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Women with hormone receptor positive breast cancer may receive 5 years of treatment with aromatase inhibitors but the magnitude of benefit was relatively small. Our goal was to develop a tool for identification of women with limited treatment benefit. Regression analyses were applied to women treated by placebo in CCTG MA.17R trial (NCT00754845) to identify important prognostic factors associated with distant recurrence and develop a nomogram for predicting 5-year likelihood of distant recurrence, which was internally validated using bootstrap resampling method. Differential treatment effects between risk categories derived from the nomogram were evaluated among all women enrolled through interaction test between treatment and risk category. A total of 1735 women were included and the final model from 866 women treated by placebo identified the following three factors associate with distant recurrence: tumor size, nodal status, and presence of cardiovascular disease. The nomogram derived from the final model exhibited good discrimination power with a bootstrap-corrected concordance index of 0.71 and, importantly, identified 64% of low risk patients in whom extended treatment has limited benefit. Interaction between treatment and risk category derived from the nomogram was significant (p = 0.04). A nomogram with good performance may be used to accurately predict distant recurrence risk and also benefits with extended treatment after 5 years of aromatase inhibitors. Future independent validation of the proposed nomogram is warranted. NCT00754845

Summary Background The benefits of secondary cytoreduction for platinum-sensitive relapsed ovarian cancer are still widely debated. We aimed to assess the efficacy of secondary cytoreduction plus chemotherapy versus chemotherapy alone in this patient population. Methods This multicentre, open-label, randomised, controlled, phase 3 trial (SOC-1), was done in four primarily academic centres in China (two in Shanghai, one in Hangzhou, and one in Guangzhou). Eligible patients were women aged 18 years and older with platinum-sensitive relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months after the end of first-line platinum-based chemotherapy and were predicted to have potentially resectable disease according to the international model (iMODEL) score and PET-CT imaging. iMODEL score was calculated using six variables: International Federation of Gynecology and Obstetrics stage, residual disease after primary surgery, platinum-free interval, Eastern Cooperative Oncology Group performance status, serum level of cancer antigen 125 at recurrence, and presence of ascites at recurrence. An iMODEL score of 4·7 or lower predicted a potentially complete resection. As per a protocol amendment, patients with an iMODEL score of more than 4·7 could only be included if the serum level of cancer antigen 125 was more than 105 U/mL, but the principal investigators assessed the disease to be resectable by PET-CT. Eligible participants were randomly assigned (1:1) via a permuted block design (block size of six) and stratified by study centre, iMODEL score, residual disease at primary surgery, and enrolment in the Shanghai Gynecologic Oncology Group SUNNY trial, to undergo secondary cytoreductive surgery followed by intravenous chemotherapy (six 3-weekly cycles of intravenous paclitaxel [175 mg/m2] or docetaxel [75 mg/m2] combined with intravenous carboplatin [area under the curve of 5 mg/mL per min]; surgery group) or intravenous chemotherapy alone (no surgery group). Primary endpoints were progression-free survival and overall survival, analysed in all participants randomly assigned to treatment, regardless of treatment received (intention-to-treat [ITT] population). Here, we report the final analysis of progression-free survival and the prespecified interim analysis of overall survival. Safety was assessed in all participants who received their assigned treatment and had available adverse event data. This study is registered with ClinicalTrials.gov, NCT01611766, and is ongoing but closed to accrual. Findings Between July 19, 2012, and June 3, 2019, 357 patients were recruited and randomly assigned to the surgery group (182) or the no surgery group (175; ITT population). Median follow-up was 36·0 months (IQR 18·1–58·3). In the no surgery group, 11 (6%) of 175 participants had secondary cytoreduction during second-line therapy while 48 (37%) of 130 participants who had disease progression crossed-over and had surgery at a subsequent recurrence. Median progression-free survival was 17·4 months (95% CI 15·0–19·8) in the surgery group and 11·9 months (10·0–13·8) in the no surgery group (hazard ratio [HR] 0·58; 95% CI 0·45–0·74; p Interpretation Secondary cytoreduction followed by chemotherapy was associated with significantly longer progression-free survival than was chemotherapy alone in patients with platinum-sensitive relapsed ovarian cancer, and patients should be counselled about the option of secondary cytoreduction in specialised centres. Long-term survival outcomes will be assessed using mature data on overall survival. Funding Zhongshan Development Program. Translation For the Chinese translation of the abstract see Supplementary Materials section.

Purpose: Expanded RAS/BRAF mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC), and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive beads, emulsion, amplification, and magnetics (BEAMing) analysis, capable of detecting alterations below standard clinical assays. Patients and Methods: CO.17 trial compared cetuximab versus best supportive care (BSC) in RAS/BRAF-unselected mCRC. We performed RAS/BRAF analysis on microdissected tissue of 242 patients in CO.17 trial using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Patients without BEAMing but with previous Sanger sequencing–detected mutations were included. Results: KRAS, NRAS, and BRAF mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival [OS; HR, 0.51; 95% confidence interval (CI), 0.32–0.81; P = 0.004] and progression-free survival (PFS; HR, 0.25; 95% CI, 0.15–0.41; P < 0.0001) compared with BSC in RAS/BRAF wild-type patients. Cetuximab did not improve OS/PFS for KRAS-, NRAS-, or BRAF-mutated tumors, and tests of interaction confirmed expanded KRAS (P = 0.0002) and NRAS (P = 0.006) as predictive, while BRAF mutations were not (P = 0.089). BEAMing identified 14% more tumors as RAS mutant than Sanger sequencing, and cetuximab lacked activity in these patients. Mutations at MAF < 5% were noted in 6 of 242 patients (2%). One patient with a KRAS A59T mutation (MAF = 2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR, 20.50; 95% CI, 3.88—96.85; P = 0.0038). Conclusions: We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance.

