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It remains unclear which patients with metastatic germ cell tumours (mGCTs) need prophylactic anticoagulation to prevent venous thromboembolic events (VTEs).To assess the risk and onset of VTEs stratified by risk factors.This multi-institutional retrospective dataset included mGCT patients treated with first-line platinum-based chemotherapy.Patients with prophylactic anticoagulation were excluded.A regression analysis was performed to select risk factors for VTEs. The simulated number needed to treat (NNT) and the number needed to harm (NNH) with prophylactic anticoagulation were calculated based on the cumulative incidences retrieved from this study and hazard rates of recently published trials describing the efficacy of prophylactic anticoagulation to prevent VTEs and the risk of bleeding events.From 1120 patients, 121 (11%) had a VTE, which occurred prior to chemotherapy in 49 (4%) and on or after chemotherapy in 72 (6%). Six patients (1%) had a bleeding event without anticoagulation. After backward regression, the one risk factor for a VTE during or after chemotherapy was the use of a venous access device. The simulated cumulative VTE incidence from prophylactic anticoagulation for patients on or after chemotherapy would translate into an NNT of 45 (95% confidence interval [CI] 36-56) and an NNH of 186 (95% CI 87-506). Limitations are mainly related to the retrospective nature of the study.The mGCTs associated VTEs are most common before and during, but not after, chemotherapy. Avoiding venous access device and/or prophylactic anticoagulation with an acceptable risk-benefit profile may decrease VTE occurring on chemotherapy.We found that venous thromboembolic events (VTEs) occur rarely after chemotherapy. Based on experience of prophylactic anticoagulation in other cancers, we conclude that the risk of VTE in men undergoing chemotherapy for metastatic germ cell tumours can be decreased by thromboprophylaxis with a reasonable risk-benefit profile and by avoidance of venous access devices.

The role of retroperitoneal lymph node dissection (RPLND) in testicular cancer is well established in both the primary and post-chemotherapy setting. The aim of this study was to report our 2 years oncological outcomes of robotic RPLND. A retrospective review was performed of all patients undergoing robotic RPLND by a single surgeon at Princess Margaret Cancer Centre. Demographic, perioperative, and oncologic data were analyzed using descriptive statistics. Between September 2014 and June 2020, 141 patients underwent an RPLND [33 (23.4%) were primary, 108 (76.6%) were post-chemotherapy]. 27 (19.1%) patients underwent a robotic bilateral template nerve-sparing RPLND. RPLND indication was primary (i.e. pre-chemotherapy) in 18 (66.7%), and post-chemotherapy in 9 (33.3%) patients. Stage at RPLND was 2A (n = 15, 55.6%), 2B (n = 9, 33.3%), 2C (n = 1, 3.7%) and 3 (n = 2, 7.4%). Median OR time (incision to closure) was 525 min and blood loss was 200 ml. Nerve sparing was performed in all but one case. Six (22.2%) adjuvant procedures were performed including two (7.4%) vascular repairs. Median length of stay was 2 days. Viable tumor was detected in 17 (63%) and teratoma in 9 (33.3%). Median follow-up was 31.3 months. No adjuvant chemotherapy was given. Three patients (11.1%) relapsed: 2 out-of-field and 1 with both in-field and out-of-field disease. Robotic RPLND can be performed safely. Long-term follow-up of series such as ours, enriched with patients with viable disease and/or teratoma, and not treated with adjuvant chemotherapy is required to ensure oncological outcomes are comparable to the open approach.

Clinical trials represent a fulcrum for oncology drug discovery and development to bring safe and effective medicines to patients in a timely manner. Clinical trials have shifted from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to become adaptively designed and biomarker-driven evaluations of molecularly targeted agents and immune therapies in selected patient subsets. This review will discuss the scientific, methodological, practical, and patient-focused considerations to transform clinical trials. A call to action is proposed to establish the framework for next-generation clinical trials that strikes an optimal balance of operational efficiency, scientific impact, and value to patients. Significance: The future of cancer clinical trials requires a framework that can efficiently transform scientific discoveries to clinical utility through applications of innovative technologies and dynamic design methodologies. Next-generation clinical trials will offer individualized strategies which ultimately contribute to globalized knowledge and collective learning, through the joint efforts of all key stakeholders including investigators and patients.

PURPOSE Testicular cancer survivors may experience mental illness as a consequence of their cancer diagnosis and treatment. METHODS All incident cases of testicular cancer treated with orchiectomy in Ontario, Canada (2000-2010), were identified using the Ontario Cancer Registry. Cases were matched to controls in a 1:5 ratio on age and geography. Population-level databases were used to identify mental health service use episodes; outpatient use included visits to a general practitioner for a mental health concern or any visit to a psychiatrist. Negative binomial regression modeling was used to estimate the rate of mental health service use in the pretreatment (2 years prior until 1 month before orchiectomy), peritreatment (1 month before until 1 month after orchiectomy), and post-treatment periods (1 month after orchiectomy until end of follow-up). Rate ratios (RR) comparing cases with controls in the peri- and post-treatment periods were adjusted for baseline mental health service use. RESULTS Two thousand six hundred nineteen cases of testicular cancer were matched to 13,095 controls. There was no baseline difference in the rate of mental health service use. Cases were significantly more likely than controls to have an outpatient visit for a mental health concern in the peritreatment (adjusted RR [aRR], 2.45; 95% CI, 2.06 to 2.92) and post-treatment periods (aRR, 1.30; 95% CI, 1.12 to 1.52). The difference in mental health service use persisted over a median follow-up of 12 years. In the postorchiectomy period, cases with baseline mental health service use were those most likely to use mental health services (aRR, 5.64; 95% CI, 4.64 to 6.85). CONCLUSION Testicular cancer survivors use mental health services more often than healthy controls. Survivorship care plans that address the long-term mental healthcare needs of this population are needed.

Background Clinician reporting of symptomatic adverse events (AEs) in phase I trials uses the Common Terminology Criteria for Adverse Events (CTCAE). The utility of the patient-reported outcomes (PROs) version of the CTCAE (PRO-CTCAE) in this setting is unknown. This prospective, observational study compared patient- and clinician-reported symptomatic AEs in phase I patients. Methods Phase I study–eligible patients at Princess Margaret were surveyed with the PRO-CTCAE full-item library (78 symptomatic AEs) at baseline (BL), mid-cycle 1, and mid-cycle 2 (C2). Patient and trial characteristics, best response, and survival data were collected. Presence or absence of patient- (PRO-CTCAE) or clinician-reported symptomatic AEs were compared (kappa) at defined timepoints and overall (BL+ mid-cycle 1 + C2). Results Of 292 patients approached from May 2017 to January 2019, a total of 265 (90.8%) were consented, with 243 (91.7%) evaluable and 552 PRO-CTCAE surveys (completion rate = 98.7%) included in analyses. Evaluation of overall patient-reported symptomatic AEs identified 50 PRO-CTCAE and 11 CTCAE items with 10% or greater reporting frequency. Nineteen CTCAE items were reported as 1% or less despite matched PRO-CTCAE items reporting as 10% or greater. Underreported categories included sexual health, bodily emissions, and cognition. Clinician- relative to patient-reporting frequency (ratio) demonstrated 9 symptomatic AEs with a 50-fold or more lower clinician reporting rate. Overall patient–clinician agreement for individual symptomatic AEs ranged from poor (κ = 0.00-0.19) to moderate (κ = 0.40-0.59), with discordance driven by lack of clinician reporting. Dyspnea (κ = 0.54) and peripheral neuropathy (κ = 0.63) at BL and limb edema (κ = 0.55) at C2 demonstrated the highest patient–clinician agreement. Conclusions Poor to moderate patient–clinician agreement for symptomatic AEs suggests clinician underreporting in phase I trials. Analyses of severity and interference PRO categories are ongoing.

