A randomised trial comparing 6-monthly adjuvant zoledronate with a single one-time dose in patients with early breast cancer.

PURPOSE: While adjuvant bisphosphonate use in early breast cancer (EBC) is associated with improvements in breast cancer-specific outcomes, questions remain around optimal bisphosphonate type, dose and scheduling. We evaluated a single zoledronate infusion in a prospective randomised trial. METHODS: Postmenopausal patients with EBC were randomised to receive a single infusion of zoledronate (4 mg IV) or 6-monthly treatment for 3 years. Outcomes measured were; Quality of Life (QoL; EQ-5D-5L), bisphosphonate-related toxicities, including acute phase reactions (APRs), recurrence-free survival (RFS), bone metastasis-free survival (BMFS) and overall survival (OS). RESULTS: 211 patients were randomized to either a single infusion (n = 107) or six-monthly treatment (n = 104). After 3 years of follow up there were no significant differences between the arms for QoL and most toxicity endpoints. APRs following zoledronate occurred in 81% (171/211) of patients (77.6% in single infusion arm and 84.6% in the 6-monthly group). While the frequency of APRs decreased over 3 years in the 6-monthly arm, they still remain common. Of 34/104 (32.7%) patients who discontinued zoledronate early in the 6-monthly treatment group, the most common reason was APRs (16/34, 47%). At the 3 year follow up, there were no differences between arms for RFS, BMFS or OS. CONCLUSION: A single infusion of zoledronate was associated with increased patient convenience, less toxicity, and lower rates of treatment discontinuation. Despite the common clinical impression that APRs decrease with time, this was not observed when patients were specifically questioned. While the study is not powered for non-inferiority, longer-term follow-up for confirmation of RFS and OS rates is ongoing.

Assessing hypercoagulability and VTE risk using thromboelastography and Khorana score in women with cancers receiving chemotherapy.

Venous thromboembolism (VTE) is a common occurrence in cancer and chemotherapy increases thrombosis risk. Current risk assessment models such as the Khorana score (KS) and its modifications have limitations in female cancers. We assessed the coagulation profile of a group of women cancer patients under chemotherapy using thromboelastography (TEG) to determine if this can inform VTE risk assessment. Cancer patients who planned to receive chemotherapy were recruited. Baseline demographics, cancer data, BMI, Khorana Score (KS), and VTE risk factors were recorded and patients were followed for 6 months, for any thrombotic events. A total of 36 patients aged 35-85 (18 breast, 11 endometrial, 7 ovarian cancer) were evaluated. Hypercoagulability was detected in 63% of patients post-chemo cycle 1 and 75% post-cycle 2, with a significant increase in MA (maximum amplitude) and CI (clotting index), reduction in R (reaction time), K (clot kinetics), and LY30 (lysis time after 30 min of MA). KS showed only 7% of patients were high risk, 23% were low, and 70% were intermediate risk. MA and CI significantly increased in patients with intermediate and high-risk KS when compared with the low-risk patients and MA was positively correlated with KS. Five patients developed actual VTE; 100% of the tested ones were hypercoagulable either post-cycle 1 or 2 and 80% were KS intermediate risk. TEG is a hypercoagulability marker and TEG-MA and CI can potentially assess VTE risk. Larger studies are needed to assess the utility of TEG as an adjuvant to KS to better predict VTE in specific female cancers.

A multi-center pragmatic, randomized, feasibility trial comparing standard of care schedules of filgrastim administration for primary febrile neutropenia prophylaxis in early-stage breast cancer.