Fibromyalgia is a common and challenging chronic pain disorder with few, if any, highly effective and well-tolerated treatments. Alpha-lipoic acid (ALA) is a nonsedating antioxidant with evidence of efficacy in the treatment of symptomatic diabetic neuropathy that has not been evaluated in the setting of fibromyalgia treatment. Thus, we conducted a single-centre, proof-of-concept, randomized, placebo-controlled, crossover trial of ALA for the treatment of fibromyalgia. Twenty-seven participants were recruited, and 24 participants completed both treatment periods of the trial. The median maximal tolerated dose of ALA in this trial was 1663 mg/day. Treatment-emergent adverse events with ALA were infrequent and not statistically different from placebo. For the primary outcome of pain intensity, and for several other validated secondary outcomes, there were no statistically significant differences between placebo and ALA. A post hoc exploratory subgroup analysis showed a significant interaction between gender and treatment with a significant favourable placebo-ALA difference in pain for men, but not for women. Overall, the results of this trial do not provide any evidence to suggest promise for ALA as an effective treatment for fibromyalgia, which is predominantly prevalent in women. This negative clinical trial represents an important step in a collective strategy to identify new, better tolerated and more effective treatments for fibromyalgia.

Background: Tamoxifen and aromatase inhibitors constitute the backbone of treatment for estrogen receptor positive early stage breast cancers based on immunohistochemical (IHC) results. While these therapies significantly reduce the risk of relapse of breast cancer, they have toxicities and add to costs. Gene expression profiling assays are widely used to quantify risk and support targeted therapies for luminal breast cancers treated with adjuvant endocrine therapy. In a prospective-retrospective analysis of the phase III CCTG MA.12 clinical trial (randomizing premenopausal women treated with adjuvant chemotherapy, to either tamoxifen or placebo for 5 years), luminal subtype by PAM50 was significantly predictive for tamoxifen benefit. However, IHC classification (as estrogen receptor positive) could not demonstrate a statistically significant benefit from tamoxifen over placebo. More accurate IHC biomarkers incorporating nestin positivity or loss of inositol polyphosphate-4-phosphate (INPP4B) have recently been optimized to identify the basal-like intrinsic subtype of breast cancer regardless of ER/PR/HER2 status. In this study, we examined the capacity of these basal biomarkers to identify intrinsic subtype and predict benefit from adjuvant tamoxifen vs. placebo in the CCTG MA.12 clinical trial Methods:492 formalin-fixed paraffin embedded blocks of primary tumor from patients randomized in the CCTG MA.12 trial were used to build tissue microarrays. IHC staining for nestin and INPP4B was done according to published methods, and interpretation was performed by pathologists with no access to molecular data. The performance of the nestin and INPP4B panel was assessed against PAM50 gene expression assay as a standard reference. A prespecified statistical plan was executed independently by the Canadian Cancer Trials Group, testing the primary hypothesis that patients with basal breast cancer, when defined as “positive for nestin or negative for INPP4B,” would not benefit from tamoxifen (primary endpoint: disease-free survival).Results: 366 primary tumor samples from the CCTG MA.12 had a full dataset available for IHCbiomarker evaluation, PAM50 subtype and clinical outcomes. Positive staining of nestin or loss of INPP4B was observed in 47 (13%) of the total cases and was significantly associated with poor prognostic factors including high grade, younger age, ER negativity, triple negative and core basal IHC status (p Citation Format: Karama Asleh, Dongxia Gao, Vivien H Bramwell, Dongsheng Tu, Lois E Shepherd, Torsten O Nielsen. Predictive significance of an optimized immunohistochemical panel for basal-like breast cancer on the CCTG MA.12 phase III randomized clinical trial [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 P2-11-03.

Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.

High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Treatment is not uniform, with some patients undergoing primary debulking surgery followed by chemotherapy (PDS) and others being treated directly with chemotherapy and only having surgery after three to four cycles (NACT). Which strategy is optimal remains controversial. We developed a mathematical framework that simulates hierarchical or stochastic models of tumor initiation and reproduces the clinical course of HGSC. After estimating parameter values, we infer that most patients harbor chemoresistant HGSC cells at diagnosis and that, if the tumor burden is not too large and complete debulking can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. These predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management.

The PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was administered at a starting dose of 100 mg bid 2 days on/5 days off weekly with TMZ 150 mg/m2 daily for 5 days/28-days cycle. Dose escalation was according to a 3 + 3 design. Secondary objectives included assessment of vistusertib safety and toxicity profile, and preliminary efficacy. 15 patients were enrolled in the study (median age 66 (range 51–77), females 8). Vistusertib 125 mg BID in combination with TMZ 150 mg/m2 daily for 5 days was well tolerated. Vistusertib treatment-related adverse events were generally grade 1–2, with the most frequently reported being fatigue, gastrointestinal symptoms, and rash. Of 13 response evaluable patients, 1 patient (8%) had a partial response ongoing at 7.6 months of follow-up, and 5 patients had stable disease (38%) as best response (median duration 9.6 months, range 3.7-not yet reached). Six-month progression-free survival (PFS) rate was 26.6%. Combination of vistusertib with TMZ in GBM patients at first recurrence demonstrated a favorable safety profile at the tested dose levels.

PURPOSE: Trial economic analyses, such as cost-effectiveness analysis, often rely on trial-collected data, which are burdensome and expensive to collect and may be incomplete. In contrast, administrative databases systematically collect health system encounters. We investigated whether administrative data could improve the performance of cancer trial economic analysis. METHODS: Health administrative data were probabilistically linked to Ontario patient data from the Canadian Cancer Trials Group CO.17 trial (n = 572), which evaluated cetuximab plus best supportive care (75 linked Ontario patients) versus best supportive care alone (73 patients) in previously treated metastatic colorectal cancer. Trial-collected resource utilization data and vital status were compared with administrative data. Cost effectiveness in 2007 Canadian dollars was determined with bootstrap incremental cost-effectiveness ratio (ICER) CIs. RESULTS: Up to trial date of last contact, administrative data vital status was concordant in more than 96%. Twenty-nine subsequent deaths occurred. Up to trial last contact, there were 50 net additional hospitalizations in administrative data and 33 net additional emergency department visits. Total costs were $3,023,034 for the cetuximab group and $1,191,118 for the control group up to trial last contact. The ICER was $211,128 per life-year gained (90% CI, $101,396 to $694,950) up to trial last contact and $164,378 (90% CI, −$138,260 to $644,555) up to administrative data last contact. ICER estimates were similar to the analysis using trial-collected data. CONCLUSION: Administrative data were more complete than trial data for hospital encounters, a key cost driver in economic analysis. There was a longer follow-up. This demonstrates the potential of administrative data to relieve the burden of collecting key data in cancer trials, which represents a considerable effort and expense.

