Prospective manipulation of the gut microbiome with microbial ecosystem therapeutic 4 (MET4) in HPV-related locoregionally-advanced oropharyngeal cancer squamous cell carcinoma (LA-OPSCC) undergoing primary chemoradiation: ROMA2 study.

BACKGROUND: Gut microbiome modulation to boost antitumor immune responses is under investigation. METHODS: ROMA-2 evaluated the microbial ecosystem therapeutic (MET)-4 oral consortia, a mixture of cultured human stool-derived immune-responsiveness associated bacteria, given with chemoradiation (CRT) in HPV-related oropharyngeal cancer patients. Co-primary endpoints were safety and changes in stool cumulative MET-4 taxa relative abundance (RA) by 16SRNA sequencing. Stools and plasma were collected pre/post-MET-4 intervention for microbiome and metabolome analysis. RESULTS: Twenty-nine patients received ≥1 dose of MET-4 and were evaluable for safety: drug-related adverse events (AEs) occurred in 13/29 patients: all grade 1-2 except one grade 3 (diarrhea). MET-4 was discontinued early in 7/29 patients due to CRT-induced toxicity, and in 1/29 due to MET-4 AEs. Twenty patients were evaluable for ecological endpoints: there was no increase in stool MET-4 RA post-intervention but trended to increase in stage III patients (p = 0.06). MET-4 RA was higher in stage III vs I-II patients at week 4 (p = 0.03) and 2-month follow-up (p = 0.01), which correlated with changes in plasma and stool targeted metabolomics. CONCLUSIONS: ROMA-2 did not meet its primary ecologic endpoint, as no engraftment was observed in the overall cohort. Exploratory findings of engraftment in stage III patients warrants further investigation of microbiome interventions in this subgroup.

Transoral Robotic Surgery and Radiation Volume Deintensification in Unknown Primary Squamous Cell Carcinoma of the Neck: The Phase 2 FIND Nonrandomized Controlled Trial.

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects. Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control. Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022. Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0. Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings. Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%). Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

Impact of teratoma on survival probabilities of patients with metastatic non-seminomatous germ cell cancer: Results from the IGCCCG Update Consortium.

AIMS: To resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT). PATIENTS AND METHODS: Using the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method. RESULTS: Among 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001). CONCLUSION: Teratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups.

The Survival Outcomes of the Metastatic Nonclear Cell Renal Cell Carcinoma in the Immunotherapy Era: Princess Margaret Cancer Centre Experience.

Immunotherapy (IO) with or without targeted therapy (TT) is the standard treatment for patients with metastatic clear cell renal cell carcinoma (RCC). The evidence supporting their use in metastatic nonclear cell renal cell carcinoma (nccRCC) subtypes is based on small prospective trials and retrospective analyses. Here, we report survival outcomes for patients with metastatic nccRCC treated with IO and/or TT at the Princess Margaret Cancer Centre, Toronto, ON, Canada. Demographics, disease characteristics, and survival outcomes were collected retrospectively. Overall (OS), progression-free survival (PFS), and objective response rates (ORR) were calculated. We identified 69 patients with metastatic nccRCC treated with IO and/or TT as the first-line treatment, and 36 (52.1%) patients as the second-line treatment. Median OS of the first line IO recipients (n = 12) and non-IO recipients (n = 57) was not reached (NR) and 17.2 months (95% confidence interval (95% CI): 7.3-27.0; P = 0.23), respectively. Median PFS of first-line IO recipients and non-IO recipients was NR and 4.7 months (95% CI: 3.7-5.6; P = 0.019), respectively. The ORR of IO recipients versus non-IO recipients was 50% versus 12.3% (P = 0.007). Median OS of the second-line IO recipients (n = 8) and non-IO recipients (n = 28) was NR and 6.3 months (95% CI: 3.2-9.3; P = 0.003), respectively. Median PFS of second-line IO recipients and non-IO recipients was 4.8 months (95% CI: 2.7-6.8) and 2.8 months (95% CI: 1.8-3.7; P = 0.014), respectively. ORR of IO recipients and non-IO recipients was 37.5% and 3.5%, respectively; P = 0.028. While the number of patients included in our retrospective review was small, our analysis suggested that patients with nccRCC have improved survival outcomes with IO treatment. Validation of prospective dataset is required before widespread clinical utilization.

A phase 1 trial of the MEK inhibitor selumetinib in combination with pembrolizumab for advanced or metastatic solid tumors.

MEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (anti‒PD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1‒14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and N-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov , NCT03833427.

Understanding the incidence, duration, and severity of symptoms through daily symptom monitoring among frail and non-frail older patients receiving metastatic prostate cancer treatments.