INTRODUCTION: The most effective duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer (EBC) patients is unknown. Despite significant differences in cost and toxicity, no prospective trial has been performed to optimize practice. We assessed the feasibility of using a novel pragmatic trial model to compare the most commonly used schedules of filgrastim. METHODS: Early breast cancer patients receiving chemotherapy were randomized to 5, 7, or 10 days of filgrastim as primary FN prophylaxis. The trial methodology integrated broad eligibility criteria, simply defined endpoints, an integrated consent model incorporating oral consent, and web-based randomization in the clinic. Feasibility was reflected through a combination of primary endpoints including patient and physician engagement (if > 50% of appropriate patients approached agree to participate, and if > 50% of physicians approached patients for the study). Secondary endpoints included the first occurrence rates of FN, treatment-related hospital admission, or chemotherapy dose reductions/delays/discontinuation. RESULTS: From May 2015 to August 2016, 142/149 (95.3%) patients approached agreed to participate and were randomized. Seventeen of 24 (70.8%) medical oncologists approached and randomized patients. The 142 patients received a total of 495 cycles of chemotherapy. Aggregate incidences of a first event by patient were FN (8/142, 5.6%), treatment-related hospitalization (6/142, 4.2%), chemotherapy discontinuation (7/142, 4.9%), chemotherapy delays (5/142, 3.5%), and chemotherapy dose reduction (18/142, 12.7%). Overall, 31.7% (45/142) of patients and 9.0% (45/495) of chemotherapy cycles were associated with one of these first events. CONCLUSION: This study met its feasibility endpoints. This novel pragmatic trial approach offers a means of comparing standard of care treatments in a practical and cost-effective manner. The trial will now be expanded to compare rates of FN between the three filgrastim schedules. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02428114.

A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer.

BACKGROUND: The mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC). METHODS: Women with HER-2 positive MBC, Performance status (PS 0-2), and no limit on number of prior chemotherapies or lines of anti-HER-2 therapies were enrolled. A 3 + 3 dose escalation design was utilized. Four dose levels were intended with starting doses of foretinib 30 mg and lapatinib 750 mg orally once a day (OD) on a 4-weekly cycle. Assessment of c-MET status from the primary archival tissue was performed. RESULTS: We enrolled 19 patients, all evaluable for toxicity assessment and for response evaluation. Median age was 60 years (34-86 years), 95% were PS 0-1, 53% were estrogen receptor-positive and 95% had at least one prior anti-HER-2-based regimen. The fourth dose level was reached (foretinib 45 mg/lapatinib 1250 mg) with dose-limiting toxicities of grade-3 diarrhea and fatigue. There was only one grade-4 non-hematological toxicity across all dose levels. There were no PK interactions between the agents. A median of two cycles was delivered across the dose levels (range 1-20) with associated progression-free survival of 3.2 months (95% CI 1.61-4.34 months). By immunohistochemical assessment with a specified cutoff, none of the 17 samples tested were classified as positive for c-Met. CONCLUSIONS: The RP2D of the combined foretinib and lapatinib is 45 mg and 1000 mg PO OD, respectively. Limited activity was seen with this combination in a predominantly unselected cohort of HER-2-positive patients with MBC.

The relationship between time to initiation of adjuvant chemotherapy and survival in breast cancer: a systematic review and meta-analysis.

BACKGROUND: It is known that adjuvant chemotherapy improves survival in women with breast cancer. It is not known whether the interval between surgery and the initiation of chemotherapy influences its effectiveness. PURPOSE: To determine the relationship between time to initiation of adjuvant chemotherapy and survival in women with breast cancer, through a systematic review of the literature and meta-analysis. METHODS: Systematic review of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Database of Controlled Trials, Google Scholar, and abstracts presented at major international oncology conferences. The primary meta-analysis included only high-validity studies which directly measured the time from surgery to initiation of adjuvant chemotherapy and which controlled for major prognostic factors. Outcomes reported in the original studies were converted to a regression coefficient (ß) and standard error corresponding to a 4-week delay in the initiation of chemotherapy. These relative risks were combined in both fixed- and random-effects models. Homogeneity was assessed by the Cochran χ 2 statistic and the I 2 statistic. Potential publication bias was investigated using standard error-based funnel plots. RESULTS: Meta-analysis of 8 high-validity studies demonstrated that a 4-week increase in TTAC was associated with a significant increase in the risk of death in both the fixed-effects model (RR 1.04; 95 % CI, 1.01-1.08) and random-effects model (RR 1.08; 95 % CI, 1.01-1.15). The association remained significant when the most highly weighted studies were sequentially removed from this analysis, and also when additional, lower validity studies were included in this analysis. Funnel plots showed no significant asymmetry to suggest publication bias. CONCLUSIONS: Increased waiting time from surgery to initiation of adjuvant chemotherapy is associated with a significant decrease in survival. Avoidance of unnecessary delays in the initiation of adjuvant chemotherapy has the potential to save the lives of many women with breast cancer.