BackgroundImmune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD-L1)-positive, triple-negative, metastatic breast cancer (MBC). Antibody-dependent cell-mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2-positive MBC previously treated with chemotherapy and anti-HER2 antibodies to assess safety, efficacy, and correlative endpoints.Patients and MethodsPatients with HER2-positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D.ResultsFifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40–86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab-emtansine (93%) for MBC. No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade ≥3 immune-related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had ConclusionThe RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2-positive PD-L1-negative MBC.Implications for PracticeThis phase Ib trial with associated correlative endpoints provides insights into the lack of activity of the combination of durvalumab and trastuzumab in heavily pretreated HER2-positive metastatic breast cancer (MBC). No significant clinical activity was observed in patients with heavily pretreated HER2-positive programmed death ligand 1 (PD-L1)-negative MBC with evidence of cytotoxic T-cell exhaustion. Furthermore, all patients had no expression of PD-L1 in the tumor cells. These data support the importance of PD-L1 as an important selection biomarker and the need to assess the tumor microenvironment for immune regulatory cells. Further work is needed to understand how to activate the “cold” tumors to be able to combine current immune-oncology agents.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

Background The safety and efficacy of targeted therapy in older patients (≥ 70 years) with metastatic colorectal cancer is not well evaluated. Patients and Methods Outcomes of older patients (including overall survival [OS], progression-free survival [PFS], toxicity, and quality of life [QoL]) were compared to young patients using data from 2 large previously reported clinical trials, CO.17 (cetuximab vs. best supportive care) and CO.20 (cetuximab plus placebo vs. cetuximab plus brivanib). Only patients with wild-type KRAS tumors were included. Results A total of 251 (26.3%) of 955 patients were ≥ 70 years old. No significant differences in OS, PFS, or grade 3/4 adverse events were observed between older and younger patients treated with cetuximab (or cetuximab with placebo) in either trial. Younger patients trended toward superior OS in both CO.17 (hazard ratio = 1.80; P = .16) and CO.20 (hazard ratio = 1.34; P = .07). QoL maintenance favored younger patients in CO.17 (3.6 vs. 5.7 months; P = .046) but no difference of QoL maintenance was observed in the larger CO.20 trial (1.7 vs. 1.8 months; P = .64). Combination therapy of cetuximab and brivanib was significantly more toxic in older adults (87% vs. 77%; P = .03). Conclusion OS, PFS, and toxicities were similar between older and younger patients with wild-type KRAS metastatic colorectal cancer when treated with cetuximab. Both age groups likely experience similar QoL maintenance with cetuximab. Dual targeted therapy was significantly more toxic in older patients.

Background: Early stage, hormone sensitive breast cancer is associated generally with a good prognosis, with only a minority of patients expected to die of breast cancer. Death from causes other than breast cancer can dilute the patients at risk of breast cancer events and result in over-estimation of risk of recurrence and consequently the benefit from breast cancer therapy, a so-called immortal time bias. The MA.17R trial (Goss et al 2016) evaluated the role of extending adjuvant treatment with letrozole from 5 to 10 years. Here we determine the effect of analyzing the MA.17R trial using methods accounting for competing risks. Methods: We compared conventional and competing risk methods for disease-free survival (DFS) and for distant recurrence-free survival (DRFS). In Kaplan-Meier analyses death from any cause was considered an event while cumulative incidence functions (CIFs) assumed death without recurrence to be a competing risk. The complement of the survival function (one minus the survival function) was used to estimate incidence of the primary event of interest. This was compared to estimates obtained using CIFs accounting for the occurrence of competing events. Results: Non-breast cancer death was the most common event defining DFS and DRFS. Over the course of follow-up, there was increasing discrepancy between the risk of disease recurrence measured using Kaplan-Meier and CIF. Among letrozole treated patients the estimated distant recurrence at 5 years of follow-up was 5.4% using CIF and 9.6% using Kaplan-Meier. At 10 years of follow-up, the estimated distant recurrence was 8.4% using CIF and 20.0% using Kaplan-Meier. Similar results were observed for the placebo group (8.5% vs 12.1% at 5 years and 14.8% vs 27.3% at 10 years), and in patients with baseline cardiovascular disease (see Table). Benefit from letrozole on DFS and DRFS was greater when accounting for competing risk (hazard ratio [HR] for DFS 0.66, 95%CI 0.48-0.90; DFRS HR 0.75, 0.50-1.14) compared to the conventional method (DFS HR 0.79, 0.62-0.99; DRFS HR 0.91, 0.70-1.18). In women with baseline cardiovascular risk, the benefits of extended adjuvant letrozole when considering competing risk (DFS HR 0.38, 0.16-0.89; DRFS HR 0.46, 0.16-1.35) were also greater than those observed in the conventional analysis (DFS HR 0.55, 0.32-0.93; DRFS HR 0.59, 0.33-1.04). Treatment with extended letrozole did not influence non-breast cancer death in women who died with disease recurrence (HR 1.06, 0.74 -1.50) or in those with competing risk or censored from the analysis (HR 1.05, 0.73 -1.49). Conclusion: Over the course of follow-up, estimates of DFS and DRFS differ increasingly if measured using Kaplan-Meier or CIF, with CIF estimates of risk being substantially lower. Using a competing risk model, the reduction in distant recurrence at 8 years with extended letrozole is less than 1%. Additional competing risk analyses of the MA.17 (Goss 2006) and MA.27 (Goss 2013) trials are ongoing. Cumulative incidence of disease recurrence in patients with baseline cardiovascular riskTime (years)CIF (%)1-KM (%)Letrozole11.51.534.46.555.813.8Placebo13.53.538.311.8512.520.3 Citation Format: Ethier J-L, Parulekar W, Shepherd L, Summers L, Strasser-Weippl K, Tu D, Amir E. Influence of competing risks of death on the interpretation of adjuvant endocrine therapy trials for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-03.