INTRODUCTION: Older adults with metastatic prostate cancer (mPC) experience high symptom burden associated with treatment. Frailty may exacerbate treatment toxicity. The aim of this study was to explore short-term treatment toxicity in patients with metastatic prostate cancer. MATERIALS AND METHODS: Older adults with metastatic prostate cancer starting chemotherapy, androgen-receptor-axis targeted therapies, or radium-223 participated in a prospective, multicentre, observational study. Participants self-reported symptoms daily using the Edmonton Symptom Assessment System for one treatment cycle via internet or telephone. The most common moderate-to-severe symptoms (score≥4), their duration, and the proportion of participants who experienced improvements in symptom severity (score<4) after reporting moderate-to-severe symptoms at baseline were determined using descriptive statistics. Once-weekly symptom questionnaires were administered and analyzed using linear mixed effect models. Symptom incidence, duration, and frailty associations were assessed using t-tests and chi-square tests. RESULTS: Ninety participants completed the study (mean age=77 years [standard deviation=6.1], 42% frail [Vulnerable Elders Survey≥3]). The most common moderate-to-severe symptoms across cohorts were fatigue (46.8%), insomnia (42.9%), poor wellbeing (41.2%), pain (37.5%), and decreased appetite (37.1%). Poor wellbeing had a higher incidence in frail participants (62.5% in frail vs. 31.4% in non-frail, p=0.039). Symptom duration varied across cohorts and between frail and non-frail participants. Among participants who reported moderate-to-severe symptoms at baseline, no more than 15% improved in any symptom. There were statistically significant improvements in weekly symptoms for fatigue, decreased appetite, and insomnia in the chemotherapy cohort only. DISCUSSION: Limitations include a short follow-up duration, lack of a control group, and few radium-223 participants. Regular symptom monitoring can help clinicians understand temporal patterns and durations of symptoms and inform supportive care approaches.

Multimodal detection of molecular residual disease in high-risk locally advanced squamous cell carcinoma of the head and neck.

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4-6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection.

INDUCE-2: A Phase I/II, open-label, two-part study of feladilimab in combination with tremelimumab in patients with advanced solid tumors.

Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors. Objectives of Part 1 were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of feladilimab in combination with tremelimumab. In Part 2, the antitumor activity of the combination (administered at the RP2D determined in Part 1) was to be assessed in patients with relapsed/refractory head and neck squamous cell carcinoma. Primary endpoints included the rates of dose-limiting toxicities (DLTs), adverse events (AEs), AEs of special interest, and serious AEs. Secondary endpoints included overall response rate, while biomarker assessment was exploratory. A total of 26 patients were enrolled, 18 (69%) of whom had completed the study at end date. One patient, in the highest dose group (24/225 mg feladilimab/tremelimumab), experienced a DLT 18 days after the first dose of study treatment. All patients experienced at least one AE; AEs led to treatment discontinuation in four (15%) patients. Partial response was observed in one patient. Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2.

CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial.

C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with previously treated advanced or metastatic castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non-small-cell lung cancer (NSCLC) were randomized 1:1 to the CXCR2 antagonist navarixin 30 or 100 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks up to 35 cycles. Primary endpoints were investigator-assessed objective response rate (RECIST v1.1) and safety. Of 105 patients (CRPC, n=40; MSS CRC, n=40; NSCLC, n=25), 3 had a partial response (2 CRPC, 1 MSS CRC) for ORRs of 5%, 2.5%, and 0%, respectively. Median progression-free survival was 1.8-2.4 months without evidence of a dose-response relationship, and the study was closed at a prespecified interim analysis for lack of efficacy. Dose-limiting toxicities occurred in 2/48 patients (4%) receiving navarixin 30 mg and 3/48 (6%) receiving navarixin 100 mg; events included grade 4 neutropenia and grade 3 transaminase elevation, hepatitis, and pneumonitis. Treatment-related adverse events occurred in 70/105 patients (67%) and led to treatment discontinuation in 7/105 (7%). Maximal reductions from baseline in absolute neutrophil count were 44.5%-48.2% (cycle 1) and 37.5%-44.2% (cycle 2) and occurred within 6-12 hours postdose in both groups. Navarixin plus pembrolizumab did not demonstrate sufficient efficacy in this study. Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov , NCT03473925).

Early changes in tumor-naive cell-free methylomes and fragmentomes predict outcomes in pembrolizumab-treated solid tumors.

Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab, but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify a cancer-specific methylation (CSM) and fragment length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïve mutation-agnostic ctDNA approach integrating methylomics and fragmentomics could predict outcomes in patients treated with pembrolizumab.

