Safety and Preliminary Efficacy of Once-Weekly Split-Dose Selinexor in Soft Tissue Sarcoma: Results of the Phase Ib METSSAR Clinical Trial.

BACKGROUND: The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile. OBJECTIVE: The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients. PATIENTS AND METHODS: Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy. RESULTS: Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥ 10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5). CONCLUSIONS: Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.

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.

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.

The role of cytoreductive nephrectomy and systemic therapy in the management of tumour thrombus in patients with metastatic renal cell carcinoma.

BACKGROUND: Outcomes for patients with metastatic renal cell carcinoma (mRCC) and tumour thrombus remain poor. Recent data suggest limited role for cytoreductive nephrectomy (CN) and data on thrombus response to systemic therapy (ST) is scarce. Here, we describe response and survival of patients with de novo mRCC and thrombi treated with ST with or without CN. METHODS: Demographics, disease characteristics and survival of patients with de novo mRCC were collected. Progression-free survival (PFS) and overall survival (OS) in months (m) was calculated using the Kaplan-Meier method (log-rank). RESULTS: Between 2002 and 2019, 226 patients with mRCC were identified, 64 (28.3%) had tumour thrombus out of which 18 (28.1%) received only ST. Among 12 evaluable patients, thrombus response, stability and progression were seen in 3 (25%), 6 (50%) and 3 (25%) patients, respectively. Median OS was similar for patients with and without tumour thrombus treated with systemic therapy alone [OS: 12.1 m (8.8-27.7) vs. 13.9 m (7.9-21.5), p = 0.87]. CN predicted for better OS in patients with tumour thrombus [OS: 29.4 m (17.4-48.9) vs. 12.1 m (8.8-27.7), p = 0.01]. CONCLUSION: In this retrospective series of patients with mRCC and tumour thrombus, addition of CN to ST improved outcomes. Validation of these findings with contemporary regimens is needed.

UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castration-sensitive prostate cancer.

OBJECTIVE: To assess the effectiveness of docetaxel rechallenge (DR) for metastatic castration-resistant prostate cancer (mCRPC) following chemohormonal therapy for metastatic castrate-sensitive prostate cancer (mCSPC). Additionally, we sought to define clinical factors predicting treatment response. PATIENTS AND METHODS: Retrospective analysis of men treated with docetaxel for mCSPC and then rechallenged in the mCRPC setting from four cancer centers in Ontario, Canada. Prostate specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) following DR were evaluated. RESULTS: Fifty five patients were identified between 2015 and 2020. Prior to DR, 94.5% of patients received androgen-receptor axis targeted therapy, 20% received radium-223, and 1.8% received cabazitaxel. Among 54 evaluable patients, 27.8% had a PSA decline ≥50%. Median PFS was 4.1 months (95% CI, 2.1-4.8) and median OS from androgen deprivation therapy initiation was 38.3 months (95% CI, 32.9-41.0). A Gleason Score of ≥8 was an independent predictor of prolonged PFS (HR 0.32, 95% CI, 0.12-0.81; P=0.02). CONCLUSIONS: DR following chemohormonal therapy for mCSPC produced a meaningful PSA response in approximately one-quarter of patients, with relatively short PFS. The impact of Gleason Score on docetaxel response warrants further investigation.

A Phase 2 Trial of Afatinib in Patients with Solid Tumors that Harbor Genomic Aberrations in the HER family: The MOBILITY3 Basket Study.

