Effects of Concurrent Administration of Spironolactone in Veterans with Metastatic Prostate Cancer Receiving Abiraterone: A Real-World Retrospective Study.

INTRODUCTION: Prostate cancer is the most common cancer in men in the United States with low survival rates once metastasized. Abiraterone is approved for use in castrate-sensitive and castrate-resistant prostate cancer and is used extensively in the Veterans Affairs (VA) healthcare system. Spironolactone, a diuretic used to treat heart failure, edema, ascites, and hypertension, may increase androgen levels and reduce effectiveness of abiraterone when used concurrently to treat prostate cancer patients. While previous case studies support this, no large epidemiology studies have been conducted. The current study utilizes the large, VA prostate cancer data core and evaluates the effect of concomitant spironolactone on efficacy of abiraterone treatment in metastatic prostate cancer patients. PATIENTS AND METHODS: The study selected 18,943 veterans with metastatic prostate cancer on abiraterone treatment. Of these, 581 patients (3.1%) were also on concomitant spironolactone. The concomitant treatment group, abiraterone + spironolactone, significantly differed from the abiraterone-only group in body mass index, prevalence rates of heart failure and liver disease, and being previously treated with docetaxel. A 1:1 propensity score matching method was used to balance sample sizes and baseline traits between the two treatment groups, abiraterone versus abiraterone + spironolactone. Kaplan-Meier curves and Cox proportional hazard model were used to compare 5-year overall survival and all-cause mortality outcomes, respectively, between the two groups. RESULTS: After propensity score matched, the abiraterone + spironolactone group was treated with abiraterone significantly longer than the abiraterone-only group (mean ± standard deviation days 549.0 ± 552.3 vs. 435.5 ± 474.1; p = 0.0002) and had a higher 5-year overall survival rate (44% vs. 37%; p = 0.0116). Veterans with metastatic prostate cancer treated with abiraterone + spironolactone also had a lower 5-year all-cause mortality compared to those only on abiraterone (hazard ratio 0.80, 95% confidence intervals 0.61-0.96; p = 0.012). CONCLUSION: This large VA observational study suggests that concomitant use of spironolactone does not compromise cancer control or survival of metastatic prostate cancer patients treated with abiraterone.

Phase 1 study of ARQ 761, a ß-lapachone analogue that promotes NQO1-mediated programmed cancer cell necrosis.

BACKGROUND: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a ß-lapachone (ß-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death. METHODS: We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200). RESULTS: A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m2 as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06). CONCLUSIONS: ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.

Randomized phase 2 trial of erlotinib in combination with high-dose celecoxib or placebo in patients with advanced non-small cell lung cancer.

BACKGROUND: Cyclooxygenase 2 (COX-2)-dependent signaling represents a potential mechanism of resistance to therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This is mediated in part through an EGFR-independent activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) by prostaglandin E2 (PGE2). PGE2 promotes downregulation of E cadherin and epithelial to mesenchymal transition. The current study investigated EGFR and COX-2 inhibition in patients with non-small cell lung cancer (NSCLC) and elevated baseline urinary metabolite of PGE2 (PGEM). METHODS: Patients with stage IIIB/IV (AJCC 6th edition) NSCLC who progressed after at least 1 line of therapy or refused standard chemotherapy were randomized to receive erlotinib and celecoxib versus erlotinib and placebo. The primary endpoint was progression-free survival (PFS) with 80% power to detect a 50% improvement with a 1-sided significance level of .2 in the intent-to-treat and elevated baseline PGEM populations. Secondary endpoints included response rate, overall survival, and evaluation of molecular markers to assess targeting COX-2-related pathways and evaluate EGFR tyrosine kinase inhibitor resistance. RESULTS: A total of 107 patients were enrolled with comparable baseline characteristics. Among the patients treated with celecoxib, those with wild-type EGFR were found to have an increased PFS (3.2 months vs 1.8 months; P = .03). PFS was numerically improved among patients in the intent-to-treat group who received erlotinib and celecoxib compared with those treated with erlotinib and placebo (5.4 months vs 3.5 months; P = .33) and was increased in patients in the erlotinib and celecoxib arm with elevated baseline PGEM (5.4 months vs 2.2 months; P = .15). Adverse events were similar in both treatment arms. CONCLUSIONS: The combination of erlotinib and celecoxib did not appear to improve outcomes in an unselected population, but selection by elevated baseline PGEM led to an increase in PFS with this combination. Patients with EGFR wild-type status may benefit from the combination of erlotinib and celecoxib.