A Retrospective Analysis of Diagnostic Breast Imaging Outcomes in Young Women at a Tertiary Care Center.

(1) Purpose: The purpose of this study was to describe the outcomes of diagnostic breast imaging and the incidence of delayed breast cancer diagnosis in the study population. (2) Methods: We collected the outcome data from diagnostic mammograms and/or breast ultrasounds (USs) performed on women between the ages of 30 and 50 with symptomatic breast clinical presentations between 2018 and 2019. (3) Results: Out of 171 eligible patients, 10 patients (5.8%) had BIRADS 0, 90 patients (52.6%) had benign findings (BIRADS 1 and 2), 41 (24.0%) patients had probable benign findings requiring short-term follow-up (BIRADS 3), while 30 (17.5%) patients had findings suspicious of malignancy (BIRADS 4 and 5). In the BIRADS 3 group, 92.7% had recommended follow-up, while in BIRADS 4 and 5, only 83.3% underwent recommended biopsy at a mean time of 1.7 weeks (range 0-22 wks) from their follow-up scan. Ten (6%) patients were diagnosed with breast cancer, all of whom had BIRADS 4 or 5, with a mean time of breast cancer diagnosis from initial diagnostic imaging of 2.2 weeks (range 1-22 wks). No patients had delayed breast cancer diagnosis in our cohort. (4) Conclusions: We conclude that diagnostic mammograms and breast US are appropriate investigations for clinical breast concerns in women aged 30-50 years.

Implementing Next-Generation Sequencing Process Changes to Increase Capacity and Improve Timeliness of Molecular Biomarker Profiling for Lung Cancer Patients.

BACKGROUND: Faced with expansion of molecular tumor biomarker profiling, the molecular genetics laboratory at Kingston Health Science Centre experienced significant pressures to maintain the provincially mandated 2-week turnaround time (TAT) for lung cancer (LC) patients. We used quality improvement methodology to identify opportunities for improved efficiencies and report the impact of the initiative. METHODS: We set a target of reducing average TAT from accessioning to clinical molecular lab report for LC patients. Process measures included percentage of cases reaching TAT within target and number of cases. We developed a value stream map and used lean methodology to identify baseline inefficiencies. Plan-Do-Study-Act cycles were implemented to streamline, standardize, and automate laboratory workflows. Statistical process control (SPC) charts assessed for significance by special cause variation. RESULTS: A total of 257 LC cases were included (39 baseline January-May 2021; 218 post-expansion of testing June 2021). The average time for baseline TAT was 12.8 days, peaking at 23.4 days after expansion of testing, and improved to 13.9 days following improvement interventions, demonstrating statistical significance by special cause variation (nonrandom variation) on SPC charts. CONCLUSIONS: The implementation of standardized manual and automated laboratory processes improved timeliness of biomarker reporting despite the increasing volume of testing at our center.

Does Pre-Emptive Availability of PREDICT 2.1 Results Change Ordering Practices for Oncotype DX? A Multi-Center Prospective Cohort Study.

