Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up.

BACKGROUND: Immune checkpoint inhibitors are a standard therapy in metastatic urothelial carcinoma (UC). Long-term follow-up is necessary to confirm durability of response and identify further safety concerns. PATIENTS AND METHODS: In KEYNOTE-045, patients with metastatic UC that progressed on platinum-containing chemotherapy were randomly assigned 1:1 to receive pembrolizumab or investigator's choice of paclitaxel, docetaxel, or vinflunine. Primary endpoints were progression-free survival per RECIST version 1.1 by blinded independent central review (BICR) and overall survival. In KEYNOTE-052, cisplatin-ineligible patients with metastatic UC received first-line pembrolizumab. The primary endpoint was objective response rate per RECIST version 1.1 by BICR. RESULTS: A total of 542 patients (pembrolizumab, n = 270; chemotherapy, n = 272) were randomly assigned in KEYNOTE-045. The median follow-up was 62.9 months (range 58.6-70.9 months; data cut-off 1 October 2020). At 48 months, overall survival rates were 16.7% for pembrolizumab and 10.1% for chemotherapy; progression-free survival rates were 9.5% and 2.7%, respectively. The median duration of response (DOR) was 29.7 months (range 1.6+ to 60.5+ months) for pembrolizumab and 4.4 months (range 1.4+ to 63.1+ months) for chemotherapy; 36-month DOR rates were 44.4% and 28.3%, respectively. A total of 370 patients were enrolled in KEYNOTE-052. The median follow-up was 56.3 months (range 51.2-65.3 months; data cut-off 26 September 2020). The confirmed objective response rate was 28.9% (95% confidence interval 24.3-33.8), and the median DOR was 33.4 months (range 1.4+ to 60.7+ months); the 36-month DOR rate was 44.8%. Most treatment-related adverse events for pembrolizumab in either study were grade 1 or 2 and manageable, which is consistent with prior reports. CONCLUSION: With ∼5 years of follow-up, pembrolizumab monotherapy continued to demonstrate durable efficacy with no new safety signals in patients with platinum-resistant metastatic UC and as first-line therapy in cisplatin-ineligible patients. CLINICAL TRIAL REGISTRY AND ID: With ClinicalTrials.gov NCT02256436 (KEYNOTE-045); https://clinicaltrials.gov/ct2/show/NCT02256436 and NCT02335424 (KEYNOTE-052); https://clinicaltrials.gov/ct2/show/NCT02335424.

Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.

BACKGROUND: Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045. PATIENTS AND METHODS: Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR. RESULTS: A total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy. CONCLUSIONS: Long-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02256436.

Sleep and daily functioning during androgen deprivation therapy for prostate cancer.

A limited body of evidence suggests that sleep problems are common in prostate cancer patients undergoing androgen deprivation therapy, yet little is known about sleep characteristics and the effects of poor sleep on daily functioning in this population. This study assessed sleep in 60 prostate cancer patients taking androgen deprivation therapy with wrist actigraphy and daily diaries for 7 days. The Epworth Sleepiness Scale and the general version of the Functional Assessment of Cancer Therapy scale were also administered. On average, total sleep time was 5.9 (SD = 1.4) h, and sleep efficiency was 75% (SD = 12.0) as assessed by actigraphy. There was generally poor concordance between actigraphy and daily diary for most sleep metrics. Subjects reported awakening, on average, 2.7 times per night, most commonly for nocturia and hot flashes. Assessment of daily functioning showed that participants had mild daytime sleepiness, which was predicted by total sleep time (F(1,47) = 4.5, P= 0.04) General quality of life was not impaired. This study supports more research on the predictors of poor sleep in order to identify effective interventions.

Inflammatory bowel disease is not associated with an increased risk of lymphoma.