Comparison of outcomes for Hispanic and non-Hispanic patients with advanced renal cell carcinoma in the International Metastatic Renal Cell Carcinoma Database.

BACKGROUND: Existing data on the impact of Hispanic ethnicity on outcomes for patients with renal cell carcinoma (RCC) is mixed. The authors investigated outcomes of Hispanic and non-Hispanic White (NHW) patients with advanced RCC receiving systemic therapy at large academic cancer centers using the International Metastatic Renal Cell Carcinoma Database (IMDC). METHODS: Eligible patients included non-Black Hispanic and NHW patients with locally advanced or metastatic RCC initiating systemic therapy. Overall survival (OS) and time to first-line treatment failure (TTF) were calculated using the Kaplan-Meier method. The effect of ethnicity on OS and TTF were estimated by Cox regression hazard ratios (HRs). RESULTS: A total of 1563 patients (181 Hispanic and 1382 NHW) (mostly males [73.8%] with clear cell RCC [81.5%] treated with tyrosine kinase inhibitor [TKI] monotherapy [69.9%]) were included. IMDC risk groups were similar between groups. Hispanic patients were younger at initial diagnosis (median 57 vs. 59 years, p = .015) and less likely to have greater than one metastatic site (60.8% vs. 76.8%, p < .001) or bone metastases (23.8% vs. 33.4%, p = .009). Median OS and TTF was 38.0 months (95% confidence interval [CI], 28.1-59.2) versus 35.7 months (95% CI, 31.9-39.2) and 7.8 months (95% CI, 6.2-9.0) versus 7.5 months (95% CI, 6.9-8.1), respectively, in Hispanic versus NHW patients. In multivariable Cox regression analysis, no statistically significant differences were observed in OS (adjusted hazard ratio [HR], 1.07; 95% CI, 0.86-1.31, p = .56) or TTF (adjusted HR, 1.06; 95% CI, 0.89-1.26, p = .50). CONCLUSIONS: The authors did not observe statistically significant differences in OS or TTF between Hispanic and NHW patients with advanced RCC. Receiving treatment at tertiary cancer centers may mitigate observed disparities in cancer outcomes.

Circulating Oncometabolite 2-hydroxyglutarate as a Potential Biomarker for Isocitrate Dehydrogenase (IDH1/2) Mutant Cholangiocarcinoma.

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (αKG). IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of patients with IDHmt glioma and CCA. Results were validated in cohorts of patients with CCA and clear-cell renal cell carcinoma. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for patients with IDHmt glioma, while circulating rRS was elevated in patients with IDHmt CCA. There were overlap distributions of circulating R2HG and total 2HG in patients with both IDHmt and wild-type (IDHwt) CCA, while there was minimal overlap in rRS values between patients with IDHmt and IDHwt CCA. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in patients with IDHmt CCA compare with patients with IDHwt CCA. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy.

Autoimmune PaneLs as PrEdictors of Toxicity in Patients TReated with Immune Checkpoint InhibiTors (ALERT).

BACKGROUND: Immune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb). METHODS: We used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI. Plasma was collected before and after ICI from cancer patients participating in two clinical trials (NCT03686202, NCT02644369). A one-time collection was obtained from healthy controls for comparison. Custom arrays with 162 autoAg were used to detect IgG and IgM reactivities. Differences of median fluorescent intensity (MFI) were analyzed with Wilcoxon sign rank test and Kruskal-Wallis test. MFI 500 was used as threshold to define autoAb reactivity. RESULTS: A total of 114 patients and 14 healthy controls were included in this study. irAEs of grade (G) ≥ 2 occurred in 37/114 patients (32%). We observed a greater number of IgG and IgM reactivities in pre-ICI collections from patients versus healthy controls (62 vs 32 p < 0.001). Patients experiencing irAEs G ≥ 2 demonstrated pre-ICI IgG reactivity to a greater number of AutoAg than patients who did not develop irAEs (39 vs 33 p = 0.040). We observed post-treatment increase of IgM reactivities in subjects experiencing irAEs G ≥ 2 (29 vs 35, p = 0.021) and a decrease of IgG levels after steroids (38 vs 28, p = 0.009). CONCLUSIONS: Overall, these results support the potential role of autoAb in irAEs etiology and evolution. A prospective study is ongoing to validate our findings (NCT04107311).

Selinexor for the treatment of recurrent or metastatic salivary gland tumors: Results from the GEMS-001 clinical trial.

OBJECTIVES: We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT). METHODS: GEMS-001 is an open-label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT. RESULTS: One hundred patients were enrolled in GEMS-001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4-10). The most common treatment-related Grade 1-2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment-related Grade 3-4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed. CONCLUSIONS: Although tumor reduction was observed across participants, single agent selinexor anti-tumor activity was limited.