Background Mutations in p110α, encoded by PIK3CA, are present in ~40% of HR+/HER2- BCs. GDC-0077, a PI3Kα-selective inhibitor and mutant PI3Kα degrader, elicits antitumor activity in PIK3CAmut preclinical models as a single agent and when combined with endocrine therapy (ET). New evidence suggests BCs harboring multiple PIK3CAmut exhibit increased signaling through the PI3K/AKT pathway and are more sensitive to PI3Kα inhibitors compared with BCs with a single PIK3CAmut. We report a preliminary analysis of PIK3CAmut status with clinical outcomes from an ongoing study of GDC-0077 alone or with ET (letrozole/fulvestrant) ± palbociclib (palbo) in pts with PIK3CAmut HR+/HER2- mBC (NCT03006172). Methods Detectable PIK3CAmut from local tumor tissue/blood-based assay or tumor tissue by cobas PIK3CA assay were required to enroll. Plasma-derived circulating tumor (ct) DNA was collected at baseline (BL), cycle 1 day 15 (C1D15), and C2D1 (in the cohort where GDC-0077 starts at C1D15) to detect PIK3CAmut. Paired tumor samples were analyzed for Ki67 and pAKT/pS6 expression by immunohistochemistry. Single vs multiple PIK3CAmut was correlated with the percentage of pharmacodynamic (PD) inhibition of Ki67/pAKT/pS6 expression; with the PIK3CAmut allele frequency ratio between BL and C1D15 or C2D1 (MAFr15); with best overall response (BOR, RECIST v1.1); and with time on treatment (TOT) in days. Statistical analyses: Kruskal-Wallis and Mann-Whitney-Wilcoxon for group and pairwise comparisons, respectively, and two-sample proportion testing for categorical comparisons. Results Data cutoff was 03/20/2020. PIK3CAmut were detected in 87/103 (84.5%) pts with BL ctDNA available for sequencing. Multiple PIK3CAmut were detected in 21/87 (24.1%) BL ctDNA samples: 9 from pts treated with single-agent GDC-0077; 8 from pts treated with GDC-0077 + letrozole/fulvestrant; and 4 from pts treated with GDC-0077 + letrozole/fulvestrant + palbo. The median number of lines of prior therapy for metastatic disease was not different between pts with multiple (3.0 lines) vs single (2.5 lines) PIK3CAmut detected at BL (p = 0.205). Median percentage inhibition of Ki67/pAKT/pS6 expression was greater in pts with multiple (-65.8, -70.3, -66.8%, respectively) vs single (-42.1, -34.1, -29.5%) PIK3CAmut detected at BL (p = 0.095, 0.002, 0.056). Median MAFr15 was lower in pts with multiple (MAFr15 0.01) vs single PIK3CAmut (MAFr15 0.15) detected at BL (p = 0.004). Of 73 pts with both BL ctDNA-detected PIK3CAmut and BOR data, 16/16 (100%) with multiple PIK3CAmut experienced BOR of partial response (PR) or stable disease (SD) while 42/57 (73.7%) with single PIK3CAmut experienced BOR of PR or SD (p = 0.051). No pts with multiple PIK3CAmut detected experienced a BOR of progressive disease. Median TOT was greater in pts with multiple PIK3CAmut (196 days) vs single PIK3CAmut (140.5 days) detected at BL, but this was not significant (p = 0.1804). Conclusions The fraction of pts in which multiple PIK3CAmut were identified from BL ctDNA in this HR+/HER2- mBC dataset (24.1%) was slightly higher than reported elsewhere. This may be due to the method of detection (blood vs tissue) and/or the definition of multiple PIK3CAmut used. Pts in which multiple PIK3CAmut were detected by ctDNA exhibited greater depth of PD biomarker inhibition in tumors and experienced PR/SD more often compared with pts in which only one PIK3CAmut was detected. However, no significant associations were observed with the number of prior lines of therapy for metastatic disease or TOT. The dataset is currently too small to assess the impact of different treatment regimens in this study but will be re-evaluated as the data mature. Citation Format: Komal Jhaveri, Dejan Juric, Andrea Varga, Nicolas Turner, Peter Schmid, Cristina Saura, Mafalda Oliveira, Ian E Krop, Kevin Kalinsky, Antoine Italiano, Erika Hamilton, Valentina Gambardella, Andrés Cervantes, Philippe L Bedard, Bonnie P Liu, Jessica W Chen, Junko Aimi, Stephanie Royer-Joo, Jennifer L Schutzman, Katherine E Hutchinson. Preliminary correlative analysis of clinical outcomes with PIK3CA mutation (mut) status from a phase I/Ib study of GDC-0077 in patients (pts) with hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-12.

Purpose: To evaluate patient-reported outcomes of adolescents and young adults (AYAs) with breast cancer treated with curative intent. Methods: AYA breast cancer patients (defined as diagnosed between 18 to 39 years of age) treated at a large tertiary cancer centre between January 2014 and December 2016 were identified. Patients routinely complete the validated symptom screening tool, the Edmonton Symptom Assessment System-revised (ESAS-r) prior to their clinical encounter. Scores from diagnosis up to 24 months post-diagnosis were obtained from our internal database, with elevated scores defined as > 4 for each individual symptom (rated 0-10). Patient, clinical and treatment characteristics were extracted from medical records. Descriptive statistics were used to describe patient, clinical and treatment characteristics, and ESAS-r scores. Time to recurrence was calculated from diagnosis to local or regional recurrence, distant metastasis or death (whichever occurred first). Kaplan-Meier survival analysis and log-rank tests were used to compare time to recurrence between women with vs. without elevated symptom scores. Chi-squared test was used to test the change in number of patients with elevated symptom scores over time. Univariable and multivariable logistic regression models were carried out to assess association between various factors and ESAS-r symptoms of depression, anxiety and well-being within 24 months of diagnosis. Results: Among 258 patients identified, 211 (82%) had accompanying ESAS-r and were eligible for analysis. Median follow-up was 3.9 years. Median age at diagnosis was 35 (20-39), most were clinical stage 2/3 at diagnosis (63%), 20% had triple negative disease, 76% received chemotherapy and 81% received radiotherapy. Overall, symptom burden was the highest (scores > 4) for decreased well-being (52%), tiredness (48%) and anxiety (44%). Although symptom burden significantly improved over time, 43%, 38% and 33% of patients, respectively, reported elevated symptoms 24 months post-diagnosis. Multivariable analysis found that elevated anxiety was significantly associated with younger age at diagnosis (p=0.036), receipt of chemotherapy (p=0.01) and presence of long-term toxicity (p=0.0032). Elevated depression, anxiety and well-being were significantly associated with referral to Psychosocial Oncology (p=0.024, p=0.036 and p=0.019, respectively), whereas well-being was also associated with referral to Survivorship Clinic (p=0.043). However, overall rates of referral (24-36%) were much lower than symptom prevalence. There was no association between elevated symptoms and time to recurrence. Conclusion: AYAs diagnosed with breast cancer report high symptom burden that continues to persist up to 24-months post-diagnosis. Patients with elevated psychosocial distress are more likely to be referred to Psychosocial Oncology and Survivorship clinics, indicating that the ESAS-r is a useful screening tool in a real-world setting. However, a gap between symptom burden and intervention exists, providing opportunities for future research. Citation Format: Revathy Krishnamurthy, Tulin Cil, Philippe Bedard, Robin Forbes, Madeline Li, Zhihui (Amy) Liu, Jennifer Croke. Patient-reported outcomes of adolescents and young adults with breast cancer treated with curative intent [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD12-09.

We investigated the prognostic utility of pre-chemotherapy neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic germ cell tumors (GCTs) undergoing first-line chemotherapy. We utilized two institutional databases to analyze the pretreatment-derived NLR (dNLR). Predictive accuracy was evaluated using the Cox proportional hazard model adjusted for the international germ cell cancer collaborative group (IGCCCG) risk classification. Discriminatory accuracy was evaluated by determining the area under the receiver operating characteristic curve (AUROC). In total, 569 of 690 patients had available dNLR (IGCCCG: good, 64%, intermediate, 21%, poor, 16%). The 5-year and 10-year overall survivals (OSs) for good, intermediate, and poor risk groups were 96.2%, 92.8%, and 62.7% and 93.9%, 90.3%, and 62.7%, respectively. A dNLR of 2 provided the best discriminatory accuracy with an AUROC of 0.58 (95% CI: 0.52&ndash, 0.65, p = 0.01) for progression-free survival (PFS), whereas for OS, a dNLR of 3 provided the best discriminatory accuracy with an AUROC of 0.62 (95% CI: 0.53&ndash, 0.70, p &lt, 0.01). A dNLR &gt, 2 was associated with a hazard ratio (HR) of 1.99 (95% CI: 1.27&ndash, 3.12, p &lt, 0.01) for PFS, which lost its effect after adjustment for IGCCCG (HR: 1.44, 95% CI: 0.90&ndash, 2.30, p = 0.13). For OS, a dNLR &gt, 3 was associated with an HR of 3.00 (95% CI: 1.79&ndash, 5.01, p &lt, 0.01), but lost its effect after adjustment for IGCCCG. Systemic inflammation plays a role in metastatic GCT, but its prognostic utility beyond established algorithms is limited. The general prognostic value of NLR can be seen across a number of tumors, although the consistency and magnitude of the effect differ according to cancer type, disease stage, and treatment received. We identified that an elevated NLR was associated with an adverse PFS and OS, but not independent of the IGCCCG risk classification. dNLRs &gt, 2 and &gt, 3 were associated with an adverse PFS and OS, respectively, in patients with metastatic GCT receiving first-line chemotherapy, but not independent of the IGCCCG risk classification.

The purpose of this study is to describe the long-term toxicities of intracranial germ cell tumor (IGCT) in the adolescent and young adult (AYA) population. We report late toxicities of a multi-center cohort of AYA patients treated for IGCT between 1975 and 2015. Charts were retrospectively reviewed for hormone deficiency, ototoxicity, seizure disorder, visual deterioration, cerebrovascular events, second neoplasm, psychiatric illness, and neurocognitive impairment. Statistical analysis was performed for late toxicities to evaluate the influence of select factors. Our patient cohort included 112 patients with IGCTs; 84% of patients had a germinoma as opposed to a non-germinomatous germ cell tumor (NGGCT), median age at radiotherapy (RT) was 19 years, and median follow-up was 8.3 years. Of the 94 patients with germinoma, 32 (34%) received both chemotherapy and RT as part of their upfront treatment, while 62 (66%) received RT alone. All 18 patients with NGGCT received chemotherapy and RT. The most common late toxicity following IGCT treatments was physician-reported neurocognitive impairment, with a 10-year cumulative incidence (CI) of 38.5%. Ten-year CI of treatment-induced ototoxicity was 39.2% for patients who received cisplatin, compared to 3.6% for those who received carboplatin but no cisplatin (p

Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB. Siu and colleagues use a bespoke ctDNA assay and show predictive utility of longitudinal ctDNA analysis in a phase II clinical trial of patients receiving pembrolizumab that included multiple solid tumor types.

PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). CONCLUSION In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

AKT inhibitors have promising activity in AKT1E17K-mutant estrogen receptor (ER)–positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1E17K-mutant (n = 153) and AKT1–wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1–wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology. Significance: We delineate the natural history of a rare genomically distinct cancer, AKT1E17K-mutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data. See related commentary by Castellanos and Baxi, p. 490.