Brief Report: Real-World Efficacy and Safety of Sotorasib in U.S. Veterans with KRAS G12C-Mutated NSCLC.

Introduction: The KRAS G12C inhibitor sotorasib was approved for treating advanced NSCLC in the second line or later on the basis of the CodeBreaK100 trial. Nevertheless, data on the real-world efficacy and safety of sotorasib, and to its optimal dose, remain limited. Methods: Patients treated with sotorasib for NSCLC through the Veterans Health Administration were retrospectively identified from the Corporate Data Warehouse. Survival, response, and toxicity data were obtained from chart review. Results: Among the 128 patients treated with sotorasib through the Veterans Health Administration, objective response rate was 34%, progression-free survival (PFS) six months, and overall survival 12 months. Similar PFS was observed among the 16 patients who received frontline sotorasib without any prior systemic therapy for NSCLC. Toxicity leading to sotorasib interruption or dose reduction occurred in 37% of patients, whereas sotorasib discontinuation for toxicity occurred in 25%. Notably, sotorasib dose reduction was associated with substantially improved PFS and OS. Conclusions: In this real-world study, the observed efficacy of sotorasib was similar to the results of CodeBreaK100. Patients who received frontline sotorasib had similar PFS to our overall cohort, suggesting that first-line sotorasib monotherapy may benefit patients who are not eligible for chemotherapy. Toxicities leading to sotorasib interruption, dose reduction, or discontinuation were common. Sotorasib dose reduction was associated with improved survival, suggesting that sotorasib dose reduction may not compromise efficacy.

Concerning Safety and Efficacy of Concurrent and Consolidative Durvalumab With Thoracic Radiation Therapy in PDL1-Unselected Stage III Non-Small Cell Lung Cancer: Brief Report.

PURPOSE: Consolidative durvalumab, an anti-programmed death ligand 1 (PDL1) immune checkpoint inhibitor, administered after concurrent chemoradiation improves outcomes of patients with locally advanced non-small cell lung cancer (NSCLC) without substantially increasing toxicities. We studied a chemotherapy-free regimen of thoracic radiation therapy (RT) with concurrent and consolidative durvalumab. METHODS AND MATERIALS: This single-arm phase 2 trial enrolled patients with stage III NSCLC (regardless of tumor PDL1 expression), Eastern Cooperative Oncology Group (ECOG) performance status 0-1, adequate pulmonary function, and RT fields meeting standard organ constraints. Participants received 2 cycles of durvalumab (1500 mg every 4 weeks) concurrently with thoracic RT (60 Gy in 30 fractions), followed by up to 13 cycles of consolidative durvalumab. RESULTS: After 10 patients were enrolled, the trial was closed because of poor clinical outcomes. With a median follow-up of 12 months, 5 patients had disease progression and 8 patients died. Six patients experienced 15 treatment-related, grade ≥3 events, including 1 grade 4 acute kidney injury during consolidation and 2 fatal pulmonary events. One fatal pulmonary event occurred during the concurrent phase in an active smoker; the other occurred after the first cycle of consolidative durvalumab. The primary endpoint of progression-free survival at 12 months was 20% (50% for PDL1≥1% vs 0% for PDL1 unavailable or <1%). Median overall survival was not reached, 10.5 months, and 7 months, for PDL1 ≥1%, <1%, and unavailable, respectively. CONCLUSIONS: In PDL1 unselected stage III NSCLC, thoracic RT plus concurrent and consolidative durvalumab is associated with high-grade toxicity and early disease progression.

Highly variable timing renders immunotherapy efficacy and toxicity impractical biomarkers of one another in clinical practice.

Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI. Methods: Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women). Results: Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE. Conclusions: In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.

Cmai: Predicting Antigen-Antibody Interactions from Massive Sequencing Data.

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.

Characteristics of Long-Term Survivors With EGFR-Mutant Metastatic NSCLC.

Introduction: Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors. Methods: Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively. Results: Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p = 0.029 and odds ratio = 1.90, p = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively). Conclusions: Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy.

Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer.