BACKGROUND: Epidermal growth factor receptor (EGFR)- and human epidermal growth factor receptor (HER)2-targeted therapies are approved for the treatment of breast, gastric/gastrointestinal junction (GEJ), and non-small cell lung cancer (NSCLC) with specific molecular aberrations affecting HER family members. Over 10 % of other cancers harbor genomic aberrations affecting HER family members, but their role remains undefined. OBJECTIVE: The MOBILITY3 trial evaluated the antitumor activity of afatinib, an oral pan-HER tyrosine kinase inhibitor (TKI) in HER-aberrant tumors outside of the licensed indications. PATIENTS AND METHODS: In this single-center basket trial, patients with advanced solid tumors that harbor mutations and/or amplifications of any of the HER family members (EGFR, ERBB2, ERBB3, ERBB4) were enrolled. The EGFR-mutated NSCLC and HER2-positive breast cancers were excluded. Participants were treated with oral afatinib 40 mg daily until disease progression or unacceptable toxicity. Objective response rate (ORR) and progression-free survival (PFS) were primary and secondary endpoints, respectively. RESULTS: The study enrolled 12 patients with 6 tumor types (NSCLC, sarcoma, salivary gland, gastric/GEJ, breast and pancreatic cancer). Objective response rate was 8 % (95 % CI 0.2-38%) and median PFS was 11.4 weeks (95% CI 4.6-33.3 weeks). All 3 patients with salivary gland cancers and 1 patient with ERBB2-mutant NSCLC had clinical benefit (stable disease or partial response lasting > 24 weeks). Due to slow accrual and a lower-than-expected response rate, trial recruitment was terminated before the target of 30 patients were enrolled. CONCLUSIONS: In the MOBILITY3 study (NCT02506517), afatinib demonstrated modest activity in tumors that possess EGFR and ERBB2 aberrations. Clinical benefit seen in all 3 salivary gland cancers supports the growing evidence for the utility of HER-targeted therapies in the treatment of this specific tumor type.

Genomic characterization of non-schistosomiasis-related squamous cell carcinoma of the urinary bladder: A retrospective exploratory study.

BACKGROUND: Non-schistosomiasis related-squamous cell carcinoma of urinary bladder (NSR-SCCUB) is a rare tumor subtype distinct from urothelial carcinoma (UC). Studies assessing molecular biomarkers in bladder cancer have generally focused on UC, and genomic data of NSR-SCCUB is limited. We aim to provide additional insight into the molecular underpinnings of this rare entity. METHODS: NSR-SCCUB patients were identified retrospectively at Princess Margaret Cancer Centre between 2002 and 2017. Demographics, disease characteristics, therapeutic approaches, and outcomes were collected. Tissue samples were interrogated using the Oncomine Comprehensive Assay v3 (ThermoFisher). Kaplan-Meier method was used to estimate the disease-free survival and overall survival (OS). RESULTS: Overall, 11 patients with NSR-SCCUB were identified between 2002 and 2017 with adequate tissue samples. Median age was 71 years (45-86), predominantly male (63.6%). At time of diagnosis, 9 patients (81.8%) had muscle-invasive disease, 1 (9.1%) had non-muscle invasive, and 1 (9.1%) had advanced disease. Nine (81.8%) patients had radical cystectomy and pelvic lymph nodes dissection. Eight (72.7%) patients had pT3 or pT4 with N0, and 5 (45.5%) were grade 3. Median OS was 12.5 months (95% CI 7.7-17.2 months). Single nucleotide variants or insertion/deletions were identified in TP53, TERT, PIK3CA, PTEN, CREBBP, FBXW7, and FGFR3. Amplifications were found in CCND1, and EGFR. CONCLUSIONS: NSR-SCCUB has potentially actionable genomic alterations with anticancer agents and many of these aberrations are also seen in UC. The recruitment of NSR-SCCUB patients harboring such mutations should be considered in biomarker driven urinary bladder cancer studies.

Clinicopathologic factors that influence prognosis and survival outcomes in men with metastatic castration-resistant prostate cancer treated with Radium-223.

