Summary Background Patients with metastatic urothelial carcinoma have limited treatment options after failure of platinum-based chemotherapy. This multicenter, single-arm phase 2 trial evaluated atezolizumab, an engineered humanized IgG1 monoclonal antibody that binds selectively to programmed death–ligand 1 (PD-L1), in this population. Methods Three hundred and ten patients received atezolizumab (1200 mg, every 3 weeks). PD-L1 expression on tumor-infiltrating immune cells (IC) was prospectively assessed by immunohistochemistry. The co-primary endpoints were the objective response rate by RECIST v1.1 and immune modified RECIST. A hierarchical testing procedure was used to test whether the objective response rate was significantly higher than the historical control of 10% at alpha level of 0·05. Exploratory analyses included assessing the association between The Cancer Genome Atlas (TCGA) molecular subtypes, CD8+ T cell infiltration, mutation load, and clinical outcomes. Findings By independent review, objective response rates were 26% (95% CI 18 to 36) in the IC2/3 group, 18% (95% CI 13 to 24) in the IC1/2/3 group and 15% (95% CI 11 to 19) in all patients. With a median follow-up of 11·7 months, ongoing responses were observed in 84% of responders. The median duration of response was not reached (range 2·0*, 13·7* months, *censored). The median overall survival was 11·4 months (95% CI 9·0 to not estimable) in the IC2/3 group, 8·8 months (95% CI 7·1 to 10·6) in the IC1/2/3, and 7·9 months (95% CI 6·6 to 9·3) in all patients. Grade 3–4 related treatment-related adverse events occurred in 16% and grade 3–4 immune-mediated adverse events occurred in 5% of treated patients. Exploratory analyses showed TCGA subtypes and mutation load to be independently predictive for response to atezolizumab. Interpretation Atezolizumab demonstrated durable activity and good tolerability in this population. PD-L1 expression on immune cells was associated with response. This is the first report to show the association of TCGA subtypes with response to immune checkpoint inhibition and demonstrate the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma. Funding F. Hoffmann-La Roche Ltd.

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Gefitinib did not result in any responses in PSA or objective measurable disease at either dose level. Gefitinib has minimal single-agent activity in HRPC.

IMPORTANCE There exists considerable biological and clinical variability between histologic variants of metastatic renal cell carcinoma (mRCC). Data reporting on patterns of metastasis in histologic variants of mRCC are sparse.OBJECTIVE To characterize sites of metastasis and their association with survival across the 3 most common histologic variants of mRCC: clear cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC). DESIGN, SETTING, AND PARTICIPANTSIn this multicenter, international cohort study, the International mRCC Database Consortium (IMDC) database was used to identify consecutive patients starting systemic therapy for mRCC between 2002 and 2019. Patients with mixed histologic subtype were excluded. Statistical analysis was performed from February to June 2020. EXPOSURES Data regarding histologic subtype and sites of metastatic involvement at the time of first systemic therapy initiation were collected. MAIN OUTCOMES AND MEASURESThe primary outcomes were prevalence of metastatic site involvement and overall survival (OS) from time of systemic therapy initiation. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases. RESULTS A total of 10 105 patients were eligible for analysis. Median (interquartile range) age at diagnosis was 60 (53-67) years, 7310 (72.4%) were men and 8526 (84.5%) underwent nephrectomy. Of these, 9252 (92%) had ccRCC, 667 (7%) had pRCC, and 186 (2%) had chrRCC. The median number of sites of metastasis was 2 (range, 0-7). In ccRCC, the most common sites of metastasis were lung (70%; 6189 of 8804 patients [448 missing]), lymph nodes (45%; 3874 of 8655 patients [597 missing]), bone (32%; 2847 of 8817 patients [435 missing]), liver (18%; 1560 of 8804 [448 missing]), and adrenal gland (10%; 678 of 6673 patients [2579 missing]). Sites of metastasis varied between subtypes. Lung, adrenal, brain, and pancreatic metastases were more frequent in ccRCC, lymph node involvement was more common in pRCC, and liver metastases were more frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (95% CI, 13.7-18.8 months) for the pleura and 50 months (95% CI, 41.1-55.5 months) for the pancreas. Compared with ccRCC, patients with pRCC tended to have lower OS, regardless of metastatic site. CONCLUSIONS AND RELEVANCESites of metastatic involvement differ according to histologic subtype in mRCC and are associated with OS. These data highlight the clinical and biological variability between histologic subtypes of mRCC. Patterns of metastatic spread may reflect (continued) Key Points Question In metastatic renal cell carcinoma (RCC), do patterns of metastasis differ between histologic subtypes and are sites of metastasis associated with survival? Findings In this cohort studyincluding 10 105 patients, patterns of metastasis varied significantly between metastatic clear cell RCC, papillary RCC, and chromophobe RCC. Sites of metastasis were associated with survival in all histologic subtype...

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BackgroundNivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer.Case presentation We illustrate the outcomes of a 63 year-old type I diabetic female patient who developed pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation. After downward titration of the patient’s immunosuppressive medications and extensive multidisciplinary review, she was treated with nivolumab in the first-line setting. Within 1 week of administration, the patient experienced acute renal allograft rejection, renal failure and concurrent diabetic ketoacidosis due to steroid therapy. Allograft function did not return, but patient made a full clinical recovery after being placed on hemodialysis. Subsequently, the patient had clinical disease progression off therapy and required re-challenge with nivolumab on hemodialysis, resulting in ongoing clinical and radiographic response.ConclusionsThis case illustrates multiple practical challenges and dangers of administering anti-PD1 immune checkpoint inhibitors to patients with solid-organ transplantation including need for titration of immunosuppressive medications, risks of allograft rejection, and treatment during hemodialysis.

The addition of ramucirumab to docetaxel met the prespecified efficacy end point for prolonging PFS in patients with locally advanced or metastatic urothelial carcinoma receiving second-line treatment and warrants further investigation in the phase III setting.