For early-stage hormone receptor (HR)-positive and HER2-negative breast cancer, tools to estimate treatment benefit include free and publicly available algorithms (e.g., PREDICT 2.1) and expensive molecular assays (e.g., Oncotype DX). There remains a need to identify patients who de-rive the most benefit from molecular assays and where this test may be of poor value. In this multicenter prospective cohort study, we evaluated whether use of PREDICT 2.1 would impact physician decision making. For the first 6 months of the study, data on physician use of both PREDICT 2.1 and Oncotype DX ordering were collected on all newly diagnosed patients eligible for molecular testing. After 6 months, an educational intervention was undertaken to see if providing physicians with PREDICT 2.1 results affects the frequency of Oncotype DX requests. A total of 602 patients across six cancer centers in Ontario, Canada were recruited between March 2020 and November 2021. Providing PREDICT 2.1 results and an educational intervention did not alter the ordering of an Oncotype DX. For patients with low clinical risk, either by clinico-pathologic features or by PREDICT 2.1, the probability of obtaining a high Oncotype DX recurrence score was substantially lower compared to patients with high-clinical-risk disease. The introduction of an educational intervention had no impact on molecular assay requests. However, routine ordering of molecular assays for patients with low-clinical-risk disease is of poor value.

Antithymocyte globulin for aplastic anemia secondary to pembrolizumab: a case report and review of literature.

Aplastic anemia is a rare but potentially serious complication of immune checkpoint inhibitor therapy. The authors present a case of pembrolizumab-induced aplastic anemia that was refractory to steroids but had some hematologic response to modified-dosing antithymocyte globulin (ATG). This is the first reported case of hematological response to ATG for immune checkpoint inhibitor-induced aplastic anemia and the first reported case of modified ATG dosing for this indication. Cases of immune checkpoint inhibitor-induced aplastic anemia and management options are also summarized. Given the high morbidity and mortality associated with ICI-induced aplastic anemia, more data is necessary to guide evidence-based management recommendations.

Immune checkpoint inhibitors (ICIs) are a form of anticancer therapy that enlists the body's own immune system to fight cancer cells. Although remarkably effective against some types of cancer, ICIs can also cause the augmented immune system to attack noncancer cells, resulting in unwanted off-target side effects. One rare but potentially serious complication of ICIs is aplastic anemia, where the body stops producing enough new blood cells. There is little known about ICI-induced aplastic anemia. The authors present a case of ICI-induced aplastic anemia that did not improve with standard treatment but had some response to antithymocyte globulin, which has not been previously reported. Previously published cases of ICI-induced aplastic anemia and management options are also summarized.

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.

INTRODUCTION: First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. METHODS: This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety. RESULTS: A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS. CONCLUSIONS: The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.

A case of successful pembrolizumab rechallenge in a patient with non-small-cell lung cancer and grade 3 dermatomyositis.

We report a case of dermatomyositis in a 59-year old female with advanced non-small-cell lung cancer post one cycle of first-line pembrolizumab monotherapy. Her symptoms resolved with high-dose methyl-prednisolone and subsequent prolonged oral prednisone taper over 11 weeks. She achieved durable response over 6 months without further pembrolizumab and was successfully rechallenged without recurrent high-grade immunotoxicity. To our knowledge, this is the only case of severe immune-related dermatomyositis successfully rechallenged with immunotherapy. In this case report, we highlight that dermatomyositis remains a clinical diagnosis with no reliable autoimmune antibody marker. It is a rare immune-related adverse event for which clinicians must remain highly vigilant. We also discuss the rationale and clinical factors to consider on immunotherapy rechallenge decisions.

Staging Investigations in Asymptomatic Early Breast Cancer Patients at the Cancer Centre of Southeastern Ontario.

