Aly-Khan A. Lalani

Pan-urologic cancer genomic subtypes that transcend tissue of origin

Urologic cancers include cancers of the bladder, kidney, prostate, and testes, with common molecular features spanning different types. Here, we show that 1954 urologic cancers can be classified into nine major genomic subtypes, on the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression). Tissue dominant effects are first removed computationally in order to define these subtypes, which reveal common processes—reflecting in part tumor microenvironmental influences—driving cellular behavior across tumor lineages. Six of the subtypes feature a mixture of represented cancer types as defined by tissue or cell of origin. Differences in patient survival and in the manifestation of specific pathways—including hypoxia, metabolism, NRF2-ARE, Hippo, and immune checkpoint—can further distinguish the subtypes. Immune checkpoint markers and molecular signatures of macrophages and T cell infiltrates are relatively high within distinct subsets of each cancer type studied. The pan-urologic cancer genomic subtypes would facilitate information sharing involving therapeutic implications between tissue-oriented domains.Urological cancers have disparate tissues and cells of origin but share many molecular features. Here, the authors use multidimensional and comprehensive molecular characterization to classify urological cancers into nine major genomic subtypes, highlighting potential therapeutic targets.

Durable clinical benefit in metastatic renal cell carcinoma patients who discontinue PD-1/PD-L1 therapy for immune-related adverse events (irAEs)

mRCC patients who had a clinical response to PD-1/PD-L1 blockade and discontinued treatment due to irAE continued to derive prolonged clinical benefit after treatment was stopped. Current clinical trials are exploring customized approaches to application of PD-1/PD-L1 blockade. The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti–PD–1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7–46.5) and median TTP was 18.4 months (95% CI, 4.7–54.3) per Kaplan–Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients (n = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% (n = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti–PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti–PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. Cancer Immunol Res; 6(4); 402–8. ©2018 AACR.

Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: a case series

Background Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor. Case presentation In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1 inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all cases) and all had progressive disease as their best response to the subsequent PD-1 inhibitor. The reported clinical information focuses on the course of the disease and the responses to all treatment regimens. Conclusions Clinicians should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of clinical trials until there is sufficient data to support this practice routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are needed to validate the efficacy and safety of these drugs in the second line or later setting. Furthermore, ongoing efforts that aim to identify mechanisms of resistance to immunotherapy will be informative and may ultimately assist physicians in select the optimal treatment following progression on PD-1/PD-L1 inhibitor.BackgroundMonoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor.Case presentationIn this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1 inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all cases) and all had progressive disease as their best response to the subsequent PD-1 inhibitor. The reported clinical information focuses on the course of the disease and the responses to all treatment regimens.ConclusionsClinicians should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of clinical trials until there is sufficient data to support this practice routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are needed to validate the efficacy and safety of these drugs in the second line or later setting. Furthermore, ongoing efforts that aim to identify mechanisms of resistance to immunotherapy will be informative and may ultimately assist physicians in select the optimal treatment following progression on PD-1/PD-L1 inhibitor.

The Clinical Activity of PD-1/PD-L1 Inhibitors in Metastatic Non–Clear Cell Renal Cell Carcinoma

A multicenter pooled analysis revealed modest antitumor activity of PD-1/PD-L1 inhibitors in patients with rare kidney cancer subtypes. Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non–clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (n = 14; 33%), chromophobe (n = 10; 23%), unclassified (n = 9; 21%), translocation (n = 3; 7%), and ccRCC with sarcomatoid differentiation (n = 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (n = 7 with ccRCC; n = 4 nccRCC). Overall, 8 patients (19%) objectively responded, including 4 patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%). The median TTF was 4.0 months [95% confidence interval (CI), 2.8–5.5] and median OS was 12.9 months (95% CI, 7.4–not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1–blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population. Cancer Immunol Res; 6(7); 758–65. ©2018 AACR.

Targeted genomic landscape of metastases compared to primary tumours in clear cell metastatic renal cell carcinoma

BackgroundThe genomic landscape of primary clear cell renal cell carcinoma (ccRCC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in ccRCC metastases, or how it compares to primary tumours in aggregate. The genomic landscape of metastases may have biological, clinical, and therapeutic implications.MethodsWe collected targeted next-generation sequencing mutation calls from two independent cohorts and described the metastases GA landscape and descriptively compared it to the GA landscape in primary tumours.ResultsThe cohort 1 (n = 578) consisted of 349 primary tumours and 229 metastases. Overall, the most common mutations in the metastases were VHL (66.8%), PBRM1 (41.87%), and SETD2 (24.7%). TP53 was more frequently mutated in metastases compared to primary tumours (14.85% versus 8.9%; p = 0.031). No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumours. Mutation burden was not significantly different between the metastases and primary tumours or between metastatic sites. The second cohort (n = 257) consisted of 177 primary tumours and 80 metastases. No differences in frequency of mutations or mutational burden were observed between primaries and metastases.ConclusionsThese data support the theory that ccRCC primary tumours and metastases encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. This study does not address variability between matched primary tumours and metastases or the change in genomic alterations over time and after sequential systemic therapies.