Background: Dysregulation of the PI3K/AKT/mTOR signaling pathway occurs in solid tumor malignancies. GDC-0077 (G) is a potent p110α-selective, p110α-mutant degrading inhibitor with anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with endocrine therapies (ET) with or without a CDK4/6 inhibitor (i). An open-label, Phase I dose escalation study of Galone and in combination with ET and P is underway in patients (pts) with locally advanced or metastatic PIK3CA-mutant solid tumors. Data from the combinations of G and L with and without P in pts with PIK3CA-mutant HR+/HER2- breast cancer are presented herein. Methods: This study (NCT03006172) assesses the safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1) of G administered daily (QD) orally at 6 or 9 mg with L (G+L) or at 3, 6, or 9 mg in combination with P+L (G+P+L). L is administered QD orally at 2.5 mg. P is administered QD orally at 125 mg on Days 1-21 followed by 7 days off in 28-day cycles. For dose expansion, prior CDK4/6i was prohibited (G+P+L) and up to one prior metastatic chemotherapy allowed (G+L and G+P+L). Tumor and ctDNA samples (collected before and after 2 weeks of G) are profiled for relevant signaling and pharmacodynamic (PD) biomarkers. Results: As of 29 March 2019, 70 pts had enrolled (G+L: 37 pts [7 at 6 mg and 30 at 9 mg]; G+P+L: 33 pts [3 at 3 mg, 3 at 6 mg, and 27 at 9 mg]). Overall, 33 pts in G+L and 31 pts in G+P+L received ≥ 1 prior metastatic therapy; 70% and 21% of pts received prior CDK4/6i in G+L and G+P+L arms, respectively. No DLTs were reported in pts receiving either combination with G. In G+L, the most frequent treatment-related AEs (TRAEs) occurring in ≥10 (27%) pts included hyperglycemia (25 pts, 68%), nausea (14 pts, 38%), and diarrhea (10 pts, 27%). Grade ≥3 TRAEs in ≥2 (5%) pts included hyperglycemia (7 pts, 19%), and fatigue and hypokalemia (2 pts each, 5%). In G+P+L, the most frequent TRAEs occurring in ≥13 (41%) pts included neutropenia (25 pts, 78%), hyperglycemia (17 pts, 52%), anemia (17 pts, 52%), diarrhea (16 pts, 49%), and nausea and thrombocytopenia (13 pts each, 39%). Grade ≥3 TRAEs in ≥2 (6%) pts included neutropenia (21 pts, 64%), hyperglycemia (5 pts, 15%), lymphopenia (3 pts, 15%), and leukopenia and thrombocytopenia (2 pts each, 6%). Hyperglycemia was manageable with oral anti-hyperglycemic medication. Stomatitis (grouped term) occurred in 11 pts (30%) in G+L and 21 pts (64%) in G+P+L and responded to treatment with dexamethasone mouthwash. 46 pts discontinued treatment, mainly due to disease progression; one due to Grade 3 hyperglycemia in G+P+L (no discontinuation due to AE in G+L). Median G treatment duration: 5.7 months (range 0.2-14.5) in G+L and 9.7 months (range 1.3-23.1) in G+P+L, with a cumulative G dose intensity of 98% for both. In G+ L, PR was reported in 6 pts (16%), confirmed PR in 3 pts (8%) and CBR 35% (13 pts). In G+P+L, PR was reported in 14 pts (42%), confirmed PR in 12 pts (36%) and CBR 76% (25 pts). G PK parameters were similar to those observed as a single agent, and P and L showed exposures comparable with historical data, suggesting an absence of PK drug-drug interaction (DDI). Robust PD downregulation of PI3K pathway effectors (pAKT, pS6) was observed in available paired biopsies and PIK3CA mutant allele frequency decreased in ctDNA on-treatment in most patients. Conclusion: This Phase Ib study of GDC-0077 in combination with letrozole with and without pabocicilb demonstrated a manageable safety profile combining GDC-0077 at its single agent recommended Phase II dose of 9 mg with letrozole with and without palbociclib at standard doses, with no evidence for DDI, high GDC-0077 dose intensity, and promising preliminary anti-tumor activity. Citation Format: Komal Jhaveri, Kevin Kalinsky, Philippe Bedard, Andres Cervantes, Cristina Saura, Ian Krop, Erika Hamilton, Peter Schmid, Andrea Varga, Nick Turner, Antoine Italiano, Valentina Gambardella, Zachary Veitch, Mafalda Oliveira, Leslie Dickmann, Naoki Kotani, Amy Kapp, Katie Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer Schutzman, Dejan Juric. A phase Ib dose escalation study evaluating the mutant selective PI3K-alpha inhibitor GDC-0077 (G) in combination with letrozole (L) with and without palbociclib (P) in patients with PIK3CA-mutant HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-46.

Background: Activating mutations in PIK3CA, encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3K), are highly prevalent in breast cancer and solid tumor malignancies. GDC-0077 is a potent p110α-selective inhibitor with a novel mechanism of action that degrades mutant p110α and anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with anti-estrogens with or without a CDK4/6 inhibitor. An open-label, Phase I dose-escalation study of GDC-0077 monotherapy and GDC-0077 combined with endocrine therapies and palbociclib is underway in patients (pts) with locally advanced or metastatic PIK3CA-mutant solid tumors. Data from the completed single agent dose escalation portion of the trial are presented herein. Methods: This study (NCT03006172) assesses the safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1) of single agent GDC-0077 administered daily (QD) orally at 6, 9, or 12 mg in 28-day cycles until intolerable toxicity or disease progression. Tumor and ctDNA samples are profiled for relevant signaling and pharmacodynamic (PD) biomarkers. Results: As of the clinical cut-off date of 29 March 2019, 20 pts were enrolled in the single agent arm, all with hormone receptor-positive breast cancer, except for 1 pt with colorectal cancer. Nineteen patients had received ≥ 2 prior lines of therapy for metastatic disease. GDC-0077 MTD was established at 9 mg QD. DLTs occurred in 2 pts at 12 mg (1 Grade 4 hyperglycemia, 1 Grade 3 fatigue). Adverse events (AEs) resulted in dose reduction in 6 pts (30%). The most frequent treatment-related (TR)AEs in ≥ 3 pts (15%) included hyperglycemia (14 pts, 70%), diarrhea (8 pts, 40%), decreased appetite and vomiting (4 pts each, 20%), and alopecia, fatigue, nausea, and weight decreased (3 pts each, 15%). Grade ≥3 TRAEs were hyperglycemia (4 pts, 20%) and lymphopenia, fatigue, nausea, weight loss, and asthenia (1 pt, 5% each). Hyperglycemia was generally manageable with oral anti-hyperglycemic medications. Stomatitis (grouped term) occurred in 4 pts (20%, all Grade 1) and responded to topical corticosteroid treatment. Rash (grouped term) occurred in 3 pts (15%) (1 unrelated Grade 2, otherwise Grade 1). No colitis was reported. Mean half-life (t1/2) of GDC-0077 was 18 hours, with the maximum concentration (Cmax) achieved 2-8 hours after dosing. The preliminary PK profile of GDC-0077 showed low-moderate variability in Cmax and area under the concentration-time curve, and dose proportionality across the tested dose levels. Accumulation with QD dosing regimen was 1.6-2.4 fold. All pts discontinued from treatment due to disease progression (radiographic or clinical). Median GDC-0077 treatment duration was 5.3 months (range 1.1-17.6) and cumulative dose intensity was 97%. Overall, partial response (PR) was observed in 5 pts (25%, range 2-10 lines of prior metastatic therapy), with confirmed PR in 4 pts (20%). The clinical benefit rate was 45% (9 of 20 pts). Decreased PI3K pathway effector expression in paired tumor biopsies and decreased PIK3CA mutant allele frequency were observed over time in the majority of specimens. In addition, 18F-fluorodeoxyglucose-positron emission tomography scans at baseline and after 2 weeks of GDC-0077 showed metabolic responses at all dose levels evaluated. Conclusion: The single agent dose escalation study of the p110α-selective and mutant-degrading inhibitor GDC-0077 demonstrated linear PK, a manageable safety profile, PD modulation of the PI3K pathway, and promising preliminary anti-tumor activity. GDC-0077 at the recommended Phase II dose of 9 mg in combination with endocrine therapies with or without the CDK4/6 inhibitor palbociclib is being investigated in this Phase I study and presented separately. Citation Format: Dejan Juric, Kevin Kalinsky, Mafalda Oliveira, Andres Cervantes, Philippe Bedard, Ian Krop, Erika Hamilton, Peter Schmid, Andrea Varga, Nick Turner, Antoine Italiano, Cristina Saura, Valentina Gambardella, Zachary Veitch, Leslie Dickmann, Naoki Kotani, Jill Fredrickson, Amy Kapp, Katie Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer Schutzman, Komal Jhaveri. A first-in-human phase Ia dose escalation study of GDC-0077, a p110a-selective and mutant-degrading PI3K inhibitor, in patients with PIK3CA-mutant solid tumors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-04.

Background Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL. Methods Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale. Results Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items. Conclusions To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients.

