Adjuvant Atezolizumab in Patients with Sarcomatoid Renal Cell Carcinoma: A Prespecified Subgroup Analysis of IMmotion010.

Patients with sarcomatoid renal cell carcinoma (sRCC) have a poor prognosis. In the randomised, double-blind phase 3 IMmotion010 trial (NCT03024996), adjuvant atezolizumab did not demonstrate a disease-free survival (DFS) benefit versus placebo in the overall population of patients with locoregional renal cell carcinoma with an increased risk of recurrence following surgery. This prespecified subgroup analysis of efficacy and safety was completed in 104 patients with sRCC. Baseline characteristics were similar between treatment arms. At a median follow-up of 45 mo, the median DFS was not evaluable (NE; 95% confidence interval [CI], 12 mo-NE) in the atezolizumab arm (n = 37) and 23 mo (95% CI, 11-NE) in the placebo arm (n = 66; hazard ratio 0.77 [95% CI, 0.44-1.4]). In the sRCC subgroup, grade 3/4 treatment-related adverse events (TRAEs) occurred in one patient (2.7%) in the atezolizumab arm and two patients (3.0%) in the placebo arm. By comparison, 54 of 353 patients (15%) and 16 of 317 patients (5.0%) with non-sarcomatoid histology reported grade 3/4 TRAEs in the respective arms. In conclusion, the difference in DFS was not statistically significant between adjuvant atezolizumab and placebo in patients with sRCC. The safety profile was similar between patients with sRCC and non-sRCC. PATIENT SUMMARY: Patients with a specific type of locoregional kidney cancer (tumours with sarcomatoid features) were treated with atezolizumab or placebo after surgery. Slightly more patients treated with atezolizumab lived longer without the disease getting worse than those treated with placebo, although this finding was not statistically significant. The side effects were similar to those seen in patients with other types of kidney cancer treated with atezolizumab in the same study (IMmotion010). In patients with sarcomatoid kidney cancer, atezolizumab was tolerable and may be more effective than placebo, but this requires further study.

Platinum ineligibility and survival outcomes in patients with advanced urothelial carcinoma receiving first-line treatment.

BACKGROUND: This study examined real-world patients with locally advanced or metastatic urothelial carcinoma considered ineligible for platinum-containing chemotherapy in the first-line setting. METHODS: This retrospective observational study used data from a nationwide (United States) de-identified patient-level electronic health record-derived database. Eligible adults (aged 18 years and older) had a locally advanced or metastatic urothelial carcinoma diagnosis on or after January 1, 2016, and initiated first-line systemic treatment at least 90 days before December 31, 2021. Platinum ineligibility was defined as Eastern Cooperative Oncology Group performance status of at least 3, creatinine clearance less than 30 mL/min, or Eastern Cooperative Oncology Group performance status of 2 and creatinine clearance of less than 45 mL/min. Overall survival and real-world progression-free survival (PFS) were summarized using the Kaplan-Meier method. RESULTS: The overall population comprised 4270 patients; 477 (11%) were considered platinum ineligible, 262 (55%) received a first-line programmed cell death 1 or programmed cell death ligand 1 immune checkpoint inhibitor, and 118 (25%) received platinum-based chemotherapy. A total of 2335 (55%) patients were platinum eligible; 677 (29%) received a first-line programmed cell death 1 or programmed cell death ligand 1 inhibitor, and 1229 (53%) received platinum-based chemotherapy. Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4 to 14.8 months) in platinum-eligible and 5.1 months (95% CI = 4.2 to 6.4 months) in platinum-ineligible patients. Median PFS was shorter in platinum-ineligible (3.4 months; 95% CI = 2.9 to 4.0 months) vs platinum-eligible patients (5.9 months; 95% CI = 5.5 to 6.2 months) overall and when stratified by first-line therapy type. CONCLUSION: This real-world study has shown for the first time the treatment patterns and outcomes in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma ineligible for platinum-based chemotherapy. These findings provide quantitative benchmarks for platinum ineligibility in the first-line advanced or metastatic urothelial carcinoma setting and highlight the need for novel therapy options.

Hallmarks of RET and Co-occuring Genomic Alterations in RET-aberrant Cancers.

Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers. Herein, we review the registrational data from the selective RET-inhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRASG12C inhibition.

The evolving treatment landscape of advanced urothelial carcinoma.

PURPOSE OF REVIEW: Bladder cancer is the 10th most common cancer in the world and the 6th most common cancer among men. In the past few years, several new agents have been approved for the treatment of urothelial tumors. In this paper, we review the evolving treatment landscape of advanced urothelial carcinoma (UC). RECENT FINDINGS: Since 2016, the Food and Drug Administration (FDA) has approved five immunotherapies targeting programmed cell death 1/programmed cell death 1 legend, an antinectin-4 antibody drug conjugate (ADC), and a fibroblast growth factor receptor (FGFR) inhibitor for the treatment of patients with advanced UC. Moreover, there are multiple targeted agents, immune checkpoint inhibitors (ICI), ADCs, and their combinations currently being tested in clinical studies with the goal of obtaining FDA approval. SUMMARY: Precision oncology efforts continue to advance our understanding of the UC biology and transform the existing treatment paradigms. An enlarging arsenal of treatment options promises further personalization of UC therapy.

Molecular Profiling of Metastatic Bladder Cancer Early-Phase Clinical Trial Participants Predicts Patient Outcomes.

Prognosis for patients with metastatic bladder carcinoma (mBC) remains limited and in need of novel therapies. We retrospectively analyzed medical records of 43 patients with platinum-refractory metastatic bladder cancer (mBC) who participated in one or more phase I trials of various investigational therapies. Patients' tumors or circulating tumor DNA were analyzed by next-generation sequencing. The median progression-free survival was 4.2 months, the median overall survival was 9.6 months, and the overall response rate was 17.5%. TP53, ERBB2, PI3KCA, FGFR3, and ARID1A alterations were detected in 66%, 29%, 27%, 24%, and 22% of all patients, respectively. Alterations in FGFR3 were almost mutually exclusive of TP53. More than half (64%) of patients with an FGFR alt received an FGFR inhibitor, 67% of which achieved disease control. Among patients with urothelial carcinoma histology, those harboring a TP53 alteration had a shorter median progression-free survival (PFS) compared with those whose tumors carry wild-type TP53. The reverse relationship was observed in patients harboring an FGFR alteration. IMPLICATIONS: Patients with platinum-refractory mBC derive clinical benefit from participating in early-phase clinical trials and their survival outcomes correlate with the genetic profile of the tumor. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/3/395/F1.large.jpg.

Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies.

PURPOSE: The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+). METHODS: A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation. RESULTS: Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16-0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04-0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25-1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation. CONCLUSION: Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

Next-generation characterization of the Cancer Cell Line Encyclopedia.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.