group SWOG trial 9346 S9346) and 597 patients with CRPC who were treated with chemotherapy (SWOG trial 9916 S9916) were eligible for this analysis. PSA-P definitions tested included the following: PSA Working Group, Prostate Cancer Working Group (PCWG 2008), and other definitions. A time-varying approach analyzed associations between PSA-P at any time and OS. A landmark analysis examined the relationship between PSA-P status at 7 months for S9346, or 3 months for S9916, and subsequent OS.
In the time-varying analysis, both working groups definitions were strongly associated with OS (P < .001) in both study settings. In patients enrolled onto S9346, both definitions predicted a 2.4-fold increased risk of death (ROD) and a greater than four-fold increased ROD if PSA-P occurred in the first 7 months. In S9916, they predicted a 40% increase in ROD and a two-fold increase in ROD if PSA-P occurred at 3 months. In landmark analyses of patients on S9346 by using the PCWG 2008 definition of PSA-P, median subsequent OS was 10 months versus 44 months in patients who did or did not have PSA-P by 7 months, respectively; in S9916, data were 11 months versus 18 months for patients who did or did not have PSA-P by 3 months, respectively.
PSA-P, defined as an increase of > or = 25% greater than the nadir and an absolute increase of at least 2 or 5 ng/mL, predicts OS in HSPC and CRPC and may be a suitable end point for phase II studies in these settings.
In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell-inflamed gene expression profile (TcellinfGEP), and ...stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC).
Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS; nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab; two-sided, chemotherapy). Significance was prespecified at α = 0.05.
In KEYNOTE-052, PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes; stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and TcellinfGEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab; chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For TcellinfGEP, PFS and OS HRs were lower in the TcellinfGEP-nonlow subgroup regardless of treatment.
Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent.
Men with metastatic castration-resistant prostate cancer (mCRPC) have limited treatment options after progressing on hormonal therapy and chemotherapy. Here, we evaluate the safety and efficacy of ...atezolizumab (anti-PD-L1) + radium-223 dichloride (radium-223) in men with mCRPC.
This phase Ib study evaluated atezolizumab + radium-223 in men with mCRPC and bone and lymph node and/or visceral metastases that progressed after androgen pathway inhibitor treatment. Following safety assessment of concurrent dosing, 45 men were randomized 1:1:1 to concurrent or one of two staggered dosing schedules with either agent introduced one cycle before the other. This was followed by a safety-efficacy expansion cohort (randomized 1:1:1). The primary endpoints were safety and objective response rate (ORR) by RECIST 1.1. Secondary endpoints included radiographic progression-free survival (rPFS), PSA responses, and overall survival (OS).
As of October 4, 2019, 44 of 45 men were evaluable. All 44 had ≥1 all-cause adverse event (AE); 23 (52.3%) had a grade 3/4 AE. Fifteen (34.1%) grade 3/4 and 3 (6.8%) grade 5 AEs were related to atezolizumab; none were related to radium-223. Confirmed ORR was 6.8% 95% confidence interval (CI), 1.4-18.7, median rPFS was 3.0 months (95% CI, 2.8-4.6), median PSA progression was 3.0 months (95% CI, 2.8-3.3), and median OS was 16.3 months (95% CI, 10.9-22.3).
This phase Ib study demonstrated that atezolizumab + radium-223, regardless of administration schedule, had greater toxicity than either drug alone, with no clear evidence of additional clinical benefit for patients with mCRPC and bone and lymph node and/or visceral metastases.
Background
Infigratinib (BGJ398) is a potent and selective fibroblast grown factor receptor 1 to 3 (FGFR1‐3) inhibitor with significant activity in patients with advanced or metastatic urothelial ...carcinoma bearing FGFR3 alterations. Given the distinct biologic characteristics of upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB), the authors examined whether infigratinib had varying activity in these settings.
Methods
Eligible patients had metastatic urothelial carcinoma with activating FGFR3 mutations and/or fusions. Comprehensive genomic profiling was performed on formalin‐fixed, paraffin‐embedded tissues. Blood was collected for cell‐free DNA analysis using a 600‐gene panel. Patients received infigratinib at a dose of 125 mg orally daily (3 weeks on/1 week off) until disease progression or intolerable toxicity occurred. The overall response rate (ORR; partial response PR plus complete response CR) and disease control rate (DCR; CR plus PR plus stable disease SD) were characterized.
Results
A total of 67 patients were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. In 8 patients with UTUC, 1 CR and 3 PRs were observed (ORR, 50%); the remaining patients achieved a best response of SD (DCR, 100%). In patients with UCB, 13 PRs were observed (ORR, 22%), and 22 patients had a best response of SD (DCR, 59.3%). Notable differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3‐TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), and a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%).
Conclusions
Differences in the cumulative genomic profile were observed between patients with UTUC and those with UCB in the current FGFR3‐restricted experience, underscoring the distinct biology of these diseases. These results support a planned phase 3 adjuvant study predominantly performed in this population.
Infigratinib demonstrates activity in patients with metastatic urothelial carcinoma (UC) bearing fibroblast growth factor receptor 3 (FGFR3) mutations and/or fusions, with particular activity noted in patients with upper tract UC (UTUC). Key differences in FGFR3 alterations are noted between UTUC and UC of the bladder in the genomically selected patients in the current study.
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