Background Metastatic germ cell tumor (mGCT) patients receiving chemotherapy have increased risk of life‐threatening venous thromboembolism (VTE). Identifying VTE risk factors may guide thromboprophylaxis in this highly curable population. Methods Data were collected from mGCT patients receiving first‐line platinum‐based chemotherapy at 22 centers. Predefined variables included International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, long‐axis diameter of largest retroperitoneal lymph node (RPLN), Khorana score, and use of indwelling vascular access device (VAD). VTE occurring at baseline, during chemotherapy and within 90 days, was analyzed. Results Data from 1135 patients were collected. Median age was 31 years (range 10‐74). IGCCCG risk was 64% good, 20% intermediate, and 16% poor. VTE occurred in 150 (13%) patients. RPLN >3.5 cm demonstrated highest discriminatory accuracy for VTE (AUC 0.632, P, Venous thromboembolism can cause morbidity in germ cell tumor patients receiving chemotherapy; large retroperitoneal lymphadenopathy (RPLN) and indwelling vascular access devices (VAD) are significant VTE risk factors. VAD insertion should be avoided and thromboprophylaxis can be considered for large RPLN.

BackgroundTrametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).MethodsAdvanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on “3 + 3” design within each HD group. PK samples were collected at cycle 1 days 15-16.ResultsForty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).ConclusionsRP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients – 1.5 mg QD in Mod group, and 1 mg QD in Sev group.Trial registrationThis study was registered in the ClinicalTrials.gov website (NCT 02070549) on February 25, 2014. .

Importance Real-world data sets that combine clinical and genomic data may be subject to left truncation (when potential study participants are not included because they have already passed the milestone of interest at the time of study recruitment). The lapse between diagnosis and molecular testing can present analytic challenges and threaten the validity and interpretation of survival analyses. Observations Effects of ignoring left truncation when estimating overall survival are illustrated using data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (GENIE BPC), and a straightforward risk-set adjustment approach is described. Ignoring left truncation results in overestimation of overall survival: unadjusted median survival estimates from diagnosis among patients with stage IV non-small cell lung cancer or stage IV colorectal cancer were overestimated by more than 1 year. Conclusions and relevance Clinicogenomic data are a valuable resource for evaluation of real-world cancer outcomes and should be analyzed using appropriate methods to maximize their potential. Analysts must become adept at application of appropriate statistical methods to ensure valid, meaningful, and generalizable research findings.

BackgroundAngiogenic factors play a role in regulating immune suppression in the tumor microenvironment and driving resistance to immune checkpoint inhibitor therapy.1 Ziv-aflibercept is a soluble decoy receptor that ”traps” endogenous vascular endothelial growth factor (VEGF) with 100-fold increased binding affinity compared to Bevacizumab.2 The combination of ziv-aflibercept with either cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1) blockade has shown promising antitumor efficacy in mouse models.3 4 We hypothesized that a novel combination of ziv-aflibercept and anti-PD-1 would be tolerable and lead to clinical benefits in tumors that traditionally do not respond to checkpoint blockade.MethodsThis is a multicenter phase 1B dose escalation study (NCT02298959) of the combination of ziv-aflibercept (at 2–4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in PD-1/PD-L1 naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (MSS CRC), and ovarian cancer (figure 1). The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy and immune population densities in the tissue and periphery.ResultsOverall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities (DLTs) were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 treatment-related adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose expansion cohort was 16.7% (5/30; 95% CI, 7–32%). Complete responses occurred in melanoma (n=2), partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Efficacy outcomes by tumor type are shown in table 1 and figure 2. Median OS was as follows: melanoma, not reached; RCC, 15.7 months (90% CI, 2.5–15.7); CRC, 3.3 months (90% CI, 0.6–3.4), ovarian, 12.5 months (90% CI, 3.8–13.6), other solid tumors, not reached (figure 3). Activated tumor infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression (figure 4), and increased memory CD8 T cells in the periphery (figure 5) correlated with clinical response to the combination therapy.Abstract 374 Figure 1Study Schema of dose escalation and dose expansion. (A) Cohort 1 included the following tumors: clear cell sarcoma, triple negative breast cancer (TNBC), and mesothelioma. (B) Other solid tumors in Cohort 2 were: epithelioid mesothelioma (2) and TNBC (1).Abstract 374 Table 1Efficacy outcomes by dose level and tumor typea. Solid tumors included clear cell sarcoma (1), breast cancer (2), mesothelioma (3).b. Both patients with CR had melanoma and were in Cohort 2 (DL2).Abstract 374 Figure 2Waterfall plot of best RECIST response. Waterfall plot of maximum change from baseline in sum of target lesions for 28 patients with tumor measurements over time. Plot is color-coded by tumor type. Triangles indicate patients who developed new lesions, yellow circles indicate the 3 patients who received DL1.Abstract 374 Figure 3Progression and overall survival by tumor type. Kaplan-Meier curves for (A) progression-free survival and (B) overall survival based on tumor type.Abstract 374 Figure 4Luminex assay analysis of clinical response. Luminex analysis of baseline biomarkers. Patients were analyzed by clinical response (complete response [CR] and partial response [PR]) and durable clinical benefit (DCB) which includes patients with CR, PR, and stable disease (SD). (A) Baseline levels of IL-6 were lower in responders vs. non-responders (median 2.605 vs. 9.847 pg/mL, p = 0.009). Baseline CD40L was increased in responders (median 2,840 vs. 2,267 pg/mL, p = 0.06). (B) Baseline levels of GroB (median 1,272 vs. 592 pg/mL, p = 0.006), CXCL5 (median 547.5 vs. 296.2 pg/mL, p = 0.02), and CD40L (median 2,807 vs. 1,595 pg/mL, p = 0.001) were higher in patients with DCB vs. no DCB. P-values for baseline comparisons were obtained through Wilcoxon rank-sum test. The solid black line indicates median. Violins show range and kernel density estimate distributions of each group. (*) p < 0.05, (**) p < 0.01.Abstract 374 Figure 5Flow cytometry analysis. Flow cytometry analysis comparing T cell populations and monocytes between patients with clinical response (CR or PR, n = 5) and non-responders (n = 18) and patients with disease control (CR, PR, or SD, n = 12) and no disease control (n = 11). (A) CD4+ populations were increased in responders vs. non-responders at all time points. (B) CD8+ populations were decreased in responders vs. non-responders at all time points. (C) Treg CD4+/CD25+/FoxP3+ was decreased at baseline in responders. (D) Treg CD4+/CD25+/FoxP3+ were decreased at baseline and 1-month in patients with disease control vs. no disease control. (E) TCM CD8+/CD45RO+/CCR7+ was increased at all time points in responders vs. non-responders. (F) TEMRA CD8+/CD45RO-/CCR7- was decreased in responders at baseline. (G) Non-classical TIE2 was increased at baseline in non-responders. (H) Classical monocytes were increased at all time points in non-responders.ConclusionsThe combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1 resistant melanoma.AcknowledgementsThis trial was supported by the National Cancer Institute (NCI) and by Merck, Sharpe, and Dohme and Sanofi via Cooperative Research and Development Agreements with the NCI. PLB was supported by NCI UM1 Grant CA186644.Trial RegistrationNCT02298959ReferencesRahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res September 15 2019;25(18):5449–5457. doi:10.1158/1078-0432.CCR-18-1543Holash J, Davis S, Papadopoulos N, et al. VEGF-trap: a VEGF blocker with potent antitumor effects. Proceedings of the National Academy of Sciences 2002;99(17):11393–11398. doi:10.1073/pnas.172398299Burova E, Ioffe E, Taduriyasas C, et al. Abstract 5035: blockade of VEGF with ziv-aflibercept (VEGF Trap) enhances anti-tumor efficacy of CTLA-4 blocking antibody in an Fc dependent manner. Cancer Research 2014;74(19 Supplement):5035–5035. doi:10.1158/1538-7445.am2014-5035Di Tacchio M, Macas J, Weissenberger J, et al. Tumor vessel normalization, immunostimulatory reprogramming, and improved survival in glioblastoma with combined inhibition of PD-1, angiopoietin-2, and VEGF. Cancer Immunology Research 2019;7(12):1910–1927. doi:10.1158/2326-6066.cir-18-0865Ethics ApprovalThis trial (NCT02298959) was approved by all participating IRBs.

BackgroundGWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed.MethodsPatients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10–1500 mg) or GWN323+spartalizumab (GWN323 10–750 mg+spartalizumab 100–300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1.ResultsOverall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures.ConclusionsGWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination.Trial registration numberNCT02740270.

Importance Contemporary observational cancer research requires associating genomic biomarkers with reproducible end points; overall survival (OS) is a key end point, but interpretation can be challenging when multiple lines of therapy and prolonged survival are common. Progression-free survival (PFS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) are alternative end points, but their utility as surrogates for OS in real-world clinicogenomic data sets has not been well characterized. Objective To measure correlations between candidate surrogate end points and OS in a multi-institutional clinicogenomic data set. Design, setting, and participants A retrospective cohort study was conducted of patients with non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) whose tumors were genotyped at 4 academic centers from January 1, 2014, to December 31, 2017, and who initiated systemic therapy for advanced disease. Patients were followed up through August 31, 2020 (NSCLC), and October 31, 2020 (CRC). Statistical analyses were conducted on January 5, 2021. Exposures Candidate surrogate end points included TTD; TTNT; PFS based on imaging reports only; PFS based on medical oncologist ascertainment only; PFS based on either imaging or medical oncologist ascertainment, whichever came first; and PFS defined by a requirement that both imaging and medical oncologist ascertainment have indicated progression. Main outcomes and measures The primary outcome was the correlation between candidate surrogate end points and OS. Results There were 1161 patients with NSCLC (648 women [55.8%]; mean [SD] age, 63 [11] years) and 1150 with CRC (647 men [56.3%]; mean [SD] age, 54 [12] years) identified for analysis. Progression-free survival based on both imaging and medical oncologist documentation was most correlated with OS (NSCLC: ρ = 0.76; 95% CI, 0.73-0.79; CRC: ρ = 0.73; 95% CI, 0.69-0.75). Time to treatment discontinuation was least associated with OS (NSCLC: ρ = 0.45; 95% CI, 0.40-0.50; CRC: ρ = 0.13; 95% CI, 0.06-0.19). Time to next treatment was modestly associated with OS (NSCLC: ρ = 0.60; 0.55-0.64; CRC: ρ = 0.39; 95% CI, 0.32-0.46). Conclusions and relevance This cohort study suggests that PFS based on both a radiologist and a treating oncologist determining that a progression event has occurred was the surrogate end point most highly correlated with OS for analysis of observational clinicogenomic data.