BACKGROUND: In 2012, the American Society for Clinical Oncology (ASCO) identified five key opportunities in oncology to improve patient care, recommending against imaging tests for the staging of patients with early breast cancer (EBC) at low risk for metastases. Similarly, the European Society of Medical Oncology (ESMO) guideline does not support radiological staging in asymptomatic EBC (aEBC). The purpose of this study was to assess local practice and outcomes of staging investigations (SIs) in aEBC at the Cancer Centre of Southeastern Ontario (CCSEO). METHODS: A retrospective electronic and paper chart review was undertaken to identify all aEBC patients treated at our institution between January 2012 and December 2014. Patients with pathological staging of T1-T2 and N0-1 with any receptor status were included. We collected patient demographics, treatment and pathologic tumor characteristics. The use and outcomes of initial and follow-up SIs were recorded. Data were analyzed to determine associations between the use of SIs and clinical characteristics (chi-square tests, independent samples t-tests and Mann-Whitney U tests). RESULTS: From 2012 to 2014, 295 asymptomatic EBC patients were identified. The mean age was 64, 81% were postmenopausal and 76% had breast conserving surgery. Stage distribution was as follows: stage I 42%, stage IIA 37% and stage IIB 21%. Receptor status was as follows: ER+ 84%, HER2+ 13% and triple negative 12%. Adjuvant chemotherapy was received by 36%, Trastuzumab by 10% and endocrine therapy by 76% of patients. Baseline SIs were performed in 168 patients (57%) for a total of 332 tests. Overt metastatic disease was found in five patients (one bone scan and four CT scans). Seventy-one out of the 168 patients (42%) who received initial staging imaging underwent 138 follow-up imaging tests, none of which were diagnostic for metastases. Nine patients with suspicious CT findings underwent biopsies, of which four were malignant (one metastatic breast cancer and three new primaries). Factors significantly associated with SI were as follows: younger age (p = 0.001), premenopausal status (p = 0.01), T2 stage (p < 0.001), N1 stage (p < 0.001), HER2 positive (p < 0.001), triple negative status (p = 0.007) and use of adjuvant chemotherapy (p < 0.001). CONCLUSIONS: Over a 3-year period at our institution, more than 50% of aEBC patients underwent a total of 470 initial and follow-up staging tests, yielding a cancer diagnosis (metastatic breast cancer or second primary cancer) in four patients. We, therefore, conclude that routine-staging investigations in aEBC patients have low diagnostic value, supporting current guidelines that recommend against the routine use of SI in this population.

Feasibility outcomes of a randomised, multicentre, pilot trial comparing standard 6-monthly dosing of adjuvant zoledronate with a single one-time dose in patients with early stage breast cancer.

BACKGROUND: Adjuvant zoledronate is widely used in patients with early stage breast cancer (EBC), but its optimal duration and dosing interval is still unknown. While a single-dose of zoledronate can improve bone density for many years, a proper evaluation of its effects on breast cancer-related outcomes would require a large trial. In this pilot study we evaluated the feasibility of performing such a trial. METHODS: Eligible patients with EBC were randomised to receive either one dose of zoledronate or 7 doses (6-monthly dosing for 3 years). Feasibility was assessed by a combination of primary outcomes including: activation of at least 6 Ontario sites within a year, active participation (i.e. approaching eligible patients for study participation) of at least half of the medical oncologists, and enrolment of at least 100 patients across all sites within 9 months of the sixth site being activated. RESULTS: All 6 sites were activated within 1 year and of 47 medical oncologists, 27 (57%) approached patients. Between November 2018 and April 2020, 211 eligible patients were randomised, 106 (50.2%) to a single dose of zoledronate and 105 (49.8%) to 6-monthly dosing. Baseline characteristics of randomised patients included; median age 59 (range 36-88), ER and/or PR positive (85%), Her2 positive (23%), menopausal status (premenopausal [19%], perimenopausal [6.7%] and postmenopausal [74%]) and 74% received neo/adjuvant chemotherapy. CONCLUSIONS: All study feasibility endpoints were met in this trial comparing alternative schedules for adjuvant zoledronate. We will now seek funding for performing a larger efficacy trial.Trial registration: NCT03664687.

Two-year results of a randomised trial comparing 4- versus 12-weekly bone-targeted agent use in patients with bone metastases from breast or castration-resistant prostate cancer.