Safety, Immunologic, and Clinical Activity of Durvalumab in Combination with Olaparib or Cediranib in Advanced Leiomyosarcoma: Results of the DAPPER Clinical Trial.

PURPOSE: Non-inflamed (cold) tumors such as leiomyosarcoma do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis or PARP inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pretreated patients with leiomyosarcoma. PATIENTS AND METHODS: Patients were randomized to receive durvalumab 1,500 mg IV every 4 weeks with either olaparib 300 mg twice a day orally (Arm A) or cediranib 20 mg every day orally 5 days/week (Arm B) until unacceptable toxicity or disease progression. Paired tumor biopsies, serial radiologic assessments and stool collections were performed. Primary endpoints were safety and immune cell changes in the TME. Objective responses and survival were correlated with transcriptomic, radiomic, and microbiome parameters. RESULTS: Among 30 heavily pretreated patients (15 on each arm), grade ≥ 3 toxicity occurred in 3 (20%) and 2 (13%) on Arms A and B, respectively. On Arm A, 1 patient achieved partial response (PR) with increase in CD8 T cells and macrophages in the TME during treatment, while 4 had stable disease (SD) ≥ 6 months. No patients on Arm B achieved PR or SD ≥ 6 months. Transcriptome analysis showed that baseline M1-macrophage and B-cell activity were associated with overall survival. CONCLUSIONS: Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some patients with leiomyosarcoma. Baseline M1-macrophage and B-cell activity may identify patients with leiomyosarcoma with favorable outcomes on immunotherapy and should be further evaluated.

The Use of Salvage Chemotherapy for Patients with Relapsed Testicular Germ Cell Tumor (GCT) in Canada: A National Survey.

BACKGROUND: Although metastatic germ cell tumor (GCT) is highly curable with initial cisplatin-based chemotherapy (CT), 20-30% of patients relapse. Salvage CT options include conventional (CDCT) and high dose chemotherapy (HDCT), however definitive comparative data remain lacking. We aimed to characterize the contemporary practice patterns of salvage CT across Canada. METHODS: We conducted a 30-question online survey for Canadian medical and hematological oncologists with experience in treating GCT, assessing treatment availability, patient selection, and management strategies used for relapsed GCT patients. RESULTS: There were 30 respondents from 18 cancer centers across eight provinces. The most common CDCT regimens used were TIP (64%) and VIP (25%). HDCT was available in 13 centers (70%). The HDCT regimen used included carboplatin and etoposide for two cycles (76% in 7 centers), three cycles (6% in 2 centers), and the TICE protocol (11%, in 2 centers). "Bridging" CDCT was used by 65% of respondents. Post-HDCT treatments considered include surgical resection for residual disease (87.5%), maintenance etoposide (6.3%), and surveillance only (6.3%). CONCLUSIONS: HDCT is the most commonly used GCT salvage strategy in Canada. Significant differences exist in the treatment availability, selection, and delivery of HDCT, highlighting the need for standardization of care for patients with relapsed testicular GCT.

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.

PURPOSE: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. PATIENTS AND METHODS: Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. RESULTS: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. CONCLUSIONS: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.

Neoadjuvant Cabazitaxel plus Abiraterone/Leuprolide Acetate in Patients with High-Risk Prostate Cancer: ACDC-RP Phase II Trial.

PURPOSE: Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer. PATIENTS AND METHODS: This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile. RESULTS: The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078). CONCLUSIONS: Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.

A tailored phase I-specific patient-reported outcome (PRO) survey to capture the patient experience of symptomatic adverse events.

BACKGROUND: Patient perspectives are fundamental to defining tolerability of investigational anti-neoplastic therapies in clinical trials. Phase I trials present a unique challenge in designing tools for efficiently collecting patient-reported outcomes (PROs) given the difficulty of anticipating adverse events of relevance. However, phase I trials also offer an opportunity for investigators to optimize drug dosing based on tolerability for future larger-scale trials and in eventual clinical practice. Existing tools for comprehensively capturing PROs are generally cumbersome and are not routinely used in phase I trials. METHODS: Here, we describe the creation of a tailored survey based on the National Cancer Institute's PRO-CTCAE for collecting patients' perspectives on symptomatic adverse events in phase I trials in oncology. RESULTS: We describe our stepwise approach to condensing the original 78-symptom library into a modified 30 term core list of symptoms which can be efficiently applied. We further show that our tailored survey aligns with phase I trialists' perspectives on symptoms of relevance. CONCLUSIONS: This tailored survey represents the first PRO tool developed specifically for assessing tolerability in the phase I oncology population. We provide recommendations for future work aimed at integrating this survey into clinical practice.