BACKGROUND & AIMS: Previous studies of the risk of lymphoma in inflammatory bowel disease patients have provided conflicting results. This study examines the risk of Hodgkin's and non-Hodgkin's lymphoma among patients with inflammatory bowel disease. METHODS: The authors performed a retrospective cohort study using the General Practice Research Database. Inflammatory bowel disease patients were matched to randomly selected controls on age, sex, and primary care practice. Lymphoma rates were also compared with published age- and sex-specific rates. RESULTS: The study included 6605 patients with Crohn's disease, 10,391 with ulcerative colitis, and 60,506 controls followed for an average of 3.7, 3.9, and 4.4 years, respectively. The incidence of lymphoma was not increased in patients with inflammatory bowel disease (relative risk = 1.20; 95% CI, 0.67-2.06). In subgroup analyses, an increased risk was not observed among patients with Crohn's disease (relative risk = 1.39; 95% CI, 0.50-3.40) or ulcerative colitis (relative risk = 1.11; 95% CI, 0.51-2.19). Compared with inflammatory bowel disease patients not treated with azathioprine or 6-MP, the relative risk of lymphoma among the 1465 inflammatory bowel disease patients treated with these medications (average, 106 mg/day for 2.0 years) was 1.27 (95% CI 0.03-8.20). CONCLUSIONS: Patients with inflammatory bowel disease do not have an increased risk of lymphoma as compared with the general population. Although we cannot completely rule out a modest increased risk of lymphoma with azathioprine or 6-MP therapy, an increased risk was not observed in this cohort.

Adjuvant chemotherapy for muscle-invasive bladder cancer.

The curability of bladder cancer is directly related to the pathologic stage of the primary tumor. If extravesical extension or lymph-node metastases are present, the risk of metastatic progression is significant. Adjuvant chemotherapy has been proposed for these patients in an attempt to reduce the probability of relapse and to improve survival. Although improved survival with cisplatin-based adjuvant chemotherapy is suggested in some studies, the actual benefit of the treatment after radical cystectomy for patients with muscle-invasive bladder cancer is still controversial due to the absence of sufficiently powered prospective randomized clinical trials. Ongoing and future trials should further define the role of adjuvant chemotherapy in bladder cancer treatment.

Effects of Bowman-Birk inhibitor concentrate (BBIC) in patients with benign prostatic hyperplasia.

BACKGROUND: The Bowman-Birk inhibitor is a soybean-derived protease inhibitor that has anti-inflammatory and anticarcinogenic activities. METHODS: A Phase I trial of Bowman-Birk inhibitor concentrate (BBIC) in 19 male subjects with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) has been performed. RESULTS: The results of the trial indicated that there was no dose-limiting toxicity of BBIC. There was a statistically significant decrease in serum PSA levels in all BBIC-treated patients. Some BBIC-treated patients exhibited a relatively large reduction in serum PSA levels, ranging up to a 43% reduction. There was also a statistically significant decrease in serum triglyceride levels and a decrease in prostate volume in the treated patients. The scores recorded in response to a urinary symptom questionnaire indicated improved urinary activities in the BBIC-treated patients; however, the control subjects exhibited similar improvements in urinary activities during the course of the trial. CONCLUSIONS: The data obtained in this trial, particularly the data suggesting that BBIC treatment may lead to reduced serum PSA levels and reduced prostate volumes, suggest that a Phase II clinical trial of BBIC for the therapy of BPH is warranted.

Phase II trial of toremifene in androgen-independent prostate cancer: a Penn cancer clinical trials group trial.

Toremifene has antiestrogenic and estrogenic properties in vitro and in vivo. In addition, it may have antiangiogenesis and antimicrotubule properties at higher doses. Studies have demonstrated the efficacy of this agent in the treatment of metastatic breast cancer. We performed a phase II trial of toremifene in patients with androgen-independent prostate cancer (AIPC). Patients with an increasing prostate-specific antigen level despite castrate testosterone levels and antiandrogen withdrawal were eligible. Patients could not have received prior salvage hormonal therapy or chemotherapy. Patients received toremifene at 300 mg/m2/d orally (maximum dose 640 mg/d). Fifteen patients were treated. Patients received treatment for a median of 13 weeks (range, 4-30 weeks). The median age was 72 years (range, 58-80 years). The median Eastern Cooperative Oncology Group performance status was 0. The treatment was well tolerated and toxicity was mild. Two patients had grade III hepatic toxicity; one had grade III hyperglycemia. There were no treatment-related deaths. No objective responses were demonstrated. In summary, toremifene is not effective therapy for AIPC at the dose and schedule evaluated in this trial.