OBJECTIVES: AXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC. MATERIALS AND METHODS: Escalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured. RESULTS: 21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7-10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes. CONCLUSION: Bemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.

A phase II clinical trial evaluating the safety and efficacy of durvalumab as first line therapy in advanced and metastatic non-small cell lung cancer patients with Eastern Cooperative Oncology Group performance status of 2.

Background: Approximately 30-40% of patients with advanced and metastatic non-small cell lung cancer (NSCLC) present with an impaired performance status (PS). There are limited prospective data on the safety and efficacy of durvalumab in these patients. Methods: In this single-arm phase II clinical trial (NCT02879617), patients with previously untreated Stage IIIB/IV NSCLC and ECOG PS of 2 received durvalumab 1500 mg every 28 days until progression or unacceptable toxicity. The primary endpoints were overall survival (OS) and safety determined by grade ≥3 treatment-related adverse events (TRAEs). Findings: Between April 2017 and March 2021, 50 patients were enrolled, of whom 47 received durvalumab. With a median follow-up of 28 months, median OS was 6 months (95% CI 4-10). TRAEs grade 3 occurred in nine of 47 patients (19%, 95% CI 9%-33%). OS in patients with a PD-L1 TPS of 0, 1-49%, and ≥50% was six months (95% CI 3-15), 11 months (95% CI 4-16), and 11 months (95% CI 0-not reached (NR)), respectively. Health related quality of life (HQRL) assessed at baseline and during therapy demonstrated no statistically significant change over the course of treatment. Interpretation: This study demonstrates that single agent durvalumab is safe and well tolerated in the 1st line treatment of patients with advanced NSCLC and ECOG PS of 2, with an encouraging OS benefit in patients with PD-L1 positive tumors. This trial is amongst the largest prospective studies evaluating durvalumab in the 1st line treatment of advanced stage NSCLC and a PS of 2. Funding: AstraZeneca, NCI P30CA047904.

Systemic immune parameters after prior radiation therapy in patients receiving immune checkpoint inhibitors.

INTRODUCTION: Preclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI. METHODS AND MATERIALS: Pre- and post-ICI blood samples were collected from patients enrolled in a prospective immunotherapy biospecimen protocol. Mutiplex panels of 40 cytokines and 120 autoantibodies (Ab) were analyzed. We identified differences in these parameters according to receipt, timing, and type of prior RT. We calculated P values using the Pearson product-moment correlation coefficient and false discovery rate (FDR) using the Benjamini-Hochberg Procedure. RESULTS: Among 277 total patients, 69 (25%) received RT in the 6 months prior to ICI initiation. Among RT-treated patients, 23 (33%) received stereotactic RT, and 33 (48%) received curative intent RT. There was no significant difference in demographics or type of immunotherapy between patients according to prior RT exposure. Baseline complement C8 Ab and MIP-1d/CCL15 were significantly higher among patients with prior RT. For MIP-1d/CCL15, only prior stereotactic RT was associated with significant differences. CONCLUSIONS: Prior RT is associated with few changes in systemic immune parameters in patients receiving ICI. The underlying mechanisms and optimal approach to harnessing the potential synergy of RT and ICI require further prospective clinical investigation.

Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked.

INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab. METHODS: This is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response. CONCLUSION: This phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024.

pan-MHC and cross-Species Prediction of T Cell Receptor-Antigen Binding.

Profiling the binding of T cell receptors (TCRs) of T cells to antigenic peptides presented by MHC proteins is one of the most important unsolved problems in modern immunology. Experimental methods to probe TCR-antigen interactions are slow, labor-intensive, costly, and yield moderate throughput. To address this problem, we developed pMTnet-omni, an Artificial Intelligence (AI) system based on hybrid protein sequence and structure information, to predict the pairing of TCRs of αß T cells with peptide-MHC complexes (pMHCs). pMTnet-omni is capable of handling peptides presented by both class I and II pMHCs, and capable of handling both human and mouse TCR-pMHC pairs, through information sharing enabled this hybrid design. pMTnet-omni achieves a high overall Area Under the Curve of Receiver Operator Characteristics (AUROC) of 0.888, which surpasses competing tools by a large margin. We showed that pMTnet-omni can distinguish binding affinity of TCRs with similar sequences. Across a range of datasets from various biological contexts, pMTnet-omni characterized the longitudinal evolution and spatial heterogeneity of TCR-pMHC interactions and their functional impact. We successfully developed a biomarker based on pMTnet-omni for predicting immune-related adverse events of immune checkpoint inhibitor (ICI) treatment in a cohort of 57 ICI-treated patients. pMTnet-omni represents a major advance towards developing a clinically usable AI system for TCR-pMHC pairing prediction that can aid the design and implementation of TCR-based immunotherapeutics.