Purpose:Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.Patients and Methods:Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W.Results:Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12–27 months) in colorectal cancer (n = 2), non–small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3–positive staining, including one patient with NSCLC who received prior PD-1 therapy.Conclusions:Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.

Some patients who participate in early phase cancer trials enroll to more than one trial. Whether these patients have different characteristics or outcomes than patients who enroll to a single phase I trial is unknown. The study included all patients who participated in the solid tumor drug development program of the Princess Margaret Cancer Centre, a specialized academic cancer center, from July 2014 to January 2017. Patients sequentially enrolled to multiple phase I trials were compared to those enrolled in a single trial according to demographics, clinical characteristics, reported toxicities and prognosis. The study cohort included 328 patients, including 61 (19%) enrolled to multiple phase I trials and 267 (81%) enrolled to a single phase I trial. Demographics, comorbidities, performance status, cancer site and time between initial diagnosis and initial enrollment to the phase I program were comparable between both groups. Patients enrolled to multiple phase I trials received more previous non-trial treatment lines (median 3 versus 2, p

PURPOSE Active surveillance (AS) for testicular nonseminomatous germ cell tumors (NSGCT) is widely used. Although there is no consensus for optimal treatment at relapse on surveillance, globally patients typically receive chemotherapy. We describe treatment of relapses in our non–risk-adapted NSGCT AS cohort and highlight selective use of primary retroperitoneal lymph node dissection (RPLND). METHODS From December 1980 to December 2015, 580 patients with clinical stage I NSGCT were treated with AS, and 162 subsequently relapsed. First-line treatment was based on relapse site and extent. Logistic regression was used to explore factors associated with need for multimodal therapy on AS relapse. RESULTS Median time to relapse was 7.4 months. The majority of relapses were confined to the retroperitoneum (66%). After relapse, first-line treatment was chemotherapy for 95 (58.6%) and RPLND for 62 (38.3%), and five patients (3.1%) underwent other therapy. In 103 (65.6%), only one modality of treatment was required: chemotherapy only in 58 of 95 (61%) and RPLND only in 45 of 62 (73%). Factors associated with multimodal relapse therapy were larger node size (odds ratio, 2.68; P = .045) in patients undergoing chemotherapy and elevated tumor markers (odds ratio, 6.05; P = .008) in patients undergoing RPLND. When RPLND was performed with normal markers, 82% required no further treatment. Second relapse occurred in 30 of 162 patients (18.5%). With median follow-up of 7.6 years, there were five deaths (3.1% of AS relapses, but 0.8% of whole AS cohort) from NSGCT or treatment complications. CONCLUSION The retroperitoneum is the most common site of relapse in clinical stage I NSGCT on AS. Most are cured by single-modality treatment. RPLND should be considered for relapsed patients, especially those with disease limited to the retroperitoneum and normal markers, as an option to avoid chemotherapy.

Background CFI-400945 is a first-in-class oral inhibitor of polo-like kinase 4 (PLK4) that regulates centriole duplication. Primary objectives of this first-in-human phase 1 trial were to establish the safety and tolerability of CFI-400945 in patients with advanced solid tumours. Secondary objectives included pharmacokinetics, pharmacodynamics, efficacy, and recommended phase 2 dose (RP2D). Methods Continuous daily oral dosing of CFI-400945 was evaluated using a 3+3 design guided by incidence of dose-limiting toxicities (DLTs) in the first 28-day cycle. Safety was assessed by CTCAE v4.0. ORR and CBR were evaluated using RECIST v1.1. Results Forty-three patients were treated in dose escalation from 3 to 96 mg/day, and 9 were treated in 64 mg dose expansion. After DLT occurred at 96 and 72 mg, 64 mg was established as the RP2D. Neutropenia was a common high-grade (19%) treatment-related adverse event at ≥ 64 mg. Half-life of CFI-400945 was 9 h, with Cmax achieved 2–4 h following dosing. One PR (45 cycles, ongoing) and two SD ≥ 6 months were observed (ORR = 2%; CBR = 6%). Conclusions CFI-400945 is well tolerated at 64 mg with dose-dependent neutropenia. Favourable pharmacokinetic profiles were achieved with daily dosing. Response rates were low without biomarker pre-selection. Disease-specific and combination studies are ongoing. Trial Registration Clinical Trials Registration Number – NCT01954316 (Oct 1st, 2013)

Objectives Conducting clinical trials in rare malignancies is challenging due to the limited number of patients and differences in biologic behavior. We investigated the feasibility and clinical utility of using genomic profiling for rare gynecologic malignancies. Methods Rare epithelial gynecologic cancer patients were analyzed for somatic variants through an institutional molecular profiling program using the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel on the MiSeq platform. Clinical trial outcomes by RECIST 1.1, and time on treatment were evaluated. Results From March 2012 to November 2015, 767 gynecologic patients were enrolled and 194 (27%) were classified as rare epithelial malignancies. At least one somatic mutation was identified in 72% of patients, most commonly in TP53 (39%), KRAS (28%) and PIK3CA (27%). A total of 14% of patients were treated on genotype-matched trials. There were no significant differences in overall response rate between genotype-matched versus unmatched trials, nor in median time on treatment between genotype trials and the immediate prior systemic standard treatment. Among 13 evaluable Low Grade Serous ovarian cancer patients treated on genotype-matched trials with MEK inhibitor-based targeted combinations, there were four partial responses. Conclusions Somatic molecular profiling is feasible and enables the identification of patients with rare gynecologic cancers who are candidates for genotype-matched clinical trials. Genotype-matched trials, predominantly MEK-based combinations in KRAS and/or NRAS mutant Low Grade Serous ovarian cancer patients, and genotype-unmatched trials, have shown potential clinical activity. Prospective trials with integrated genotyping are warranted to assess the clinical utility of next generation sequencing tests as a standard clinical application in rare malignancies.

Better knowledge of the tumor genomic landscapes has helped to develop more effective targeted drugs. However, there is no tool to interpret targetability of genomic alterations assessed by next-generation sequencing in the context of clinical practice. Our aim is to rank the level of evidence of individual recurrent genomic alterations observed in breast cancer based on the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) in order to help the clinicians to prioritize treatment. Analyses of databases suggested that there are around 40 recurrent driver alterations in breast cancer. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations were classified tier of evidence IA based on large randomized trials showing antitumor activity of targeted therapies in patients presenting the alterations. NTRK fusions and microsatellite instability (MSI) were ranked IC. ESR1 mutations and PTEN loss were ranked tier IIA, and ERBB2 mutations and AKT1 mutations tier IIB. Somatic BRCA 1/2 mutations, MDM2 amplifications and ERBB 3 mutations were ranked tier III. Seventeen genes were ranked tier IV based on preclinical evidence. Finally, FGFR1 and CCND1 were ranked tier X alterations because previous studies have shown lack of actionability., SCOPUS: re.j, info:eu-repo/semantics/published

BACKGROUND A subset of patients treated with immune checkpoint inhibitors experience an accelerated tumor growth rate (TGR) in comparison with pretreatment kinetics; this is known as hyperprogression. This study assessed the relation between hyperprogressive disease (HPD) and treatment-related toxicity and clinical factors. METHODS This study reviewed patients with solid tumors who were enrolled in early-phase immunotherapy trials at Princess Margaret Cancer Centre between August 2012 and September 2016 and had computed tomography scans in the pre-immunotherapy (reference) and on-immunotherapy (experimental) periods. HPD was defined as progression according to Response Evaluation Criteria in Solid Tumors 1.1 at the first on-treatment scan and a ≥2-fold increase in TGR between the reference and experimental periods. Treatment-related toxicities requiring systemic therapy, drug delays, or discontinuation were considered clinically significant adverse events (CSAEs). RESULTS Of 352 patients, 182 were eligible for analysis. The median age was 60 years, and 54% were male. The Eastern Cooperative Oncology Group performance status was 0 (32%) or 1 (68%). The Royal Marsden Hospital (RMH) prognostic score was 0/1 in 59%. Single-agent immunotherapy was given to 80% of the patients. Most patients (89%) received anti-programmed death (ligand) 1 antibodies alone or in combination with other therapies. HPD occurred in 12 of 182 patients (7%). A higher proportion of females was seen among HPD patients (P = .01), but no association with age, performance status, tumor type, RMH prognostic score, combination immunotherapy, or CSAEs was found. The 1-year overall survival rate was 28% for HPD patients and 53% for non-HPD patients (hazard ratio, 1.7; 95% confidence interval, 0.9-3.3; P = .11). CONCLUSIONS HPD was observed in 7% of patients with solid tumors treated with immunotherapy. HPD was not associated with CSAEs, age, tumor type, or the type of immunotherapy but was more common in females.