Recent developments in chemotherapy for bladder cancer.

Invasive bladder cancer is a chemotherapy-sensitive neoplasm. Historically, the development of cisplatin (Platinol)-based chemotherapy regimens has represented an important advance for patients with metastatic disease. More recently, investigations of new agents, such as gemcitabine (Gemzar) and paclitaxel (Taxol), have resulted in further options for these patients. Randomized trials comparing new regimens with cisplatin-based therapies have been initiated. The role of chemotherapy in the adjuvant and neoadjuvant settings is an area that is undergoing active investigation. The application of prognostic biological markers to risk-stratify patients has resulted in new avenues of investigation in these ongoing early disease trials.

Eastern Cooperative Oncology Group Phase I trial of protracted venous infusion fluorouracil plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer: a regimen with unexpected early toxicity.

PURPOSE: We performed a phase I trial of protracted venous infusion (PVI) fluorouracil (5-FU) plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer to determine the maximum-tolerated dose of gemcitabine that could be safely administered. We also sought to identify the toxicities associated with this treatment protocol. PATIENTS AND METHODS: Seven patients with locally advanced pancreas cancer were treated with planned doses of radiation (59.4 Gy) and PVI of 5-FU (200 mg/m(2)/d) with gemcitabine doses of 50 to 100 mg/m(2)/wk. RESULTS: Two of three patients at the 100-mg/m(2)/wk dose level experienced dose-limiting toxicity (DLT), as did three of four at the 50-mg/m(2)/wk dose level. One patient experienced a mucocutaneous reaction described as a Stevens-Johnson syndrome that was attributed to chemotherapy. Three patients developed gastric or duodenal ulcers with severe bleeding requiring transfusion. One patient developed severe thrombocytopenia lasting longer than 4 weeks. Three of the five episodes of DLT developed at radiation doses < or = 36 Gy. CONCLUSION: Based on this experience, we cannot recommend further investigation of regimens incorporating gemcitabine into regimens of radiation with PVI 5-FU. The mechanism of this synergistic toxicity remains to be determined.

Paclitaxel and carboplatin in bladder cancer: recent developments.

Paclitaxel demonstrates significant single-agent activity in advanced urothelial carcinoma. Paclitaxel/carboplatin is an active and tolerable outpatient chemotherapy treatment regimen for these patients. This regimen has been studied in several phase II trials with response rates ranging from 14 to 65%. Paclitaxel/carboplatin may be considered in patients with advanced urothelial cancer and renal insufficiency, and a recent Eastern Cooperative Oncology Group (ECOG) phase II trial investigates this regimen specifically in this patient population. Ongoing ECOG trials are comparing paclitaxel/carboplatin with M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) in both the advanced disease and adjuvant settings.

Outcome of pancreaticoduodenectomy and impact of adjuvant therapy for ampullary carcinomas.