Risk of renal failure in cancer patients with bone metastasis treated with renally adjusted zoledronic acid.

PURPOSE: The purpose of this study was to evaluate the incidence of acute renal failure (ARF) in patients with mild to moderate renal dysfunction, receiving renally adjusted zoledronic acid (ZA) and compare it to patients with normal baseline renal function, receiving standard-dose ZA. METHODS: This was a retrospective study of patients receiving ZA for the treatment of bone metastasis due to cancer. Patients were divided into two groups: (1) normal group with baseline creatinine clearance (CrCl) of greater than 60 mL/min and standard ZA dose; (2) impaired group with baseline CrCl of 30-60 mL/min and renally adjusted ZA dose. Primary endpoint of ARF was defined as an increase in serum creatinine (SCr) of 0.5 mg/dL or 1.0 mg/dL from a baseline SCr of <1.4 mg/dL or ≥ 1.4 mg/dL, respectively. RESULTS: In total, 1,472 evaluable doses of ZA were given to 220 patients. Of these, 184 patients were in the normal group and 36 patients in the impaired group. There were 38 patients (20.7%) who developed ARF in the normal group versus 7 patients (19.4%) in the impaired group. There was no difference in the mean time to the incidence of ARF at 6.1 months in both groups. Incidence of ARF based on CrCl (≥ 25% decline in CrCl) was similar between groups (39.1% vs. 41.7%; p = 0.78). CONCLUSION: The incidence of ARF is similar between patients in the normal group and impaired group when the ZA dose is renally adjusted.

Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial.

Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.

Association between Antibiotic Exposure and Systemic Immune Parameters in Cancer Patients Receiving Checkpoint Inhibitor Therapy.

Antibiotic administration is associated with worse clinical outcomes and changes to the gut microbiome in cancer patients receiving immune checkpoint inhibitors (ICI). However, the effects of antibiotics on systemic immune function are unknown. We, therefore, evaluated antibiotic exposure, therapeutic responses, and multiplex panels of 40 serum cytokines and 124 antibodies at baseline and six weeks after ICI initiation, with p < 0.05 and false discovery rate (FDR) < 0.2 considered significant. A total of 251 patients were included, of whom the 135 (54%) who received antibiotics had lower response rates and shorter survival. Patients who received antibiotics prior to ICI initiation had modestly but significantly lower baseline levels of nucleolin, MDA5, c-reactive protein, and liver cytosol antigen type 1 (LC1) antibodies, as well as higher levels of heparin sulfate and Matrigel antibodies. After ICI initiation, antibiotic-treated patients had significantly lower levels of MDA5, CENP.B, and nucleolin antibodies. Although there were no clear differences in cytokines in the overall cohort, in the lung cancer subset (53% of the study population), we observed differences in IFN-γ, IL-8, and macrophage inflammatory proteins. In ICI-treated patients, antibiotic exposure is associated with changes in certain antibodies and cytokines. Understanding the relationship between these factors may improve the clinical management of patients receiving ICI.

Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway.

Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G1-phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling.

Retrospective analysis of the consequences of acid suppressive therapy on ketoconazole efficacy in advanced castration-resistant prostate cancer.