Purpose: Accurate IHC biomarkers incorporating nestin positivity or inositol polyphosphate-4-phosphate (INPP4B) loss have recently been optimized to identify the basal-like intrinsic breast cancer subtype regardless of estrogen, progesterone, or Her2 status. We examined the predictive capacity of these basal biomarkers in the CCTG MA.5 chemotherapy and MA.12 endocrine therapy trials. Experimental Design: Formalin-fixed paraffin embedded blocks of primary tumors from patients randomized in the two trials were used to build tissue microarrays. IHC staining for nestin and INPP4B followed published methods and REMARK criteria. A prespecified statistical plan tested the hypothesis that patients with basal breast cancer (nestin+ or INPP4B−) would not benefit from anthracycline substitution in MA.5 or from tamoxifen in MA.12. Results: Nestin positivity or INPP4B loss was observed in 110/453 (24%) interpretable samples from MA.5 and 47/366 (13%) from MA.12, and was associated with high grade, younger age, estrogen receptor negativity, triple-negative, core basal, and PAM50 basal-like subtypes. In the MA.5 trial, patients assigned as basal experienced lower benefit from anthracycline versus nonanthracycline adjuvant chemotherapy [HR, 1.49; 95% confidence interval (CI), 0.72–3.10] when compared with non-basal (nestin− and INPP4B+) cases where there was a higher benefit from anthracyclines (HR, 0.75; 95% CI, 0.54–1.04; Pinteraction = 0.01). In the MA.12 trial, patients assigned as basal did not demonstrate a benefit from adjuvant tamoxifen versus placebo (HR, 0.48; 95% CI, 0.12–1.86; P = 0.29), whereas nonbasal cases displayed significant benefit (HR, 0.66; 95% CI, 0.45–0.98; P = 0.04), although the interaction test was not significant. Conclusions: The nestin/INPP4B IHC panel identifies women with basal breast cancers who benefit from nonanthracycline chemotherapy but not endocrine adjuvant treatments.

Missing patient-reported outcome (PRO) data can seriously threaten the validity of randomized clinical trials (RCTs). Identifying which factors predict missing instruments may help researchers develop strategies to prevent it from happening. This study examined the association of factors with time to the first missing instrument after randomization in three cooperative group RCTs. We performed descriptive analyses and Cox proportional hazards regressions for three RCTs selected from the Canadian Cancer Trials Group: MA17 (breast cancer), PR7 (prostate cancer), and LY12 (non-Hodgkin’s lymphoma). The outcome was the time from randomization to the first missing instrument. Variables for 15 factors were used as covariates based on availability and previously-reported putative associations with missing PRO data. Nine percent of 1352 subjects on MA17, 37% of 923 subjects on PR7, and 59% of 477 subjects on LY12 had a missing instrument. Twenty-five percent of subjects on MA17 had first missing instrument within 4.6 years. The median time to first missing instrument was: not observed for MA17, 7.3 years for PR7, 0.12 years for LY12. Cox regression revealed statistically significant independent associations with outcome for only five factors: baseline age (PR7) and level of well-being (LY12), and centre level of activity (LY12), presence of post-graduate residency training program (MA17, PR7), and centre geographic location (PR7, LY12). Many factors reported to have association with missing instruments do not seem to predict time to the first missing instrument after randomization in RCTs. Context is important in understanding the few that may.

IntroductionEconomic analyses of well-conducted clinical trials are critical to rational health policy that informs value-based decision making. Trial economic analyses, such as cost-effectiveness analysis, often rely on trial-collected data, which are burdensome and expensive to collect. In contrast, administrative databases systematically collect health system encounters and are available at low cost for nearly all patients with cancer in Ontario, Canada, and many other jurisdictions. Objectives and ApproachWe investigated whether administrative data could improve the performance of trial economic analysis. Health administrative data were probabilistically linked to 148 Ontario patients from the Canadian Cancer Trials Group CO.17 trial (n=572), which evaluated cetuximab plus best supportive care (n=75) versus best supportive care alone (n=73) in previously treated metastatic colorectal cancer. Trial-collected resource utilization data and vital status were compared with administrative data. Cost-effectiveness in 2007 Canadian dollars according to administrative data was determined with bootstrap incremental cost-effectiveness ratio (ICER) confidence intervals (CIs). ResultsUp to trial date of last contact, administrative data vital status was concordant in >96%. Twenty-nine subsequent deaths occurred. Up to trial last contact, there were 50 net additional hospitalizations and 33 net additional emergency department visits in administrative data. Total costs were $3,023,034 for the cetuximab group and $1,191,118 for the control group up to trial last contact. ICER was $211,128 per life-year gained (90% CI: $101,396 to $694,950) up to trial last contact and $164,378 (90% CI: -$138,260 to $644,555) up to administrative data last contact. ICER estimates were similar to analyses using trial-collected data. Conclusion/ImplicationsAdministrative data were more complete than trial data for hospital encounters, a key cost driver in economic analysis and there was longer follow-up. This study demonstrates the potential of administrative data to relieve the burden of collecting key data in cancer trials, which represents considerable effort and expense.

In cancer research, two-stage designs are usually used to assess the effect of a new agent in phase II clinical trials. Optimal two-stage designs with two co-primary endpoints have been proposed to assess the effects of new cancer treatments, such as cytostatic or molecularly targeted agents (MTAs), based on both response rate and early progression rate. Accurate estimation of response and early progression rates based on the data from the phase II trials conducted according to the optimal two-stage designs would be very useful for further testing of the agents in phase II trials. In this paper, we derive some estimation procedures, which include both standard and bias-corrected maximum likelihood estimates (MLE) and uniformly minimum variance unbiased estimate (UMVUE), for two binomial probabilities which are used to define the hypotheses for two co-primary endpoints tested in a two-stage phase II clinical trial. Simulation studies were performed to evaluate the performance of these procedures. These procedures are also applied to analyze the data from a phase II trial conducted by the Canadian Cancer Trials Group.