Background Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. Patients and methods Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. Results A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95–5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P Conclusions In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.

Introduction MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial. Methods Patients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5 mg oral daily and panitumumab 4.8 mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR, or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) was collected and profiled using Oncomine Lung cfDNA assay. Results Fourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI, 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression. Conclusion The addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data.

Introduction: Imaging is an integral component of active surveillance following orchiectomy for stage 1 non-seminoma (NSGCT) and seminoma germ cell tumors. In this population-based study, we describe use of imaging among patients with early-stage testicular cancer and evaluate whether they are concordant with guideline recommendations. Methods: This is a population-based, retrospective cohort study to describe utilization of imaging among all patients with early-stage testicular cancer treated with active surveillance in the Canadian province of Ontario. The Ontario Cancer Registry was linked to electronic records of treatment to identify use of chest and abdomen/pelvis imaging. Data from 2000–-2010 were included with followup for up to five years for patients with non-seminoma and 10 years for patients with seminoma. The key outcome of interest was the frequency of imaging at temporal milestones following orchiectomy. Compared to the most contemporaneous guidelines in Ontario, any discordant frequency of imaging was defined as underutilization or overutilization. Substantial under- or overutilization was defined as >1 imaging test less/more than what was recommended during a 12-month period. Results: The study population included 569 patients with NSGCT (median age 28) and 1107 with seminoma (median age 37). Among patients with NSGCT, adherence with body imaging was low in years 1–3 of surveillance (range 26–37%, predominantly underuse) and higher in years 4–5 (63–67%, predominantly overuse). Adherence with chest imaging was even lower (range 11–34% during years 1–5). Among patients with seminoma, adherence with abdominal and chest imaging was relatively stable and comparable throughout the 10-year followup period (range 23–47% abdomen and 28–47% chest). Multivariable analysis confirmed that underutilization of imaging was more common in recent years. NSGCT histology was associated with underutilization in years 1–2 but overutilization in years 3–5. Conclusions: In routine clinical practice, patients with testicular cancer commonly receive imaging discordant to the protocol for active surveillance, with a substantial proportion receiving both under- and overutilization at various times during surveillance followup.

Background and aims Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation and management. Methods Patients treated with anti-PD-1, PDL-1 or CTLA-4 therapy in Phase I/II clinical trials between August 2012 and December 2018 were included. Clinical records of patients with significant liver enzyme elevations were retrospectively reviewed. Results Of 470 ICI-treated patients, liver enzyme elevation occurred in 102 (21.6%), attributed to disease progression (56; 54.9%), other drugs/toxins (7; 6.9%), other causes (22; 21.6%) and ICI immunotoxicity (17; 16.7%; 3.6% of total cohort). Immunotoxicity was associated with higher peak ALT than other causes of enzyme elevation (N = 17; M = 217, 95% CI 145–324 for immunotoxicity, N = 103; M = 74, 95% CI 59–92 for other causes; ratio of means 0.34, 95% CI 0.19–0.60, p = Conclusions Liver enzyme elevation is common in patients receiving ICI, but often has a cause other than immunotoxicity. A biochemical signature with higher ALT and ALT/AST ratio, a history of prior ICI exposure and other organ immunotoxicities may help to identify patients at a higher likelihood of immunotoxicity. Liver biopsy can be safely deferred in most patients. We propose an approach to diagnostic evaluation in patients with liver enzyme elevations following ICI exposure.

Background The correlation between blood-based tumor mutation burden (bTMB) and tissue-based tumor mutation burden(tTMB) has not been broadly tested in a multicancer cohort. Here, we assess the correlation between bTMB with tTMB in phase I trial patients treated with immunotherapy. As an exploratory analysis, we evaluated circulating tumor DNA (ctDNA) dynamics in responders. Methods Patients treated with immunotherapy at the Princess Margaret phase I trials unit were enrolled. Pretreatment plasma ctDNA and matched normal blood controls were collected. Available archival tissue formalin-fixed paraffin-embedded (FFPE) samples were analyzed. A 425-gene panel was used to sequence both ctDNA and FFPE samples. Samples with TMB within the highest tertile were considered as high TMB. Results Thirty-eight patients were accrued from 25 different trials, 86.8% of which involved an anti-PD-1/PD-L1 agent. Thirty patients (78.9%) had detectable mutations in ctDNA, of which the median (range) bTMB was 5 (1-53) mutations per megabase (mut/Mb). Of the 22 patients with available FFPE samples, mutations were detected in 21 (95.4%); the median (range) tTMB was 6 (2-124) mut/Mb. Among the 16 patients with detectable mutations in both FFPE and ctDNA, a statistically significant correlation between bTMB and tTMB was observed (ρ = 0.71; P = .002). High TMB was not associated with better survival. All 3 responders had a decrease in the variant allele frequency of mutations detected in ctDNA at a second timepoint relative to baseline, indicating a potential early marker of response. Conclusions In this small series, bTMB correlated with tTMB. An on-treatment decrease in VAF of mutations detected in ctDNA at baseline was observed in responders. Larger studies to verify our findings are warranted.

Background: Routine early palliative care (EPC) improves quality of life (QoL) for patients with advanced cancer, but it may not be necessary for all patients. We assessed the feasibility of Symptom screening with Targeted Early Palliative care (STEP) in a phase II trial. Methods: Patients with advanced cancer were recruited from medical oncology clinics. Symptoms were screened at each visit using the Edmonton Symptom Assessment System-revised (ESAS-r); moderate to severe scores (screen-positive) triggered an email to a palliative care nurse, who called the patient and offered EPC. Patient-reported outcomes of QoL, depression, symptom control, and satisfaction with care were measured at baseline and at 2, 4, and 6 months. The primary aim was to determine feasibility, according to predefined criteria. Secondary aims were to assess whether STEP identified patients with worse patient-reported outcomes and whether screen-positive patients who accepted and received EPC had better outcomes over time than those who did not receive EPC. Results: In total, 116 patients were enrolled, of which 89 (77%) completed screening for ≥70% of visits. Of the 70 screen-positive patients, 39 (56%) received EPC during the 6-month study and 4 (6%) received EPC after the study end. Measure completion was 76% at 2 months, 68% at 4 months, and 63% at 6 months. Among screen-negative patients, QoL, depression, and symptom control were substantially better than for screen-positive patients at baseline (all PPConclusions: STEP is feasible in ambulatory patients with advanced cancer and distinguishes between patients who remain stable without EPC and those who benefit from targeted EPC. Acceptance of the triggered EPC visit should be encouraged. ClinicalTrials.gov identifier: NCT04044040.

Background Human leukocyte antigen class 1 (HLA-1)–dependent immune activity is linked to autoimmune diseases. HLA-1–dependent CD8+ T cells are required for immune checkpoint blockade antitumor activity. It is unknown if HLA-1 genotype is predictive of toxicity to immune checkpoint blockade. Methods Patients with advanced solid tumors stratified into 5 cohorts received single agent pembrolizumab (anti-programmed cell death-1) 200 mg intravenously every 3 weeks in an investigator-initiated phase II trial (Investigator-Initiated Phase II Study of Pembrolizumab Immunological Response Evaluation study, NCT02644369). Germline whole-exome sequencing of peripheral blood mononuclear cells was performed using the Illumina HiSeq2500 platform. HLA-1 haplotypes were predicted from whole-exome sequencing using HLAminer and HLAVBSeq. Heterozygosity of HLA-A, -B, and -C, individual HLA-1 alleles, and HLA haplotype dimorphism at positions −21 M and −21 T of the HLA-A and -B leader sequence were analyzed as predictors of toxicity defined as grade 2 or greater immune-related adverse events and clinical benefit defined as complete or partial response, or stable disease for 6 or more cycles of pembrolizumab. Statistical significance tests were 2-sided. Results In the overall cohort of 101 patients, the frequency of toxicity and clinical benefit from pembrolizumab was 22.8% and 25.7%, respectively. There was no association between any of the HLA-1 loci or alleles with toxicity. HLA-C heterozygosity had an association with decreased clinical benefit relative to HLA-C homozygosity when controlling for cohort (odds ratio = 0.28, 95% confidence interval = 0.09 to 0.91, P = .04). HLA-A and -B haplotype −21 M/T dimorphism and heterozygosity of HLA-A, -B, and -C were not predictive of outcomes. Conclusions HLA-C heterozygosity may predict decreased response to pembrolizumab. Prospective validation is required.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 TGS, 152 RNA-Seq, 67 SNP Arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA and RB1 mutations; MDM4, MYC amplifications; ARID1A deletions. An increase in clonality was observed in driver genes like ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-Enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune permissive cells. High TMB correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could impact treatment strategies in MBC., info:eu-repo/semantics/published

At the Canadian Testis Cancer Workshop, the multidisciplinary management of testis cancer care was discussed. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents, fellows, nurses, patients, and patient advocacy group members. This review summarizes the discussion regarding clinical dilemmas in local and regional testis cancer. We present cases that highlight the need for a coordinated approach to individualize care. Overarching themes include the importance of a multidisciplinary approach to testis cancer, willingness to involve a high-volume experienced center, and given that the oncological outcomes are excellent, a reminder that clinical decisions need to prioritize selecting a strategy with the least treatment-related morbidity when safe to do so.

