Endocrine immune-related adverse events in patients with metastatic renal and urothelial cancer treated with immune checkpoint-inhibitors.

PURPOSE: To evaluate the incidence, diagnosis and treatment of immune-related adverse events (e-irAE) of checkpoint inhibition (ICI) in metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC). METHODS: A retrospective, single-center study was conducted to identify a cohort that received ICI for mUC or mRCC. e-irAE were classified according to the CTCAE V.5.0. Patients received ICI for mUC or mCC between 01/2017 and 03/2021. A retrospective chart review was performed. T-Test, the chi-squared test, and Fisher's exact test were performed. RESULTS: 102 Patients received ICI [mUC: 40 (39%), mRCC: 62 (61%)]. 64 (63%) received an ICI monotherapy, 27 (27%) a dual ICI therapy, 11 (11%) a combination with VEGFi. e-irAE occurred in 19 (19%) patients [grade 1-2: 17 (84%), grade 3: 3 (16%)]. The median time until e-irAE was 42 days (range 11-211 days). 14 Patients developed thyroidism (14%), 4 (4%) a hypophysitis, 1 (1%) an adrenal insufficiency (AI). 7 patients (7%) had to discontinue ICI therapy [hypophysitis (100%), AI (100%), thyroidism (14%)]. 6 (86%) received cortisone. After a median range of 34 days 5 patients (71%) restarted ICI therapy. All patients (n = 4) with hypophysitis continued ICI [4 (100%) prednisone, 3 (75%) levothyroxine]. 11 (79%) presented with hyperthyroidism. 4 (37%) needed therapy (1 (7%) prednisone, 3 (21%) thiamazole, 2 (14%) beta blocker). The 9 (64%) patients with hypothyroidism received levothyroxine. Hypophysitis appears only on dual ICI (CTLA-4/PD-1) inhibition (p 0.007). CONCLUSION: This study shows the importance of adequate diagnosis and therapy of e-irAEs.

Impact of COVID-19 crisis on medical care of patients with metastasized uro-oncologic disease under systemic cancer therapy: a multicenter study in German university hospitals.

PURPOSE: To date, over 4.2 million Germans and over 235 million people worldwide have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Uro-oncology (UO) patients are particularly vulnerable but in urgent need of life-saving systemic treatments. Our multicentric study examined the impact of the COVID-19 crisis on the medical care of UO patients in German university hospitals receiving ongoing systemic anti-cancer treatment and to detect the delay of medical care, defined as deferred medical treatment or deviation of the pre-defined follow-up assessment. METHODS: Data of 162 UO patients with metastatic disease undergoing systemic cancer treatment at five university hospitals in Germany were included in our analyses. The focus of interest was any delay or change in treatment between February 2020 and May 2020 (first wave of the COVID-19 crisis in Germany). Statistical analysis of contingency tables were performed using Pearson's chi-squared and Fisher's exact tests, respectively. Effect size was determined using Cramér's V (V). RESULTS: Twenty-four of the 162 patients (14.8%) experienced a delay in systemic treatment of more than 2 weeks. Most of these received immuno-oncologic (IO) treatments (13/24, 54.2%, p = 0.746). Blood tests were delayed or canceled significantly more often in IO patients but with a small effect size (21.1%, p = 0.042, V = 0.230). Treatment of patients with renal cell carcinoma (12/73, 16.4%) and urothelial carcinoma (7/32, 21.9%) was affected the most. CONCLUSIONS: Our data show that the COVID-19 pandemic impacted the medical care of UO patients, but deferment remained modest. There was a tendency towards delays in IO and ADT treatments in particular.

Parallel PI3K, AKT and mTOR inhibition is required to control feedback loops that limit tumor therapy.

Targeting the PI3K pathway has achieved limited success in cancer therapy. One reason for the disappointing activity of drugs that interfere with molecules that are important player in this pathway is the induction of multiple feedback loops that have been only partially understood. To understand these limitations and develop improved treatment strategies, we comprehensively characterized molecular mechanisms of PI3K pathway signaling in bladder cancer cell lines upon using small molecule inhibitors and RNAi technologies against all key molecules and protein complexes within the pathway and analyzed functional and molecular consequences. When targeting either mTORC1, mTOR, AKT or PI3K, only S6K1 phosphorylation was affected in most cell lines examined. Dephosphorylation of 4E-BP1 required combined inhibition of PI3K and mTORC1, independent from AKT, and resulted in a robust reduction in cell viability. Long-term inhibition of PI3K however resulted in a PDK1-dependent, PIP3 and mTORC2 independent rephosphorylation of AKT. AKT rephosphorylation could also be induced by mTOR or PDK1 inhibition. Combining PI3K/mTOR inhibitors with AKT or PDK1 inhibitors suppressed this rephosphorylation, induced apoptosis, decreased colony formation, cell viability and growth of tumor xenografts. Our findings reveal novel molecular mechanisms that explain the requirement for simultaneous targeting of PI3K, AKT and mTORC1 to achieve effective tumor growth inhibition.