OBJECTIVE: The aim of the study was to quantify baseline estradiol (E2) and estrone (E1) concentrations according to selected patient characteristics in a substudy nested within the MAP.3 chemoprevention trial. METHODS: E2 and E1 levels were measured in 4,068 postmenopausal women using liquid chromatography-tandem mass spectrometry. Distributions were described by age, years since menopause, race, body mass index (BMI), smoking status, and use and duration of hormone therapy using the Kruskal-Wallis test. Multivariable linear regression was also used to identify characteristics associated with estrogen levels. RESULTS: After truncation at the 97.5th percentile, the mean (SD)/median (IQR) values for E2 and E1 were 5.41(4.67)/4.0 (2.4–6.7) pg/mL and 24.7 (14.1)/21 (15–31) pg/mL, respectively. E2 and E1 were strongly correlated (Pearson correlation [r] = 0.8, P < 0.01). The largest variation in E2 and E1 levels was by BMI; mean E2 and E1 levels were 3.5 and 19.1 pg/mL, respectively for women with BMI less than 25 and 7.5 and 30.6 pg/mL, respectively, for women with BMI greater than 30. E2 and E1 varied by age, BMI, smoking status, and prior hormone therapy in multivariable models (P < 0.01). CONCLUSIONS: There was large interindividual variability observed for E2 and E1 that varied significantly by participant characteristics, but with small absolute differences except in the case of BMI. Although the majority of participant characteristics were independently associated with E1 and E2, together, these factors only explained about 20% of the variation in E1 and E2 levels.

PURPOSE: To examine associations between the UGT2B17 gene deletion and exemestane metabolites, and commonly reported side-effects (fatigue, hot flashes, and joint pain) among postmenopausal women participating in the MAP.3 chemoprevention trial. METHODS: The analytical samples for the UGT2B17 analysis comprised 1,752 women on exemestane and 1,721 women on placebo; the exemestane metabolite analysis included 1,360 women on exemestane with one-year serum samples. Both the UGT2B17 gene deletion and metabolites were measured in blood. The metabolites were conceptualized as a ratio (17-DHE-Gluc:17-DHE). Symptoms were assessed using the CTCAE v4.0 at approximately 1-year intervals. Log-binomial regression was used to examine the associations between UGT2B17 deletion, exemestane metabolites and each side effect at 1 and up to 5 year follow-up, adjusting for potential confounders. RESULTS: Among individuals on exemestane with the UGT2B17 gene deletion (i.e. lower detoxification), a higher risk of severe fatigue (RR=2.59 95% CI: 1.14–5.89) was observed at up to 5-year follow-up. Among individuals on placebo, those with the UGT2B17 gene deletion had a higher risk of any fatigue (RR=1.39, 95% CI: 1.02–1.89) at year 1. A lower metabolite ratio (poor detoxification) was associated with a higher risk of any fatigue, hot flashes and joint pain at year 1 (fatigue: RR=1.89, 95% CI: 1.16–3.09; hot flashes: RR=1.77, 95% CI: 1.40–2.24; joint pain: RR=2.05, 95% CI: 1.35–3.12); similar associations were observed at 5-year follow-up. CONCLUSION: Variation in the metabolism of exemestane through the UGT2B17-mediated pathway is associated with subsequent risk of commonly reported symptoms in MAP.3.

Identification of a subset of patients who may be sensitive to a specific treatment is an important problem in clinical trials. In this paper, we consider the case where the treatment effect is measured by longitudinal outcomes, such as quality of life scores assessed over the duration of a clinical trial, and the subset is determined by a continuous baseline covariate, such as age and expression level of a biomarker. A threshold linear mixed model is introduced, and a smoothing maximum likelihood method is proposed to obtain the estimation of the parameters in the model. Broyden-Fletcher-Goldfarb-Shanno algorithm is employed to maximize the proposed smoothing likelihood function. The proposed procedure is evaluated through simulation studies and application to the analysis of data from a randomized clinical trial on patients with advanced colorectal cancer.

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.

PURPOSE Metastatic colorectal cancers (mCRCs) assigned to the transit-amplifying (TA) CRCAssigner subtype are more sensitive to anti–epidermal growth factor receptor (EGFR) therapy. We evaluated the association between the intratumoral presence of TA signature (TA-high/TA-low, dubbed as TA-ness classification) and outcomes in CRCs treated with anti-EGFR therapy. PATIENTS AND METHODS The TA-ness classes were defined in a discovery cohort (n = 84) and independently validated in a clinical trial (CO.20; cetuximab monotherapy arm; n = 121) and other samples using an established NanoString-based gene expression assay. Progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) according to TA-ness classification were assessed by univariate and multivariate analyses. RESULTS The TA-ness was measured in 772 samples from 712 patients. Patients (treated with anti-EGFR therapy) with TA-high tumors had significantly longer PFS (discovery hazard ratio [HR], 0.40; 95% CI, 0.25 to 0.64; P < .001; validation HR, 0.65; 95% CI, 0.45 to 0.93; P = .018), longer OS (discovery HR, 0.48; 95% CI, 0.29 to 0.78; P = .003; validation HR, 0.67; 95% CI, 0.46 to 0.98; P = .04), and higher DCR (discovery odds ratio [OR]; 14.8; 95% CI, 4.30 to 59.54; P < .001; validation OR, 4.35; 95% CI, 2.00 to 9.09; P < .001). TA-ness classification and its association with anti-EGFR therapy outcomes were further confirmed using publicly available data (n = 80) from metastatic samples (PFS P < .001) and patient-derived xenografts ( P = .042). In an exploratory analysis of 55 patients with RAS/BRAF wild-type and left-sided tumors, TA-high class was significantly associated with longer PFS and trend toward higher response rate (PFS HR, 0.53; 95% CI, 0.28 to 1.00; P = .049; OR, 5.88; 95% CI, 0.71 to 4.55; P = .09; response rate 33% in TA-high and 7.7% in TA-low). CONCLUSION TA-ness classification is associated with prognosis in patients with mCRC treated with anti-EGFR therapy and may further help understanding the value of sidedness in patients with RAS/BRAF wild-type tumors.

