Alterations in the gene encoding fibroblast growth factor receptor (
) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine ...kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with
alterations.
In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified
alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival.
A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths.
The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with
alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).
Despite the previously reported improvement in progression-free survival with first-line combination of atezolizumab plus platinum-based chemotherapy versus placebo plus platinum-based chemotherapy ...in the primary analysis (stratified hazard ratio HR 0·82 95% CI 0·70–0·96; one-sided p=0·007),3 this did not translate into an improvement in overall survival (median overall survival was 16·1 months 95% CI 14·2–18·8; 336 death in group A vs 13·4 months 12·0–15·3 in group C; stratified HR 0·85 95% CI 0·73–1·00; one-sided p=0·023).1 The investigators designed the trial with the aim of answering many questions regarding front-line immune checkpoint inhibition. Recent results from CheckMate901 reported an improvement in overall survival with nivolumab combined with gemcitabine and cisplatin versus gemcitabine and cisplatin alone (median overall survival 21·7 months 95% CI 18·6–26·4 vs 18·9 months 14·7–22·4) with an objective response rate of 175 (57·6%) of 304 patients with nivolumab combination therapy versus 131 (43·1%) of 304 patients with gemcitabine and cisplatin alone, and complete response rates of 21·7% and 11·8% respectively.4 The duration of complete response appeared quite promising, with a median duration of 37·1 months with combination therapy and 13·2 months with gemcitabine plus cisplatin. If the survival remains this high, sequencing of treatment might also be relevant since 25% of patients received subsequent platinum-based therapy. ...it might be too early to consider retirement of platinum-based chemotherapy.
Background
In this multicenter, single‐arm, multicohort, phase 2 trial, the efficacy of nivolumab and ipilimumab was evaluated in patients with advanced rare genitourinary cancers, including bladder ...and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, platinum‐refractory germ cell tumors, penile carcinoma, and prostate cancer of variant histology (NCT03333616).
Methods
Patients with rare genitourinary malignancies and no prior immune checkpoint inhibitor exposure were enrolled. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg intravenously every 3 weeks for 4 doses, and this was followed by 480 mg of nivolumab intravenously every 4 weeks. The primary endpoint was the objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors (version 1.1).
Results
Fifty‐five patients were enrolled at 6 institutions between April 2018 and July 2019 in 3 cohorts: BUTCVH (n = 19), adrenal tumors (n = 18), and other tumors (n = 18). The median follow‐up was 9.9 months (range, 1 to 21 months). Twenty‐eight patients (51%) received 4 doses of nivolumab and ipilimumab; 25 patients received nivolumab maintenance for a median of 4 cycles (range, 1‐18 cycles). The ORR for the entire study was 16% (80% confidence interval, 10%‐25%); the ORR in the BUTCVH cohort, including 2 complete responses, was 37%, and it was 6% in the other 2 cohorts. Twenty‐two patients (40%) developed treatment‐related grade 3 or higher toxicities; 24% (n = 13) required high‐dose steroids (≥40 mg of prednisone or the equivalent). Grade 5 events occurred in 3 patients; 1 death was treatment related.
Conclusions
Nivolumab and ipilimumab resulted in objective responses in a subset of patients with rare genitourinary malignancies, especially those with BUTCVH. An additional cohort exploring their activity in genitourinary tumors with neuroendocrine differentiation is ongoing.
Lay Summary
Patients with rare cancers are often excluded from studies and have limited treatment options.
Fifty‐five patients with rare tumors of the genitourinary system were enrolled from multiple sites and were treated with nivolumab and ipilimumab, a regimen used for kidney cancer.
The regimen showed activity in some patients, particularly those with bladder or upper tract cancers of unusual or variant histology; 37% of those patients responded to therapy.
Additional studies are ongoing to better determine who benefits the most from this combination.
Patients with rare genitourinary malignancies have limited treatment options and are underrepresented in clinical trials. In this phase 2 trial, which has accrued 55 patients in less than 18 months, the combination of nivolumab and ipilimumab is active in a subset of patients with rare genitourinary malignancies, particularly those with bladder or upper tract carcinoma of variant histology (objective response rate 37%).