BACKGROUND: In men with metastatic castration-resistant prostate cancer (mCRPC) with primarily bone metastases, radium-223 (223 Ra) improves overall survival (OS). However, the selection of 223 Ra is not guided by specific validated clinicopathologic factors, and thus outcomes are heterogeneous. PATIENTS AND METHODS: This retrospective survival analysis was performed in men with mCRPC treated with 223 Ra at our cancer center. Demographics and disease characteristics were collected. OS was calculated using the Kaplan-Meier method (log-rank). The potential prognostic factors were determined using both univariable (UVA) and multivariable analysis (MVA) (Cox-regression) methods. RESULTS: In total, 150 patients with a median age of 74 years (52-93) received 223 Ra between May 2015 and July 2018, and 58% had 6-20 bone metastases. Ninety-four (63%) patients received >4 223 Ra doses, and 56 (37%) received ≤4. The following pre-treatment factors were analyzed (median [range]): eastern cooperative oncology group performance status (ECOG PS), (1 [0-3]); Albumin (ALB), (39 g/L [24-47]); alkaline phosphatase (ALP), (110 U/L [35-1633]); and prostate-specific antigen (PSA), (49 µg/L [0.83-7238]). The median OS for all patients was 14.5 months (95% CI: 11.2-18). These factors were associated with poor survival outcomes in UVA and MVA: ALB <35 g/L, ALP >150 U/L, ECOG PS 2-3, and PSA >80 µg/L. By assigning one point for each of these factors, a prognostic model was developed, wherein three distinct risk groups were identified: good, 0-1 (n = 103); intermediate, 2 (n = 30); and poor risk, 3-4 points (n = 17). The median OS was 19.4, 10.0, and 3.1 months, respectively (p < 0.001). CONCLUSIONS: Pre-treatment ALB, ALP, ECOG, and PSA, were significantly correlated with OS and could guide treatment selection for men with mCRPC by identifying those who are most or least likely to benefit from 223 Ra. Validation in an independent dataset is required prior to widespread clinical utilization.

A phase 1b trial of selinexor, a first-in-class selective inhibitor of nuclear export (SINE), in combination with doxorubicin in patients with advanced soft tissue sarcomas (STS).

BACKGROUND: Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound with single-agent activity in soft tissue sarcoma (STS). The study's aim was to determine the safety and efficacy of selinexor in combination with doxorubicin in patients with locally advanced/metastatic STS. METHODS: This phase 1b study used a mTPI design. Patients received selinexor at either 60 or 80 mg weekly PO plus doxorubicin (75 mg/m2 IV q21 days). Patients with clinical benefit (defined as ≥stable disease via RECIST 1.1) after six cycles of combination treatment received maintenance selinexor until disease progression or unacceptable toxicity. Disease assessments were conducted every two cycles. Pharmacokinetic data were collected on the first three patients per dose level. RESULTS: Twenty-five patients were enrolled (20 female, ECOG 0/1: 13/12, median age 57 years [range 21-74]). Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumour (n = 3) and other sarcomas (n = 16). Three (12%) and 22 (88%) patients were treated at 60 mg and 80 mg of selinexor, respectively. The most common ≥G3 drug-related adverse events (AEs) were haematological, including neutropenia (56%), febrile neutropenia (28%) and anaemia (24%). There were four dose-limiting toxicities (febrile neutropenia (x2), vomiting, fatigue) all at the 80 mg dose level. There was one death secondary to heart failure. Of the 24 evaluable patients, 5 (21%) had a partial response and 15 (63%) had SD as best response. The estimated median progression-free survival (PFS) and overall survival (OS) were 5.5 (95% CI:4.1-5.7) and 10.5 (95% CI:7.5-14) months. CONCLUSION: In a heterogeneous group of patients with locally advanced/metastatic STS, the combination of selinexor and doxorubicin fulfilled the prespecified boundary for tolerability.

Selinexor, a First in Class, Nuclear Export Inhibitor for the Treatment of Advanced Malignant Peripheral Nerve Sheath Tumor.

Malignant peripheral nerve sheath tumor (MPNST) is a highly malignant neoplasm arising from peripheral nerve or its attendant sheath and is derived from Schwann or pluripotent cells of neural crest origin. Patients with recurrent, unresectable, or advanced stage disease have limited treatment options, and current therapies are associated with little benefit. In this article, we report nine cases of MPNST treated with selinexor, an orally bioavailable, selective inhibitor of nuclear export, accompanied by tumor stabilization or regression.

Clinical outcomes of non-osteogenic, non-Ewing soft-tissue sarcoma of bone--experience of the Toronto Sarcoma Program.