PURPOSE: To determine the clinical outcomes and potential impact of adjuvant chemoradiation in patients undergoing surgical resection of ampullary carcinoma. PATIENTS AND METHODS: Between 1988 and 1997, 39 patients underwent pancreaticoduodenectomy for ampullary adenocarcinomas. Clinical and pathologic factors, adjuvant therapy records, and disease status were obtained from chart review. Thirteen (33%) patients received adjuvant chemoradiation. Radiation therapy was delivered to the surgical bed and regional nodes to a median dose of 4,860 cGy with concurrent bolus or continuous infusion of 5-fluorouracil. Outcomes measures included locoregional control, disease-free survival, and overall survival. Univariate analysis was used to assess the impact of various patient- and tumor-related factors and the use of adjuvant therapy. Twenty (51%) patients with tumor invasion into the pancreas (T3) or node-positive disease were classified in a "high-risk" subgroup. RESULTS: After a median follow-up of 45 months for survivors, overall 3-year survival was 55%. Survival was significantly worse for patients with positive nodes (23% vs. 73%, p < 0.001) and high-risk status (30% vs. 80%, p = 0.002). Disease-free survival was 54% at 3 years. There were 3 postoperative deaths, and these patients (all high risk) are excluded from further analysis on adjuvant therapy. In univariate analysis, the use of adjuvant chemoradiation had no clear impact on local-regional control or overall survival. However, by controlling for risk status in multivariate analysis, the use of adjuvant therapy reached statistical significance for overall survival (p = 0. 03). Among the high-risk patients, 7 (77%) of 9 patients receiving adjuvant therapy remained disease-free during follow-up compared with only 1 (14%) of 7 patients not receiving adjuvant therapy (p = 0.012). CONCLUSION: Despite the relatively favorable prognosis of ampullary carcinomas compared with other pancreaticobiliary tumors, patients with nodal metastases or T3 disease are at high risk for disease relapse. The use of adjuvant chemoradiation may improve long-term disease control in these patients.

A phase II pilot study of KW-2189 in patients with advanced renal cell carcinoma.

BACKGROUND: KW-2189 is a semi-synthetic, water-soluble analog of duocarmycin B2, a new class of potent antitumor antibiotics produced by streptomyces, with improved in vitro antitumor potency. PATIENTS AND METHODS: Forty patients with pathologically confirmed metastatic renal cell carcinoma were treated in this multicenter, open-label phase II trial. All patients received 0.4 mg/m2 KW-2189 as an i.v. infusion for Cycle I. Cycles were repeated every 5 to 6 weeks with escalations to 0.5 mg/m2 in the absence of significant toxicity or disease progression. RESULTS: No patient had an objective response. The most common drug-related toxicity was hematological-delayed neutropenia and thrombocytopenia, with recovery by week 6. Non-hematologic toxicity consisted of mild to moderate fatigue, nausea and vomiting, and anorexia that was generally manageable. CONCLUSIONS: KW-2189 in this dose and schedule has a predictable safety profile of reversible myelosuppression. No activity in metastatic renal cell carcinoma was demonstrated.

A phase II study of gemcitabine and 5-fluorouracil in metastatic pancreatic cancer: an Eastern Cooperative Oncology Group Study (E3296).

Gemcitabine has recently been compared favorably to 5-fluorouracil (5-FU) as the standard chemotherapy for advanced pancreas cancer. Based on phase I data that combining gemcitabine with 5-FU is safe and has evidence for clinical activity, a phase II trial was conducted by the Eastern Cooperative Oncology Group (ECOG). Patients with metastatic disease, good performance status and organ function were eligible and enrolled after providing informed consent. Patients were given gemcitabine (1,000 mg/m(2)) followed by 5-FU (600 mg/m(2)) weekly for 3 weeks of every 4. Of 37 patients enrolled over a 3-month period, 36 were eligible. Partial responses were seen in 5 patients (14%). Median survival was 4.4 months with a 1-year survival rate of 8.6%. A randomized trial of the combination of 5-FU and gemcitabine versus gemcitabine alone is currently accruing patients in ECOG.

A phase II trial of 5-fluorouracil, leucovorin, and interferon alpha 2A (IFN-alpha 2a) in metastatic pancreatic carcinoma: a Penn Cancer Clinical Trials Group (PCCTG) trial.

A phase II study was performed to evaluate the activity and toxicity of 5-fluorouracil (5-FU), leucovorin, and inteferon alpha-2a in metastatic pancreatic carcinoma. Twenty-three patients were entered in this study. Four patients withdrew before receiving treatment and one patient was nonevaluable for response because of treatment-related toxicity. The most common significant toxicity was nausea and vomiting. Treatment-related hospitalization was significant. Of 18 evaluable patients, 4 maintained stable disease and 14 had disease progression. None had an objective clinical response. We conclude that this biochemically modulated 5-FU regimen is ineffective treatment for advanced pancreatic carcinoma, with significant toxicity even in highly selected patients with an ambulatory performance status.