BACKGROUND: The area under the curve of a single ketoconazole dose has been shown to decrease significantly when administered with acid suppressive therapy. No published studies have examined the clinical impact of concurrent ketoconazole and acid suppressive therapy in patients with castration-resistant prostate cancer (CRPC). OBJECTIVE: To evaluate the effect of acid suppressive therapy on prostate-specific antigen (PSA) response rate in CRPC patients receiving ketoconazole. METHODS: This retrospective study evaluated CRPC patients treated with ketoconazole 3 times daily between January 1, 1999, and September 30, 2009. Patients included in the analysis had failed androgen deprivation therapy, and were subsequently initiated on ketoconazole. Response (PSA decline ≥50% maintained ≥4 weeks) was evaluated in patients receiving ketoconazole with (group 1 [G1]) or without (group 2 [G2]) concurrent acid suppressive therapy. RESULTS: Thirty patients (G1: 11 patients; G2: 19 patients) were included in the analysis. Mean age in G1 and G2 was 71.8 and 69.6 years, respectively. Most patients had received prior therapy with an antiandrogen (90.9% G1; 100% G2) and fewer patients received antiandrogen withdrawal therapy (27.3% G1; 21.1% G2). Median baseline PSA was 109.4 (G1) and 86.9 ng/mL (G2) (p = 0.55). Median duration of ketoconazole was 7.2 months in G1 and 5.8 months in G2 (p = 0.09). Ketoconazole adherence was 82% (G1) and 100% (G2). Median duration of concurrent acid suppressive therapy was 3.8 months (range 2.0-20.4) in G1. PSA response (72.7% and 47.4%; p = 0.26) and time to PSA response (1.2 vs 0.9 mo; p = 0.53) were statistically similar between G1 and G2, respectively. Median progression free survival was higher in G1 (11.5 vs 6.9 months in G2; p = 0.047). CONCLUSIONS: Use of concurrent acid suppressive therapy and ketoconazole in CRPC patients did not decrease PSA response rate, and progression free survival was unexpectedly higher compared with the non-acid suppressive therapy group. Larger studies are needed to verify the clinical impact of acid suppressive therapy in combination with ketoconazole.

Predictors of prognosis of synchronous brain metastases in small-cell lung cancer patients.

Patients with small cell lung cancer (SCLC) are more likely to have synchronous brain metastasis (SBM) at the time of diagnosis than patients with any other extracranial primary malignancy. We sought to identify which factors predicted an increased risk of SBM in SCLC as well as which factors affected the prognosis of these patients. 38,956 Patients in the Surveillance, Epidemiology, and End Results (SEER) database with microscopically confirmed SCLC from 2010 to 2016 were identified. 6264 (16.1%) Patients with SCLC had SBM at the time of diagnosis. In the multivariable logistic regression, disease specific factors that were predictive of SBM were primary tumor size > 7 cm (adjusted OR = 1.14, 95% CI [1.02, 1.28], p = 0.02), synchronous lung metastases, and synchronous bone metastases. Demographic specific factors predictive of increased SBM risk in this model were younger age, male sex, and race (American Indian/Alaska Native and black patients). Patients insured through Medicaid were less likely to present with SBM. In the multivariate Cox proportional hazards model, lack of insurance was the strongest predictor of mortality (adjusted HR = 1.47, 95% CI [1.26, 1.73], p < 0.001). Other factors associated with an increased risk of mortality include male sex, older age, health insurance coverage through Medicaid, synchronous liver metastasis, synchronous lung metastasis, and primary tumor size > 7 cm. In contrast, Asian patients had a lower risk of mortality. This study identifies risk factors for SBM among patients with SCLC, as well as indicators of prognosis among this patient population.

The impact of consenter characteristics and experience on patient interest in clinical research.

BACKGROUND: To explain the historically low rates of participation in cancer clinical trials, several factors have been studied. These include subject characteristics and attitudes, clinical trial availability and eligibility criteria, and physician attitudes and communication skills. However, the impact of nonphysician research personnel, who often consent patients for studies, is unclear. We therefore evaluated the association between consenter characteristics and subject interest in clinical research. METHODS: We performed a retrospective review of subjects enrolled in a university-based cancer center tissue repository. During enrollment, subjects were asked if they were willing to be contacted in the future to (a) provide medical follow-up information and (b) participate in other clinical research. We analyzed the association between responses to these questions and consenter characteristics using univariate analysis and multivariate logistic regression. RESULTS: In total, 181 consenters enrolled 922 subjects. The majority of subjects agreed to be contacted for follow-up (84.9%) and future research (83.1%). Subject willingness to be contacted for future research was associated with greater consenter experience in univariate and multivariate analyses. In multivariate analysis, subject willingness to be contacted for future research was associated with discordance between subject and consenter gender, but not with subject gender, race, or income, or consenter gender or race. CONCLUSIONS: Consenter experience and subject-consenter gender discordance were associated with greater subject interest in participating in future research. The role of consenters in clinical research merits future study and should be considered in efforts to increase cancer clinical trial accrual.