Non-osteogenic, non-Ewing soft-tissue sarcoma (NONE-STS) of bone is a rare presentation of primary bone cancers. Optimal treatments and outcomes for this heterogenous group are poorly described. We evaluated the factors associated with long-term outcomes in patients with this disease. Patients with localized NONE-STS of bone treated at the Toronto Sarcoma Program from 1987 to 2017 were identified. Clinical characteristics, treatment, and survival information were collected. Kaplan-Meier (log-rank) survival estimates from the time of definitive surgery, with uni-/multivariate analyses (Cox) of sarcoma-specific survival were performed. A total of 106 patients (60.4% male; median age 46 years) with NONE-STS of bone were identified. Common histologies included undifferentiated pleomorphic sarcoma [UPS]/malignant fibrous histiocytoma [MFH] (UPS/MFH, 41.5%), leiomyosarcoma (LMS, 20.8%), and fibrosarcoma (FS, 11.3%). Tumors were often high grade (59.4%) and involved the extremities (88.7%), with most receiving chemotherapy (67.9%) with cisplatin/doxorubicin-based regimens (73.6%). In the full cohort, 10-year DFS (45.7%, [95%CI: 35.7-55.8%]), OS (53.4%, [95%CI: 41.7-62.2%]), and SSS (63.9%, [95%CI: 53.9-72.5%]) were moderate. Histology specific, 10-year SSS was 70.7% [95%CI: 56.1-85.5%] for UPS/MFH, 51.8% [95%CI: 29.8-73.8%] for LMS, and 72.2% [95%CI: 45.1-99.2%] for FS. Only UPS/MFH (n = 4) showed sarcoma-related death >10 years. Multivariate analysis identified axial location (HR = 35.5, [95%CI: 3.4-369.6]), high grade (HR = 16.9, [95%CI: 1.6-185.1]), and disease relapse (HR = 485.1, [95%CI: 36.3-6482.6]) as risk factors for death (p < 0.05). Treatment with chemotherapy (HR = 0.1, [95%CI: 0.01-0.86]) and necrosis ≥85% (HR = 0.2, [95%CI: 0.04-0.99]) showed improved survival (p < 0.05). NONE-STS of bone has favorable long-term survival similar to osteosarcoma. Patients receiving chemotherapy derive benefit in retrospective analyses. UPS/MFH histologies show sarcoma-related death beyond 10 years. Further data on histologic subgroups are needed.

Evaluation of the Diagnostic and Predicative Values of 8-Iso-Prostaglandin F2α as a Biomarker of Breast Cancer.

BACKGROUND: Breast cancer (BC) is a commonly reported cancer that is widely prevalent among women. Its early detection improves patient survival and results in better outcomes. For diagnosis and follow-up care, tumor markers are one of the feasible investigations to be ordered. 8-Iso-prostaglandin F2α (8-iso-PGF2α) serves as a serum marker reflecting oxidative stress and subsequent damaging of DNA. In the present study, we aimed to evaluate both diagnostic and predictive values of 8-iso-PGF2α in BC patients. MATERIALS AND METHODS: Serum levels of 8-iso-PGF2α were assessed for 66 women with benign breast tumors and 65 women who had malignant BC. To compare the patients who had breast tumors with healthy individuals, 63 women free of breast diseases were selected as controls. RESULTS: The serum level of 8-iso-PGF2α in the BC patients (57.92 pg/mL) was significantly higher compared to those with benign tumors (18.89 pg/mL) (p < 0.001). In addition, individuals with no breast diseases had less 8-iso-PGF2α (4.02 pg/mL) compared to those who had developed a tumor (p < 0.001). Serum 8-iso-PGF2α was found to be positively correlated with both carcinoembryonic antigen (r = 0.74, p < 0.001) and cancer antigen 15-3 (r = 0.80, p < 0.001). Furthermore, serum 8-iso-PGF2α showed high diagnostic performance in BC (AUC = 0.999, sensitivity = 100%, specificity = 99.2% at a cutoff value of 36.18 pg/mL). CONCLUSIONS: Our study found that the high level of serum 8-iso-PGF2α helps to provide a non-invasive indicator to detect BC. Future work with a larger sample size and various phases of BC can confirm the current results which provide insights into the early detection of cancer.