BACKGROUND: We present the 2-year results of a randomised trial comparing 4- versus 12-weekly bone-targeting agents (BTAs) in patients with bone metastases from breast or castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Patients with bone metastases from breast or CRPC, who were going to start or were already receiving BTAs, were randomised to 4- or 12-weekly BTA treatment for 2 years. The endpoints were: symptomatic skeletal events (SSE) rates, time to SSEs, toxicity and cost-effectiveness. RESULTS: Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). After 2 years, the cumulative incidence rate (95% CI) of SSEs was 32.7% (24.6% to 41.1%) and 28.1% (20.3% to 36.4%) for the 4- and 12-weekly intervention groups respectively. The hazard ratio for time to first SSE was 0.96 (95% CI = 0.63 to 1.47). However, in a post hoc analysis, those patients who had an on-study SSE, there was a small non-statistical increased risk of subsequent SSEs among patients on the 12-weekly dosing arm (HR = 1.14; 95% CI - 0.90-1.44). BTA-related toxicity rates were similar between study arms. A cost-utility analysis showed that 12-weekly BTA is cost-effective from a public payer's perspective. CONCLUSION: These results in addition to those previously reported for de-escalating zoledronate, would support that de-escalation of commonly used BTAs is a reasonable and economically valid treatment option. While not statistically significant, the increase in subsequent SSEs in the 12-weekly arm requires further exploration.

Cost-Effectiveness Analysis of 12-Versus 4-Weekly Administration of Bone-Targeted Agents in Patients with Bone Metastases from Breast and Castration-Resistant Prostate Cancer.

A cost-utility analysis was performed based on the Rethinking Clinical Trials (REaCT) bone-targeted agents (BTA) clinical trial that compared 12-weekly (once every 12 weeks) (n = 130) versus 4-weekly (once every 4 weeks) (n = 133) BTA dosing for metastatic breast and castration-resistant prostate (CRPC) cancer. Using a decision tree model, we calculated treatment and symptomatic skeletal event (SSE) costs as well as quality-adjusted life-years (QALYs) for each treatment option. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the study findings. The total cost of BTA treatment in Canadian dollars (C$) and estimated QALYs was C$8965.03 and 0.605 QALY in the 4-weekly group versus C$5669.95 and 0.612 QALY in the 12-weekly group, respectively. De-escalation from 4-weekly to 12-weekly BTA reduces cost (C$3293.75) and improves QALYs by 0.008 unit, suggesting that 12-weekly BTA dominates 4-weekly BTA in breast and CRPC patients with bone metastases. Sensitivity analysis suggests high levels of uncertainty in the cost-effectiveness findings. De-escalation of bone-targeted agents is cost-effective from the Canadian public payer's perspective.

A randomised trial of 4- versus 12-weekly administration of bone-targeted agents in patients with bone metastases from breast or castration-resistant prostate cancer.

BACKGROUND: Optimal dosing of bone-targeted agents (BTAs), in patients with bone metastases remains an important clinical question. This trial compared 4-weekly versus 12-weekly therapy. PATIENTS AND METHODS: Patients with bone metastases from breast or castration-resistant prostate cancer (CRPC), who were going to start or already on BTAs, were randomised 1:1 to 4-weekly or 12-weekly BTA treatment for one year. Primary end point was change in health-related quality of life (HRQoL)-physical function European Organisation for Research and Treatment of Cancer (EORTC)-QLQ-C30). Secondary end points included pain (EORTC-QLQ-BM22), global health status (EORTC-QLQ-C30), symptomatic skeletal events (SSEs) rates and time to SSEs. Primary analysis was per protocol and a non-inferiority margin of 5 points was used. RESULTS: Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). Using repeated-measures analysis, across all time points, patients in the 4-weekly arm had a mean HRQL-physical subdomain score which was 1.2 (95% confidence interval: -1.6 to 4.0) higher than the 12-weekly arm. The study met the definition of non-inferiority for our primary outcome. Secondary outcomes showed no significant difference in scores for pain, global health status, SSE rates and SSE-free survival between arms. Subgroup analyses for cancer type, prior BTA use or BTA type showed no significant difference between arms. CONCLUSION: These results in addition to those previously reported for de-escalating zoledronate and systematic reviews in both breast and prostate cancers, would support that de-escalation of commonly used BTAs is a reasonable treatment option.