Background Optimal management of clinical stage I (CSI) testicular cancer is controversial due to lack of robust prognostic factors; miRNA-371a-3p holds promise as a biomarker, although its clinical utility for identifying patients at risk of relapse is unknown. Objective To explore the association between serum miR-371a-3p and CSI surveillance relapse. Design, setting, and participants Serial banked sera from 151 CSI (101 seminomas and 50 nonseminomatous germ cell tumors [NSGCTs]) samples from our Princess Margaret active surveillance cohort were tested. Outcome measurements and statistical analysis Using the ampTSmiR test, miR-371a-3p was assayed. Multivariate logistic regression was used to assess the association between postorchiectomy miRNA and relapse. Results and limitations Thirty-four (23%) patients relapsed. There was no association between postorchiectomy miR-371a-3p (2.43 vs 2.74, p = 0.31) or percent decline from before to after orchiectomy (95.8% vs 93.1%, p = 0.14) and relapse. After adjustment for clinical prognostic factors, there remained no association between postorchiectomy miR-371a-3p and relapse (seminoma: odds ratio [OR] 1.33, 95% confidence interval [CI] 0.87–2.02, p = 0.18; NSGCT: OR 0.45, 95% CI 0.21–1.00, p = 0.05). Postorchiectomy miR-371a-3p levels rose as the date of miRNA assessment approached relapse. At relapse, serum markers alpha-fetoprotein and human chorionic gonadotropin were normal in 62%; yet, miR-371a-3p was elevated in 32/34 (94.1%). The magnitude of miR-371a-3p elevation at relapse correlated with disease burden (N1/M0 122.5 vs N2-N3/M0: 521.1; p = 0.05). Limitations include small numbers of relapses and variable time points of serum collection. Conclusions In our cohort of CSI testis cancer patients on surveillance, postorchiectomy miR-371a-3p levels were not associated with relapse, suggesting that miR-371a-3p may not be a useful biomarker for guiding adjuvant therapy. Our data suggest that miR-371a-3p holds potential as an early relapse marker and warrants a prospective study, as this may allow a window for less morbid relapse therapy. Patient summary The promising novel blood biomarker for testis cancer miR-371a-3p may not provide information at testicle removal, but serial monitoring may lead to earlier detection of relapse.

PurposeTo evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab.Experimental designPD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1–14 (cycles 1–3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1–21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated. Patients underwent paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) collection for immune-profiling, transcriptomic and epigenomic analyzes.ResultsA total of 28 patients were enrolled, 19 patients treated on regimen A and 9 on regimen B. The combination of CC-486 and durvalumab was tolerable. Regimen B, with a lower dose of CC-486 extended over a longer treatment course, showed less grade 3/4 adverse effects. Global LINE-1 methylation assessment of serial PBMCs and genome-wide DNA methylation profile in paired tumor biopsies demonstrated minimal changes in global methylation in both regimens. The lack of robust tumor DNA demethylation was accompanied by an absence of the expected ‘viral mimicry’ inflammatory response, and consequently, no clinical responses were observed. The disease control rate was 7.1%. The median progression-free survival was 1.9 months (95% CI 1.5 to 2.3) and median overall survival was 5 months (95% CI 4.5 to 10).ConclusionsThe evaluated treatment schedules of CC-486 in combination with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors. Lessons learned from this biomarker-rich study should inform continued drug development efforts using these agents.Trial registration numberNCT02811497.

In November 2018, The Canadian Testis Cancer Workshop was convened. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents and fellows, nurses, patients and patient advocacy groups. One of the goals of the workshop was to discuss the challenging areas of testis cancer care where guidelines may not be specific. The objective was to distill through discussion around cases, expert approach to working through these challenges. Herein we present a summary of discussion from the workshop around controversies in the management of clinical stage 1 (CS1) disease. CS1 represents organ confined non-metastatic testis cancer that represents approximately 70-80% of men at presentation. Regardless of management, CS1 has an excellent prognosis. However, without adjuvant treatment, approximately 30% of CS1 nonseminomatous germ cell tumors (NSGCT) and 15% of CS1 seminoma relapse. The workshop reviewed that while surveillance has become the standard for the majority of patients with CS1 disease there remains debate in the management of patients at high-risk of relapse. The controversy in the management of CS1 testis cancer surrounds the optimal balance between the morbidity of overtreatment and the identification of patients who may derive most benefit from adjuvant treatment. The challenge lies in a shared decision process where discussion of options extends beyond the simple risk of relapse but to include the long-term toxicities of adjuvant treatments and the favorable cancer-specific survival.

At the Canadian Testis Cancer Workshop, the rationale and feasibility of regionalization of testis cancer care were discussed. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents and fellows, and nurses, as well as patients and patient advocacy groups. This review summarizes the discussion and recommendations of one of the central topics of the workshop — the centralization of testis cancer in Canada. It was acknowledged that non-guideline-concordant care in testis cancer occurs frequently, in the range of 18–30%. The National Health Service in the U.K. stipulates various testis cancer care modalities be delivered through supra-regional network. All cases are reviewed at a multidisciplinary team meeting and aspects of care can be delivered locally through the network. In Germany, no such network exists, but an insurance-supported online second opinion network was developed that currently achieves expert case review in over 30% of cases. There are clear benefits to regionalization in terms of survival, treatment morbidity, and cost. There was agreement at the workshop that a structured pathway for diagnosis and treatment of testis cancer patients is required. Regionalization may be challenging in Canada because of geography; independent administration of healthcare by each province; physicians fearing loss of autonomy and revenue; patient unwillingness to travel long distances from home; and the inability of the larger centers to handle the ensuing increase in volume. We feel the first step is to identify the key performance indicators and quality metrics to track the quality of care received. After identifying these metrics, implementation of a “networks of excellence” model, similar to that seen in sarcoma care in Ontario, could be effective, coupled with increased use of health technology, such as virtual clinics and telemedicine.

Background: Validated biomarkers are needed to identify patients at increased risk of immune-related adverse events (irAEs) to immune checkpoint blockade (ICB). Antibodies directed against endogenous antigens can change after exposure to ICB. Methods: Patients with different solid tumors stratified into cohorts received pembrolizumab every 3 weeks in a Phase II trial (INSPIRE study). Blood samples were collected prior to first pembrolizumab exposure (baseline) and approximately 7 weeks (pre-cycle 3) into treatment. In a discovery analysis, autoantibody target immuno-mass spectrometry was performed in baseline and pre-cycle 3 pooled sera of 24 INSPIRE patients based on clinical benefit (CBR) and irAEs. Results: Thyroglobulin (Tg) and thyroid peroxidase (TPO) were identified as the candidate autoantibody targets. In the overall cohort of 78 patients, the frequency of CBR and irAEs from pembrolizumab was 31% and 24%, respectively. Patients with an anti-Tg titer increase ≥1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without this increase in unadjusted, cohort adjusted, and multivariable models (OR=17.4, 95% CI 1.8–173.8, p=0.015). Similarly, patients with an anti-TPO titer ≥ 1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without the increase in unadjusted and cohort adjusted (OR=6.1, 95% CI 1.1–32.7, p=0.035) models. Further, the cohort adjusted analysis showed patients with anti-Tg titer greater than median (10.0 IU/mL) at pre-cycle 3 were more likely to have irAEs (OR=4.7, 95% CI 1.2–17.8, p=0.024). Patients with pre-cycle 3 anti-TPO titers greater than median (10.0 IU/mL) had a significant difference in overall survival (23.8 vs 11.5 months; HR=1.8, 95% CI 1.0–3.2, p=0.05). Conclusions: Patient increase ≥1.5x of anti-Tg and anti-TPO titers from baseline to pre-cycle 3 were associated with irAEs from pembrolizumab, and patients with elevated pre-cycle 3 anti-TPO titers had an improvement in overall survival.

Supplemental Digital Content is available in the text., Objectives: SLC-0111 is an ureido-substituted benzenesulfonamide small molecule inhibitor of carbonic anhydrase IX. The objectives of this first-in-human Phase 1 study were to determine the safety and tolerability of SLC-0111 in patients with advanced solid tumors and to establish the recommended Phase 2 dose for future clinical investigations. Materials and Methods: Using a 3+3 design, dose escalation started at 500 mg oral daily dosing of SLC-0111 in cohort 1 and increased to 1000 and 2000 mg in cohorts 2 and 3. Drug-related adverse events (AEs) were monitored to determine safety and tolerability. Pharmacokinetic analyses assessed plasma concentrations of single and repeated doses of SLC-0111. RECIST 1.1 criteria were used to assess disease progression. Results: No dose-limiting toxicities were reported and patients dosed at ≤1000 mg exhibited fewer drug-related AEs ≥ grade 3 and fewer AEs such as nausea and vomiting, compared with the 2000-mg cohort. Forty-one percent of patients experienced dose interruptions or discontinuation and the majority (71%) of these occurred in the 2000-mg cohort. Mean Cmax and AUC(0-24) values for single doses were similar at the 1000-mg and 2000-mg dose levels. Mean Tmax and T1/2 values of SLC-0111 were similar after single and repeated dosing. Power-law analysis of Cmax and AUC0-24 showed that exposure to SLC-0111 was generally dose proportional. No objective responses were observed, but stable disease >24 weeks was observed in 2 patients. Conclusions: SLC-0111 was safe in patients with previously treated, advanced solid tumors. The safety and pharmacokinetic data support 1000 mg/d as the recommended phase 2 dose for SLC-0111.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; PCONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794. opens in new tab.)