Background Clinical trials are important but extremely costly. Utilization of routinely collected administrative data may simplify and enhance clinical trial data collection. Purpose The aim of this study was to test the feasibility of use of administrative databases in Ontario, Canada, for long-term clinical trial follow-up, specifically (a) to determine whether limited patient identifiers held by the Canadian Cancer Trials Group can be used to probabilistically link with individuals in the Institute for Clinical Evaluative Sciences databases and if so, (b) the level of concordance between the two data sets. Methods This retrospective study was conducted through collaboration of established health service (Institute for Clinical Evaluative Sciences) and clinical trial (Canadian Cancer Trials Group) research groups in the province of Ontario, Canada, where healthcare is predominantly funded by the government. Adults with pre-treated metastatic colorectal cancer previously enrolled in the Canadian Cancer Trials Group CO.17 and CO.20 randomized phase III trials were included, limited to those in Ontario. The main outcomes were rate of successful probabilistic linkage and concordance of survival data, stated a priori. Results Probabilistic linkage was successful in 266/293 (90.8%) participants. In those patients for whom linkage was successful, the Canadian Cancer Trials Group (trial) and the Institute for Clinical Evaluative Sciences (administrative) data sets were concordant with regard to the occurrence of death during the period of clinical trial follow-up in 206/209 (98.6%). Death was recorded in the Institute for Clinical Evaluative Sciences, but not the Canadian Cancer Trials Group, for 57 cases, where the event occurred after the clinical trial cut-off dates. The recorded date of death matched closely between both databases. During the period of clinical trial conduct, administrative databases contained details of hospitalizations and emergency room visits not captured in the clinical trial electronic database. Conclusion Prospective use of administrative data could enhance clinical trial data collection, both for long-term follow-up and resource utilization for economic analyses and do so less expensively than current primary data collection. Recording a unique identifier (e.g. health insurance number) in trial databases would allow deterministic linkage for all participants.

Background Two germ line Fc‐γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A; His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)], produce altered proteins through amino acid substitutions. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab‐treated chemotherapy‐refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial. Methods After germ line DNA genotyping, polymorphic relationships with survival were assessed using log‐rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis. Results Of 592 wild‐type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28%) had improved OS (HR: 0.66, P

Summary Background Napabucasin is a first-in-class cancer stemness inhibitor that targets STAT3, which is a poor prognostic factor in colorectal cancer. This study aimed to test napabucasin in advanced colorectal cancer. Methods This study was a double-blind randomised phase 3 trial done at 68 centres in Canada, Australia, New Zealand, and Japan. Patients with advanced colorectal cancer with a good Eastern Cooperative Oncology Group (ECOG) performance status (0–1) for whom all available standard therapies had failed were eligible for the study. Patients were randomly assigned (1:1) to receive placebo or napabucasin through a web-based system with a permuted block method, after stratification by ECOG performance status, KRAS status, previous VEGF inhibitor treatment, and time from diagnosis of metastatic disease. Napabucasin 480 mg or matching placebo was taken orally every 12 h. All patients received best supportive care. The primary endpoint was overall survival assessed in an intention-to-treat analysis. This is the final analysis of this trial, which is registered at ClinicalTrials.gov, number NCT01830621. Findings Accrual began on April 15, 2013, and was stopped for futility on May 23, 2014, at which point 282 patients had undergone randomisation (138 assigned to the napabucasin group and 144 to the placebo group). Overall survival did not differ significantly between groups: median overall survival was 4·4 months (95% CI 3·7–4·9) in the napabucasin group and 4·8 months (4·0–5·3) in the placebo group (adjusted hazard ratio [HR] 1·13, 95% CI 0·88–1·46, p=0·34). The safety population included 136 patients in the napabucasin group and 144 patients in the placebo group. More patients who received napabucasin had any grade of treatment-related diarrhoea (108 [79%] of 136 patients), nausea (69 [51%]), and anorexia (52 [38%]) than did patients who received placebo (28 [19%] of 144 patients, 35 [24%], and 23 [16%], respectively). The most common severe (grade 3 or worse) treatment-related adverse events were abdominal pain (five [4%] patients receiving napabucasin vs five [3%] receiving placebo), diarrhoea (21 [15%] vs one [1%]), fatigue (14 [10%] vs eight [6%]), and dehydration (six [4%] vs one [1%]). 251 (89%) patients had data on pSTAT3 expression, of whom 55 (22%) had pSTAT3-positive tumours (29 in the napabucasin group, 26 in the placebo group). In a prespecified biomarker analysis of pSTAT3-positive patients, overall survival was longer in the napabucasin group than in the placebo group (median 5·1 months [95% CI 4·0–7·5] vs 3·0 months [1·7–4·1]; HR 0·41, 0·23–0·73, p=0·0025). Interpretation Although there was no difference in overall survival between groups in the overall unselected population, STAT3 might be an important target for the treatment of colorectal cancer with elevated pSTAT3 expression. Nevertheless, these results require validation. Funding Canadian Cancer Society Research Institute and Boston Biomedical.

BACKGROUND: The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (i.p.) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC). PATIENTS AND METHODS: We carried out a multicenter, two-stage, phase II trial. Eligible patients with stage IIB–IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (

// Bernhard Josef Eigl 1 , Kim Chi 1 , Dongsheng Tu 2 , Sebastien J. Hotte 3 , Eric Winquist 4 , Christopher M. Booth 5 , Christina Canil 6 , Kylea Potvin 4 , Richard Gregg 2 , Scott North 7 , Muhammad Zulfiqar 1 , Susan Ellard 8 , Joseph Dean Ruether 9 , Lyly Le 10 , A. Saranya Kakumanu 11 , Mohammad Salim 12 , Alison L. Allan 4 , Harriet Feilotter 2 , Ashley Theis 2 and Lesley Seymour 2 1 BC Cancer Agency, Vancouver, BC, Canada 2 Canadian Cancer Trials Group, Kingston, ON, Canada 3 Juravinski Cancer Centre, Hamilton, ON, Canada 4 London Health Sciences Centre, London, ON, Canada 5 Cancer Centre of Southeastern Ontario, Kingston, ON, Canada 6 Ottawa Regional Cancer Center, Ottawa, ON, Canada 7 Cross Cancer Centre, Edmonton, AB, Canada 8 BC Cancer Agency, Kelowna, BC, Canada 9 Tom Baker Cancer Centre, Calgary, AB, Canada 10 BC Cancer Agency, Surrey, BC, Canada 11 Cancer Care Manitoba, Winnipeg, MB, Canada 12 Regina Cancer Centre, Regina, SK, Canada Correspondence to: Bernhard Josef Eigl, email: Bernie.eigl@bccancer.bc.ca Keywords: prostate cancer; oncolytic viruses; chemotherapy; clinical trial Received: October 12, 2017 Accepted: January 02, 2018 Published: January 17, 2018 ABSTRACT Background: Pelareorep is an oncolytic virus with activity in many cancers including prostate. It has in vitro synergism with microtubule-targeted agents. We undertook a clinical trial evaluating pelareorep in mCRPC patients receiving docetaxel. Patients and Methods: In this randomized, open-label phase II study, patients received docetaxel 75mg/m 2 on day 1 of a 21-day cycle and prednisone 5mg twice daily, in combination with pelareorep (arm A) or alone (arm B). The primary endpoint was 12 weeks lack of disease progression rate (LPD). Results: Eighty-five pts were randomized. Median age was 69, ECOG performance status was 0/1/2 in 31%/66%/3% of patients. Bone/regional lymph node/liver metastases were present in 98%/24%/6%. The median prognostic score was slightly higher in Arm A (144 vs. 129 p= 0.005). Adverse events were as expected but more prevalent in arm A. The 12-week LPD rate was 61% and 52.4% in arms A/B (p=0.51). Median survival was 19.1 on Arm A and 21.1 months on Arm B (HR 1.83; 95% CI 0.96 to 3.52; p=0.06). No survival benefit of pelareorep was found. Conclusion: Pelareorep with docetaxel was tolerable with comparable LPD in both arms but response and survival were inferior and so this combination does not merit further study.

Pelareorep, a serotype 3 reovirus, has demonstrated preclinical and early clinical activity in breast cancer and synergistic cytotoxic activity with microtubule targeting agents. This multicentre, randomized, phase II trial was undertaken to evaluate the efficacy and safety of adding pelareorep to paclitaxel for patients with metastatic breast cancer (mBC). Following a safety run-in of 7 patients, 74 women with previously treated mBC were randomized either to paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 4 weeks plus pelareorep 3 × 1010 TCID50 intravenously on days 1, 2, 8, 9, 15, and 16 every 4 weeks (Arm A) or to paclitaxel alone (Arm B). Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate, overall survival (OS), circulating tumour cell counts, safety, and exploratory correlative analyses. All comparisons used a two-sided test at an alpha level of 20%. Survival analyses were adjusted for prior paclitaxel. Final analysis was performed after a median follow-up of 29.5 months. Pelareorep was well tolerated. Patients in Arm A had more favourable baseline prognostic variables. Median adjusted PFS (Arm A vs B) was 3.78 mo vs 3.38 mo (HR 1.04, 80% CI 0.76–1.43, P = 0.87). There was no difference in response rate between arms (P = 0.87). Median OS (Arm A vs B) was 17.4 mo vs 10.4 mo (HR 0.65, 80% CI 0.46–0.91, P = 0.1). This first, phase II, randomized study of pelareorep and paclitaxel in previously treated mBC did not show a difference in PFS (the primary endpoint) or RR. However, there was a significantly longer OS for the combination. Further exploration of this regimen in mBC may be of interest.

// Natasha B. Leighl 1, 2, 3 , Ming-Sound Tsao 1, 2, 3 , Geoffrey Liu 1, 2, 3 , Dongsheng Tu 1 , Cheryl Ho 1, 4 , Frances A. Shepherd 1, 2, 3 , Nevin Murray 1, 4 , John R. Goffin 1, 5 , Garth Nicholas 1, 6 , Shingo Sakashita 3 , Zhuo Chen 3 , Lucia Kim 3 , Jean Powers 1 , Lesley Seymour 1 , Glenwood Goss 1, 6 and Penelope A. Bradbury 1, 2 1 Canadian Cancer Trials Group (Formerly NCIC Clinical Trials Group), Kingston ON, Canada 2 Princess Margaret Cancer Centre/University Health Network, Toronto ON, Canada 3 Ontario Cancer Institute, Toronto ON, Canada 4 British Columbia Cancer Agency, Vancouver BC, Canada 5 Juravinski Cancer Centre, Hamilton ON, Canada 6 Ottawa Hospital Cancer Centre, Ottawa ON, Canada Correspondence to: Natasha B. Leighl, email: Natasha.Leighl@uhn.ca Keywords: foretinib, erlotinib, MET, AXL, non-small cell Received: April 19, 2017 Accepted: May 22, 2017 Published: June 28, 2017 ABSTRACT Purpose: MET and AXL mediate resistance to EGFR TKI in NSCLC. Foretinib, a MET/RON/AXL/TIE-2/VEGFR kinase inhibitor may overcome EGFR kinase resistance. This dose escalation study combined foretinib and erlotinib in advanced pretreated NSCLC patients. Experimental Design: The primary endpoint was to define the RP2D of foretinib plus erlotinib as continuous oral daily dosing. Secondary objectives included safety, pharmacokinetics, response and potential biomarkers of response including EGFR, KRAS genotype, MET, AXL expression, and circulating HGF levels. Erlotinib (E100-150 mg) was commenced on day 1 cycle 1; if well tolerated, foretinib (F30-45 mg) was added on day 15 cycle 1, using standard 3+3 dose escalation. Results: Of 31 patients enrolled in 3 dose levels, 6 were inevaluable for DLT and replaced. DLT occurred in 3/15 patients at DL2 (E150 mg, F30 mg): Gr3 pain, mucositis, fatigue and rash. Cycle 1 DLT was not seen at DL3 (E150 mg, F45 mg) but 27% experienced dose reduction/interruption. Adverse events in ≥20% included diarrhea, fatigue, anorexia, dry skin, rash and hypertension. No PK interaction was seen with the combination. RP2D was defined as erlotinib 150 mg daily x 14 days with foretinib 30 mg added on day 15 (continuous dosing in 28-day cycles). Responses were seen in 17.8% of response evaluable patients (5/28). In 18 samples, baseline MET expression uncontrolled for EGFR genotype appeared associated with response. AXL expression was associated with neither EGFR mutation nor response. Conclusion: Combining foretinib and erlotinib demonstrated response in unselected advanced NSCLC but also incremental toxicity. Future development will require molecular patient selection.