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0–300): intensity of c-Met staining (0–3) x % of positive cells (0–100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

Immunotherapy in the Elderly

CONTEXT Immunotherapy has historic and contemporary presence in prostate, urothelial (UC), and renal cell (RCC) carcinomas. However, robust data on utility and generalizability of these treatments in older patients are lacking. OBJECTIVE To systematically evaluate evidence regarding the efficacy and safety of immunotherapy in elderly patients with prostate cancer, UC, or RCC. EVIDENCE ACQUISITION PubMed/Medline, Embase, Web of Knowledge, and Cochrane Library databases were searched up to October 2017 and according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A narrative review of studies was performed. EVIDENCE SYNTHESIS Twenty-one reports were included regarding prostate cancer (four studies), UC (eight), and RCC (nine). In prostate cancer, sipuleucel-T improves survival (median age >70 yr) and similar results were seen in the PROSTVAC phase 2 trial. Ipilimumab has not improved survival independent of age; data for programmed cell death 1 inhibition is evolving. In metastatic UC, ≥50% of patients enrolled in pivotal checkpoint inhibitor studies were aged ≥65 yr. Three studies reported similar objective response rates (ORRs) in patients aged <65 versus ≥65 yr, whereas one study reported comparable ORRs in patients <80 versus ≥80 yr. In metastatic RCC, cytokine studies showed no efficacy difference by age; one study reported more ≥grade 3 toxicity in patients aged ≥65 yr. One vaccine-based study suggests that older age was associated with shorter survival. The benefit of nivolumab in second-line therapy was more apparent for patients aged 65-<75 yr than for those aged ≥75 yr. Across tumor subtypes, immunotherapy was well tolerated with minimal data stratifying toxicity by age. CONCLUSIONS Contemporary immunotherapy has informed practice in genitourinary malignancies independent of patient age. Trial reporting of outcomes by age will be important to understand the generalizability of ongoing investigations for elderly patients. PATIENT SUMMARY With the growing use of immunotherapy in genitourinary malignancies, benefits appear to apply independent of age. As the field advances, detailed reporting on outcomes and toxicities by age will be informative for both patients and physicians when discussing treatment options.

Upper Tract Urothelial Carcinomas: Prognostic Factors and Outcomes in Patients With Non–Lymph Node Distant Metastasis

Micro‐Abstract Metastatic UTUC is an aggressive disease. 45 patients with distant metastasis were analysed at the time of initiating chemotherapy in a risk score that includes anemia and receipt of cisplatin helping stratify overall survival patients for future clinical trials. Background: Upper tract urothelial carcinomas (UTUCs) are increasingly recognized as separate malignancies. Additional insight into clinical outcomes and key prognostic factors are needed. Objectives: To detail outcomes of patients with UTUCs recurring after radical nephroureterectomy (RNU) and to determine a risk score that predicts outcomes of patients with non–lymph node distant metastasis. Design, Setting, and Participants: Chart review of all patients who had an extraurothelial recurrence after RNU for UTUC at Dana‐Farber Cancer Institute between 2009 and 2014. Outcome Measurements and Statistical Analysis: Median overall survival defined as time from chemotherapy for distant relapse to death. Prognostic relevance of performance status, hemoglobin, and receipt of cisplatin were assessed by Cox regression model. Results and Limitations: A total of 102 patients were identified, 57 of whom had non–lymph node distant metastases at relapse; 45 received chemotherapy. Median follow‐up was 29.8 months; median overall survival was 14.7 months. Objective response rate to any chemotherapy in the first‐line setting was only 22%. Hemoglobin > 11 g/dL and receipt of cisplatin was associated with numerically longer median survival but did not reach statistical significance in univariate and multivariate analysis. Prognostic risk score scale including hemoglobin < 11 g/dL and receipt of cisplatin was inversely associated with survival, with scores of 0, 1, and 2 leading to median survival of 19.0, 14.9, and 7.2 months (P = .38), respectively. Conclusions: Advanced UTUC portends a poor prognosis, and most patients cannot receive cisplatin‐based chemotherapy. A risk score that includes anemia and receipt of cisplatin helps stratify patients with distant metastasis for inclusion into eventual clinical trials. More studies are needed to validate these findings. Patient Summary: Metastatic UTUC is an aggressive disease, where anemia and ineligibility to receive cisplatin are adverse features associated with shorter survival.

Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma

BackgroundMetastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC.MethodsmUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan–Meier methods.ResultsOf the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3–TACC3 fusion.ConclusionsCombination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.

Proton Pump Inhibitors and Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma

Micro‐Abstract Proton pump inhibitors (PPIs) can affect optimal absorption of concomitant oral cancer treatments. We conducted a pooled analysis to investigate the effect of PPI use in 2188 metastatic renal cell carcinoma patients treated with oral targeted therapy. Survival outcomes were similar between PPI users and nonusers. Our data highlight the importance of anticipating risks associated with polypharmacy in patients who receive oral targeted therapy. Introduction: Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and can affect the optimal absorption of concomitant oral medications, such as vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs). The purpose of this study was to investigate the effect of PPI use on survival in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. Materials and Methods: We conducted a pooled analysis of mRCC patients treated in phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan–Meier method. Results: We identified 2188 patients treated with sunitinib (n = 952), axitinib (n = 626) or sorafenib (n = 610), of whom 120 were PPI users. Overall, PPI users showed similar overall survival compared with non‐PPI users (hazard ratio [HR], 1.051; 95% confidence interval [CI], 0.769‐1.438; P = .754; median, 24.1 vs. 21.3 months). Similarly, progression‐free survival (HR, 1.016; 95% CI, 0.793‐1.301; P = .902; median, 5.5 vs. 8.0 months) and objective response rates (23.3% vs. 27.4%; P = .344) were not different between PPI users and nonusers. These findings were consistent across International mRCC Database Consortium risk groups and according to line of therapy. Adverse events were similar between PPI users and nonusers. Conclusion: We showed that PPI use does not appear to negatively affect the efficacy and safety of select VEGF‐TKIs in patients with mRCC. Documentation of concomitant medications and patient education on potential drug interactions are critical for optimizing the use of oral cancer‐targeting therapy.