Background: A pilot inter-laboratory proficiency scheme for 5 Ontario clinical laboratories testing tumour samples for the Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) study was undertaken to assess proficiency in the identification and reporting of next-generation sequencing (NGS) test results in solid tumour testing from archival formalin-fixed, paraffin-embedded (FFPE) tissue. Methods: One laboratory served as the reference centre and provided samples to 4 participating laboratories. An analyte-based approach was applied: each participating laboratory received 10 FFPE tissue specimens profiled at the reference centre, with tumour site and histology provided. Laboratories performed testing per their standard NGS tumour test protocols. Items returned for assessment included genes and variants that would be typically reported in routine clinical testing and variant call format (VCF) files to allow for assessment of NGS technical quality. Results: Two main aspects were assessed: (1) Technical quality and accuracy of identification of exonic variants; (2) Site-specific reporting practices. Technical assessment included evaluation of exonic variant identification, quality assessment of the VCF files to evaluate base calling, variant allele frequency, and depth of coverage for all exonic variants. Concordance at 100% was observed from all sites in the technical identification of 98 exonic variants across the 10 cases. Variability between laboratories in the choice of variants considered clinically reportable was significant. Of the 38 variants reported as clinically relevant by at least 1 site, only 3 variants were concordantly reported by all participating centres as clinically relevant. Conclusions: Although excellent technical concordance for ngs tumour profiling was observed across participating institutions, differences in the reporting of clinically relevant variants were observed, highlighting reporting as a gap where consensus on the part of Ontario laboratories is needed.

Purpose After chemotherapy, approximately 50% of patients with metastatic testicular germ cell tumors (GCTs) who undergo retroperitoneal lymph node dissections (RPNLDs) for residual masses have fibrosis. Radiomics uses image processing techniques to extract quantitative textures/features from regions of interest (ROIs) to train a classifier that predicts outcomes. We hypothesized that radiomics would identify patients with a high likelihood of fibrosis who may avoid RPLND. Patients and Methods Patients with GCT who had an RPLND for nodal masses > 1 cm after first-line platinum chemotherapy were included. Preoperative contrast-enhanced axial computed tomography images of retroperitoneal ROIs were manually contoured. Radiomics features (n = 153) were used to train a radial basis function support vector machine classifier to discriminate between viable GCT/mature teratoma versus fibrosis. A nested 10-fold cross-validation protocol was used to determine classifier accuracy. Clinical variables/restricted size criteria were used to optimize the classifier. Results Seventy-seven patients with 102 ROIs were analyzed (GCT, 21; teratoma, 41; fibrosis, 40). The discriminative accuracy of radiomics to identify GCT/teratoma versus fibrosis was 72 ± 2.2% (area under the curve [AUC], 0.74 ± 0.028); sensitivity was 56.2 ± 15.0%, and specificity was 81.9 ± 9.0% ( P = .001). No major predictive differences were identified when data were restricted by varying maximal axial diameters (AUC range, 0.58 ± 0.05 to 0.74 ± 0.03). The prediction algorithm using clinical variables alone identified an AUC of 0.76. When these variables were added to the radiomics signature, the best performing classifier was identified when axial masses were limited to diameter < 2 cm (accuracy, 88.2 ± 4.4; AUC, 0.80 ± 0.05; P = .02). Conclusion A predictive radiomics algorithm had a discriminative accuracy of 72% that improved to 88% when combined with clinical predictors. Additional independent validation is required to assess whether radiomics allows patients with a high predicted likelihood of fibrosis to avoid RPLND.

Purpose Fine-needle biopsy (FNB) and liquid biopsy are minimally invasive methods of tumor sampling that provide feasible means to assess tumor genotypes in real time. However, more data are needed to establish the strength of these methods by benchmarking against the current gold standard methods, core-needle biopsy (CNB) or surgical excision of the tumor. Patients and Methods Eligible patients with advanced solid tumors were prospectively recruited. We performed mutation profiling using matched tumor DNA obtained by CNB, FNB and liquid biopsy, and matrix-assisted laser desorption/ionization time-of-flight custom mass-spectrometry or targeted next-generation DNA sequencing. The actionability of detected mutations was determined using the OncoKB Web tool. Agreement between mutations detected in CNBs, FNBs, and circulating tumor DNA (ctDNA) was examined. Results Forty-one patients underwent tumor biopsy. Thirty CNBs (73%) and 34 FNBs (83%) had sufficient tumor and DNA for mutation profiling. Median DNA yield from CNB and FNB were 775 ng (interquartile range, 240 to 347 4ng) and 649 ng (interquartile range, 180 to1350 ng), respectively. Of 29 CNB/FNB pairs available for comparison, actionable mutation results were concordant in 28 (96%). Six of nine actionable mutations (67%) that were found by CNB, FNB, or both were detectable in ctDNA. Two additional actionable mutations were found exclusively in ctDNA. Conclusion Optimally processed FNB and liquid biopsy can be used routinely for tumor mutation profiling to identify actionable mutations.

Purpose: This single-arm, open-label phase II study evaluated the safety and efficacy of taselisib (GDC-0032) plus fulvestrant in postmenopausal women with locally advanced or metastatic HER2-negative, hormone receptor (HR)-positive breast cancer.Patients and Methods: Patients received 6-mg oral taselisib capsules daily plus intramuscular fulvestrant (500 mg) until disease progression or unacceptable toxicity. Tumor tissue (if available) was centrally evaluated for PIK3CA mutations. Adverse events (AE) were recorded using NCI-CTCAE v4.0. Tumor response was investigator-determined using RECIST v1.1.Results: Median treatment duration was 4.6 (range: 0.9–40.5) months. All patients experienced ≥1 AE, 30 (50.0%) had grade ≥3 AEs, and 19 (31.7%) experienced 35 serious AEs. Forty-seven of 60 patients had evaluable tissue for central PIK3CA mutation testing [20 had mutations, 27 had no mutation detected (MND)]. In patients with baseline measurable disease, clinical activity was observed in tumors with PIK3CA mutations [best confirmed response rate: 38.5% (5/13; 95% CI, 13.9–68.4); clinical benefit rate (CBR): 38.5% (5/13; 95% CI, 13.9–68.4)], PIK3CA-MND [best confirmed response rate: 14.3% (3/21; 95% CI, 3.0–36.3); CBR: 23.8% (5/21; 95% CI, 8.2–47.2)], and unknown PIK3CA mutation status [best confirmed response rate: 20.0% (2/10; 95% CI, 2.5–55.6); CBR: 30.0% (3/10; 95% CI, 6.7–65.2)].Conclusions: Taselisib plus fulvestrant had clinical activity irrespective of PIK3CA mutation status, with numerically higher objective response rate and CBR in patients with PIK3CA-mutated (vs. -MND) locally advanced or metastatic HER2-negative, HR-positive breast cancer. No new safety signals were reported. A confirmatory phase III trial is ongoing. Clin Cancer Res; 24(18); 4380–7. ©2018 AACR.

Background Matched tumor-normal sequencing, applied in precision cancer medicine, can identify unidentified germline Medically Actionable Variants (gMAVS) in cancer predisposition genes. We report patient preferences for the return of additional germline results, and describe various gMAV scenarios delivered through a clinical genetics service. Methods Tumor profiling was offered to 1960 advanced cancer patients, of which 1556 underwent tumor-normal sequencing with multigene hotspot panels containing 20 cancer predisposition genes. All patients were provided with an IRB-approved consent for return of additional gMAVs. Results Of the whole cohort 94% of patients consented to be informed of additional germline results and 5% declined, with no statistically significant differences based on age, sex, race or prior genetic testing. Eight patients were found to have gMAVs in a cancer predisposition gene. Five had previously unidentified gMAVs: three in TP53 (only one fulfilled Chompret’s Revised criteria for Li-Fraumeni Syndrome), one in SMARCB1 in the absence of schwannomatosis features and one a TP53 variant at low allele frequency suggesting an acquired event in blood. Conclusion Interest in germline findings is high among patients who undergo tumor profiling. Disclosure of previously unidentified gMAVs present multiple challenges, thus supporting the involvement of a clinical genetics service in all tumor profiling programs. Electronic supplementary material The online version of this article (10.1186/s12920-018-0383-5) contains supplementary material, which is available to authorized users.

Purpose: We investigated the safety and antitumor activity of the anti–programmed death 1 monoclonal antibody pembrolizumab in patients with estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer with programmed death ligand 1–positive (PD-L1–positive) tumors in the phase Ib open-label, multicohort KEYNOTE-028 (NCT02054806) study. Patients and Methods: Patients with ER+/HER2− advanced breast cancer with PD-L1–positive tumors (combined positive score ≥1) received pembrolizumab (10 mg/kg every 2 weeks) up to 2 years or until confirmed progression/intolerable toxicity. Primary endpoints were safety and overall response rate (ORR), based on Response Evaluation Criteria in Solid Tumors, version 1 (RECIST v1.1) as assessed by investigator review. Results: Between April 2014 and January 2015, 25 patients were enrolled. Median number of prior therapies for breast cancer, including endocrine agents, was 9 (range, 3–15). Median follow-up was 9.7 months (range, 0.7–31.8 months). Three patients experienced partial response (PR) and none experienced complete response (CR), resulting in an ORR of 12.0% (95% CI, 2.5%–31.2%); 16% of patients had stable disease (SD) and clinical benefit rate (CR + PR + [SD for ≥24 weeks]) was 20% (95% CI, 7–41). Median duration of response was 12.0 months (range, 7.4–15.9 months). The incidence of treatment-related adverse events was 64%; nausea (20%) and fatigue (12%) were most common and were predominantly grade 1/2. No treatment-related discontinuations or deaths occurred. Conclusions: Pembrolizumab was well tolerated with modest but durable overall response in certain patients with previously treated, advanced, PD-L1–positive, ER+/HER2− breast cancer. Clin Cancer Res; 24(12); 2804–11. ©2018 AACR.