Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is ...poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population.
This multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients.
Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1-22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1-40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10
).
MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.
Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report ...the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714).
Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
Overall, 260 patients were enrolled and treated (A-CD, n = 101; A-ID, n = 103; B, n = 44; unconfirmed FGF/FGFR status, n = 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR 95% confidence interval (CI) in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n = 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n = 3; V553M, n = 1; N540K/S, n = 2; M528I, n = 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each).
Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements.
•Pemigatinib was evaluated in metastatic UC with FGFR3 mutations/rearrangements and other FGF/FGFR alterations.•Objective response in patients with FGFR3 mutations/rearrangements was 18% (continuous) and 23% (intermittent dosing).•Limited clinical activity was observed in patients whose tumors harbored other FGF/FGFR alterations.•FGFR3 S249C mutations (52.5%) were the most common FGFR3 alterations, and PI3K pathway co-alterations predicted nonresponse.•Continuous and intermittent dosing of pemigatinib had clinical activity in metastatic FGFR3-altered UC.
Cabozantinib prolongs overall survival (OS) and progression-free survival (PFS) in patients with metastatic clear cell renal cell carcinoma (RCC) that progressed on first-line vascular endothelial ...growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI). The role of cabozantinib has not been established in non-clear cell renal cell carcinoma (nccRCC).
This is a retrospective study of 30 patients with nccRCC who received cabozantinib from January 2013 to January 2017. Information collected included baseline characteristics, toxicity, dose reductions, PFS and OS. A fellowship trained abdominal radiologist, blinded to patient history and clinical data, assessed radiographic response using RECIST, v1.1.
With a median follow-up of 20.6 months (95% confidence interval CI: 11.4–28.8), median PFS was 8.6 months (95% CI: 6.1–14.7), and median OS was 25.4 months (95% CI: 15.5–35.4). Of the 28 patients with measurable disease, 4 had partial responses (2 papillary, 1 chromophobe and 1 unclassified RCC), 18 had stable disease (64.2%) and 6 had progressive disease (21.4%), resulting in a 14.3% objective response rate and a 78.6% disease control rate. Two patients with papillary RCC who had experienced disease progression on savolitinib achieved durable partial response and stable disease, respectively, following treatment with cabozantinib. Of the 21 patients who started cabozantinib at 60 mg/d, 12 (57.1%) required dose reduction due to toxicity.
In this retrospective study, cabozantinib produced a clinically meaningful benefit in patients with metastatic nccRCC, the majority of whom had disease progression on prior VEGFR-TKIs. Prospective trials of cabozantinib in nccRCC are warranted.
•Non-clear cell histology renal cell carcinoma (nccRCC) represents 30% of all RCC cases.•nccRCC includes papillary, chromophobe, translocation, unclassified and others.•Cabozantinib (cabo) treatment has substantial activity in metastatic nccRCC.•Disease control with cabo was found in multiple subtypes of metastatic nccRCC.
Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus ...sunitinib in patients with treatment-naive advanced sRCC.
The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses.
A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003) and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification.
In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC.
•Patients with sarcomatoid renal cell carcinoma had improved progression-free survival with avelumab + axitinib versus sunitinib.•The objective response rate was 46.8% for patients in the avelumab + axitinib arm versus 21.3% for those in the sunitinib arm.•Correlative analyses showed enrichment for cancer-associated fibroblasts and regulatory T cells, and CD274 and CD8A expression.•Our findings suggest that avelumab + axitinib may improve the chance of overcoming the aggressive features of this subtype.
Quantum multifractality is a fundamental property of systems such as non-interacting disordered systems at an Anderson transition and many-body systems in Hilbert space. Here we discuss the origin of ...the presence or absence of a fundamental symmetry related to this property. The anomalous multifractal dimension $\Delta_q$ is used to characterize the structure of quantum states in such systems. Although the multifractal symmetry relation \mbox{$\Delta_q=\Delta_{1-q}$} is universally fulfilled in many known systems, recently some important examples have emerged where it does not hold. We show that the reason for this is the presence of atypically small eigenfunction amplitudes induced by two different mechanisms. The first one was already known and is related to Gaussian fluctuations well described by random matrix theory. The second one, not previously explored, is related to the presence of an algebraically localized envelope. While the effect of Gaussian fluctuations can be removed by coarse graining, the second mechanism is robust to such a procedure. We illustrate the violation of the symmetry due to algebraic localization on two systems of very different nature, a 1D Floquet critical system and a model corresponding to Anderson localization on random graphs.
The field of genitourinary malignancies has been a showcase for therapeutic cancer vaccine success since the application of intravesicular Bacillus Calmette-Guerin (BCG) for bladder cancer in the ...1970s and enjoyed a renaissance in 2010 with the US Food and Drug Administration (FDA) approval of sipuleucel-T for prostate cancer. Several vaccine strategies have emerged, such as autologous or allogeneic whole-tumor vaccines, DNA vaccines, use of viral vectors, and peptides as immunostimulatory adjuvants. Despite impressive early trials, vaccine monotherapy has achieved limited success in the clinical world; however, combinations of vaccine and immune checkpoint inhibition or vaccine and cytokine stimulation are expected to move the field forward. This article reviews pivotal trials of cancer vaccines in prostate, renal, and bladder cancer and ongoing trials combining vaccines with other immune therapy agents.
Purpose
In this study, we aimed to describe the real-life practice outcomes of pertuzumab–trastuzumab–taxane (PTT) combination in visceral organ metastatic, trastuzumab-naive breast cancer (BC) ...patients.
Methods
This study was conducted by Turkish Oncology Group and included 317 patients’ data from 36 centers.
Results
Median age was 51 (22–82). Median PFS was 28.5 months, while median OS was 40.3 months. Patients with brain metastases (
n
: 13, 4.1%) had worse PFS (16.8 m vs. 28.5 m;
p
= 0.002) and OS (26.7 m vs. 40.3 m;
p
= 0.009). Patients older than 65 years of age (
n
: 42, 13.2%) had significantly lower OS results (19.8 m vs. 40.3 m;
p
= 0.01). Two hundred sixty-eight patients (86.7%) received docetaxel while 37 patients (11.7%) received paclitaxel. PFS and OS were similar between taxane groups. In eight patients (2.5%), 5–40% ejection fraction decrement from baseline was detected without any clinical sign of heart failure.
Conclusions
Our RLP trial included only visceral metastatic, trastuzumab-naïve BC patients including cases with brain involvement who received PTT combination in the first-line treatment. Regardless of negative prognostic characteristics, our results are in parallel with pivotal trial. Further strategies for brain metastasis should be developed to improve outcomes despite encouraging results with PTT treatment. Taxane selection can be personalized and endocrine maintenance may further improve outcomes after taxanes were discontinued. To our knowledge, this is the largest scale real-life clinical practice study of pertuzumab–trastuzumab–taxane therapy to date.
PDF