Summary Background Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We ...assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen. Methods In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov , number NCT02387996 , and is completed. Follow-up is still ongoing. Findings Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96–8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0–24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9–39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5–32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5–23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3–4 treatment-related adverse events occurred in 48 (18%) of 270 patients—most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure). Interpretation Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. Funding Bristol-Myers Squibb.
Abstract Background Gene expression profiling (GEP) suggests there are three subtypes of muscle-invasive urothelial cancer (UC): basal, which has the worst prognosis; p53-like; and luminal. We ...hypothesized that GEP of transurethral resection (TUR) and cystectomy specimens would predict subtypes that could benefit from chemotherapy. Objective To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B) and the impact of UC subtype. Design, setting, and participants Sixty patients enrolled in a neoadjuvant trial of four cycles of DDMVAC + B between 2007 and 2010. TUR and cystectomy specimens for GEP were available from 38 and 23 patients, respectively, and from an additional confirmation cohort of 49 patients treated with perioperative MVAC. Outcome measurements and statistical analysis Relationships with outcomes were analyzed using multivariable Cox regression and log-rank tests. Results and limitations Chemotherapy was active, with pT0N0 and ≤pT1N0 downstaging rates of 38% and 53%, respectively, and 5-yr overall survival (OS) of 63%. Bevacizumab had no appreciable impact on outcomes. Basal tumors had improved survival compared to luminal and p53-like tumors (5-yr OS 91%, 73%, and 36%, log-rank p = 0.015), with similar findings on multivariate analysis. Bone metastases within 2 yr were exclusively associated with the p53-like subtype (p53-like 100%, luminal 0%, basal 0%; p ≤ 0.001). Tumors enriched with the p53-like subtype at cystectomy suggested chemoresistance for this subtype. A separate cohort treated with perioperative MVAC confirmed the UC subtype survival benefit (5-yr OS 77% for basal, 56% for luminal, and 56% for p53-like; p = 0.021). Limitations include the small number of pretreatment specimens with sufficient tissue for GEP. Conclusion GEP was predictive of clinical UC outcomes. The basal subtype was associated with better survival, and the p53-like subtype was associated with bone metastases and chemoresistant disease. Patient summary We can no longer think of urothelial cancer as a single disease. Gene expression profiling identifies subtypes of urothelial cancer that differ in their natural history and sensitivity to chemotherapy.
Objective
To determine whether the recovery window (RW) between neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) affects 90‐day postoperative morbidity and incidence of lymph node ...metastasis.
Patients and methods
We reviewed patients treated with NAC and RC from 1995 to 2013 for ≤cT4N0M0 bladder cancer. The association of the RW with 90‐day perioperative morbidity and lymph node metastasis was determined. Generalised linear models were used to determine predictors of each endpoint. Patients were stratified into four RWs by 21‐day intervals (18–42; 43–63; 64–84; and ≥85 days) from last day of NAC to RC.
Results
We evaluated 306 patients with RW information during the study period. The median (range) RW was 46 (18–199) days. There was no difference in overall morbidity, re‐admission, or major complication rates amongst the four RWs. In the multivariable analysis extravesical disease was an independent predictor of overall morbidity (odds ratio OR 1.95, 95% confidence interval CI 1.16–3.26; P = 0.011). Age (OR 1.05, 95% CI: 1.02–1.09; P = 0.004), and surgical duration ≥7 h (OR 2.87, 95% CI: 1.52–5.42; P = 0.001) were independent predictors of major complications. Only surgical duration ≥7 h was a predictor of re‐admission (OR 2.24; 95% CI: 1.26–3.98; P = 0.006). A RW of ≥85 days had the highest incidence of node‐positive disease (pN+; 40%). In a separate multivariable model that included clinical predictors for pN+, a RW of ≥85 days was an independent predictor of nodal metastasis (OR 2.92, 95% CI: 1.20–7.09; P = 0.018).
Conclusion
Patients treated with NAC for bladder cancer can undergo RC between 18 and 84 days (2.5–12 weeks) after NAC with no difference in the risk of perioperative morbidity. Delaying surgery beyond 12 weeks was associated with a significant risk of lymph node metastasis.
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