Review and outlook for the role of paclitaxel in urothelial carcinoma.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is an active agent in the treatment of patients with advanced urothelial carcinoma. The lack of nephrotoxicity and the ability to administer this agent to select patients with renal insufficiency provide potential advantages over the standard cisplatin-based regimens in this patient population. Paclitaxel-based combination regimens have recently been developed and reported. Paclitaxel plus carboplatin is an active and tolerable outpatient regimen for patients with advanced urothelial cancer. Ongoing cooperative group trials will help to further define the activity and toxicity of this regimen in previously untreated patients, patients with prior treatment, and patients with abnormal renal function. A cooperative group trial will compare paclitaxel plus carboplatin with the cisplatin-based regimen cisplatin/ methotrexate/vinblastine/doxorubicin (MVAC). The role of paclitaxel in the early disease and combined-modality settings in urothelial cancer remains to be determined.

A phase II trial and pharmacokinetic analysis of 96-hour infusional paclitaxel in patients with metastatic colorectal cancer.

A phase II study was conducted to evaluate the activity and toxicity of 96-hour infusional paclitaxel in patients with previously untreated metastatic colorectal cancer. Twelve patients were enrolled in this study. The first patient received a total dose of 140 mg/m2 over 96 hours resulting in grade 4 neutropenia, neutropenic fever, and grade 3 stomatitis. Subsequent patients received a total dose of 120 mg/m2 over 96 hours. Grade 3 to 4 neutropenia occurred in four of these patients. No significant thrombocytopenia was observed. Grade 3 to 4 nonhematologic toxicities in the group treated at 120 mg/m2 over 96 hours included nausea/vomiting in one patient, stomatitis in one patient, and diarrhea in two patients. One patient experienced a possible pulmonary hypersensitivity reaction. None of the 12 patients achieved an objective response. Two patients had stable disease and ten had progressive disease. Pharmacokinetic parameters including maximum plasma concentration and area under the concentration time curve were significantly higher in patients with grade 3 to 4 neutropenia than patients who experienced less toxicity. The authors conclude that further study of 96-hour infusional paclitaxel in patients with metastatic colorectal carcinoma is not warranted.

Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: an active and tolerable outpatient regimen.

PURPOSE: To determine the toxicity and efficacy of an outpatient regimen of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium. PATIENTS AND METHODS: Patients received paclitaxel 150 to 225 mg/m2 over 3 hours followed by carboplatin (targeted area under the concentration-time curve [AUC], 6 mg/mL x min) every 3 weeks. During phase I accrual, 16 patients were treated; 17 additional patients were enrolled at the phase II dose. The median age was 70 years (range, 47 to 82). The median serum creatinine concentration was 1.1 mg/dL (range, 0.7 to 2.7) and the median estimated creatinine clearance was 52 mL/min (range, 24 to 110). RESULTS: During phase I accrual, the maximum-tolerated dose (MTD) of the regimen was not defined. Phase II accrual occurred at the paclitaxel 225 mg/m2 dose level. A total of 156 cycles were administered. The median number of cycles received was five (range, one to eight). Sensorimotor neuropathy was the principal nonhematologic toxicity. Significant granulocytopenia was common, but significant thrombocytopenia was not. Objective responses were demonstrated at all dose levels. At the phase II dose (paclitaxel 225 mg/m2 followed by carboplatin at AUC 6 mg/mL x min), the objective response rate was 50% (95% confidence interval [CI], 28% to 72%). CONCLUSION: Paclitaxel plus carboplatin is an active and tolerable outpatient treatment for patients with advanced carcinoma of the urothelium. The ability to administer this combination over multiple cycles even to patients with advanced age and abnormal renal function makes it well suited for this patient population. Confirmatory trials of this regimen are ongoing.