The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32.

BACKGROUND: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo. METHODS: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. RESULTS: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone. CONCLUSION: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.

A phase IB study of durvalumab with or without tremelimumab and platinum-doublet chemotherapy in advanced solid tumours: Canadian Cancer Trials Group Study IND226.

This multicenter phase Ib study aimed to establish a recommended phase II dose for durvalumab (Du) ± tremelimumab (Tr) in combination with standard platinum-doublet chemotherapy. Eligible patients were enrolled into one of six dose levels (DL) of Du ± Tr which included concomitant treatment with standard platinum-doublet regimens; (pemetrexed, gemcitabine, etoposide, (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)). Dose escalation was according to a Rolling Six type design. Both weight-based and fixed dosing of Du and Tr were explored. Du was continued until progression. Tr dosing was finite (up to 6 doses) with increasing dose and/or frequency by DL. 136 patients were enrolled. The majority of drug-related adverse events (AEs) were ≤ grade 2 and attributable to chemotherapy. AEs considered related to immunotherapy were mainly ≤ grade 2; the most frequent (occurring ≥10 %) were colitis/diarrhea, skin, and thyroid dysfunction. Seven patients had DLTs including pneumonitis, myocarditis, diarrhea, encephalitis, motor neuropathy, and enterocolitis. There were 2 treatment-related deaths. Tr and Du exposures did not appear affected by chemotherapy. Among the 73 non-small cell lung cancer (NSCLC) patients treated, the objective response rate was 51 % (95 %CI = 38.7-62.6 %) with a median progression-free and overall survival of 6.5 months (95 % CI = 5.5-9.4 months) and 19.8 months (95 % CI = 14.8 months - not yet reached) respectively. Anti-tumour activity was observed across PD-L1 subtypes. Du 1500 mg q3w and Tr 75 mg q3wx5 can be safely combined with platinum-doublet chemotherapy. Efficacy among NSCLC patients appears comparable to results from other immunotherapy and chemotherapy combination trials. NCT02537418.

Improving Timeliness of Oncology Assessment and Cancer Treatment Through Implementation of a Multidisciplinary Lung Cancer Clinic.

PURPOSE: Timely lung cancer care has been associated with improved clinical outcomes and patient satisfaction. We identified improvement opportunities in lung cancer management pathways at Kingston Health Sciences Centre. Quality improvement strategies led to the implementation of a multidisciplinary lung cancer clinic (MDC). METHODS: We set an outcome measure of decreasing the time from diagnosis to first cancer treatment by 10 days within 6 months of clinic implementation. We implemented a weekly MDC that involved respirologists, medical oncologists, and radiation oncologists at which patients with new lung cancer diagnoses were offered concurrent oncology consultation. We used Plan-Do-Study-Act cycles to guide our improvement initiatives. A total of five Plan-Do-Study-Act cycles spanned 14 months and consisted of an MDC pilot clinic, large-scale MDC launching, debriefing meetings, and clinic expansion. Pre-MDC data were analyzed retrospectively to establish baseline and prospectively for improvement. Statistical Process Control XmR(i) charts were used to report data. RESULTS: Since MDC initiation, 128 patients have been seen in 34 MDC clinics (3.8 patients per clinic). Mean days from diagnosis to first oncology assessment decreased from 12.4 days to 3.9 days, and mean days from diagnosis to first cancer treatment decreased from 39.5 to 15.0 days, both of which demonstrated special cause variation. Time to assessment and treatment improved for patients with every stage of lung cancer and for both small-cell and non-small-cell subtypes. CONCLUSION: MDC shortens the time from lung cancer diagnosis to oncology assessment and treatment. Time to treatment improved more than time to oncology assessment, which suggests the improvement is related to benefits beyond faster oncology assessment.

First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers.

PURPOSE: CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS: Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS: Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION: Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.