High-grade serous carcinoma of uterine adnexa (HGSC) is the most frequent histotype of epithelial ovarian cancer and has a poor 5-year survival rate due to late-stage diagnosis and the poor efficacy of standard treatments. Novel biomarkers of cancer outcome are needed to identify new targetable pathways and improve personalized treatments. Cell-surface screening of 26 HGSC cell lines by high-throughput flow cytometry identified junctional adhesion molecule 1 (JAM-A, also known as F11R) as a potential biomarker. Using a multi-labeled immunofluorescent staining coupled with digital image analysis, protein levels of JAM-A were quantified in tissue microarrays from three HGSC patient cohorts: a discovery cohort (n = 101), the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158), and the Canadian Cancer Trials Group OV16 cohort (n = 267). Low JAM-A level was associated with poorer outcome in the three cohorts by Kaplan–Meier (p = 0.023, p

High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Whether treatment order—primary debulking surgery followed by adjuvant chemotherapy (PDS) or neo-adjuvant chemotherapy with interval surgery (NACT)—affects outcome is controversial. We developed a mathematical framework that holds for hierarchical or stochastic models of tumor initiation and reproduces HGSC clinical course. After estimating parameter values, we infer that most patients harbor chemo-resistant HGSC cells at diagnosis, and that if complete debulking (Significance StatementThe optimal order and timing of surgery and chemotherapy, and the potential benefits of earlier diagnosis of HGSC, remain controversial. We developed a mathematical framework of tumor dynamics to address such issues, populated the model with primary clinical data and reliably recapitulated clinical observations. Our model prospectively predicts that: (1) PDS is superior to NACT when complete debulking is feasible; (2) timely adjuvant chemotherapy is critical for the outcome of PDS with 1mm, residual tumors; (3) earlier detection of relapse is unlikely to be beneficial with current therapies; (4) earlier detection of primary HGSC, followed by complete debulking, could have substantial benefit. Our model provides insights into the evolutionary dynamics of HGSC, argues for new clinical trials to optimize HGSC therapy, and is potentially applicable to other tumor types.

Background Economic evaluations commonly accompany trials of new treatments or interventions; however, regression methods and their corresponding advantages for the analysis of cost-effectiveness data are not widely appreciated. Methods To illustrate regression-based economic evaluation, we review a cost-effectiveness analysis conducted by the Canadian Cancer Trials Group’s Committee on Economic Analysis and implement net benefit regression. Results Net benefit regression offers a simple option for cost-effectiveness analyses of person-level data. By placing economic evaluation in a regression framework, regression-based techniques can facilitate the analysis and provide simple solutions to commonly encountered challenges (e.g., the need to adjust for potential confounders, identify key patient subgroups, and/or summarize “challenging” findings, like when a more effective regimen has the potential to be cost-saving). Conclusions Economic evaluations of patient-level data (e.g., from a clinical trial) can use net benefit regression to facilitate analysis and enhance results.

Economic evaluations are an integral component of many clinical trials. Costs used in those analyses are based on the prices of branded drugs when they first enter the market. The effect of genericization on the cost-effectiveness (ce) or cost&ndash, utility (cu) of an intervention is unknown because economic analyses are rarely updated using the costs of generic drugs. We re-examined the ce or cu of regimens previously evaluated in Canadian Cancer Trials Group (cctg) studies that included prospective economic evaluations and where genericization has occurred or is anticipated in Canada. We incorporated the new costs of generic drugs to characterize changes in ce or cu. We also determined acceptable cost levels of generic drugs that would make regimens reimbursable in a publicly funded health care system. The four randomized controlled trials included (representing 1979 patients) were cctg br.10 (early lung cancer, adjuvant vinorelbine&ndash, cisplatin vs. observation, n = 172), cctg br.21 (metastatic lung cancer, erlotinib vs. placebo, n = 731), cctg co.17 (metastatic colon cancer, cetuximab vs. best supportive care, n = 557), and cctg ly.12 (relapsed or refractory lymphoma, gemcitabine&ndash, dexamethasone&ndash, cisplatin vs. cytarabine&ndash, cisplatin, n = 619). Since the initial publication of those trials, the genericization of vinorelbine, erlotinib, cetuximab, and cisplatin has taken place or is expected in Canada. Costs of generics improved the ces and cus of treatment significantly. For example, genericization of erlotinib ($1460.25 per 30 days) resulted in an incremental cost-effectiveness ratio (icer) of $45,746 per life-year gained compared with $94,638 for branded erlotinib. Likewise, genericization of cetuximab ($275.80 per 100 mg) produced an icer of $261,126 per quality-adjusted life-year (qaly) gained compared with $299,613 for branded cetuximab. Decreases in the cost of generic cetuximab to $129.39 and $63.51 would further improve the icer to $150,000 and $100,000 per QALY respectively. Genericization of a costly oncology drug can modify the ce and cu of a regimen significantly. Failure to revisit economic analyses with the costs of generics could be a missed opportunity for funding bodies to optimize value-based allocation of health care resources. At current levels, the costs of generics might not be sufficiently low to sustain publicly funded health care systems.

Background Resistance to Epidermal Growth Factor inhibition (EGFRi) in patients with KRAS wild-type (wt) Colorectal Cancer (CRC) may occur as a result of PI3K/AKT/mTOR signaling. We conducted a study to establish the recommended phase II dose (RP2D) and response rate of panitumumab, an EGFRi, plus BKM120, a PI3K inhibitor, in advanced CRC. Methods Patients with chemotherapy refractory KRAS wt CRC, who were EGFRi naive were enrolled. A 3 + 3 dose escalation design was utilized. The starting dose of panitumumab was 6 mg/kg iv every 2 weeks with BKM120 at 60 mg oral daily. Results Nineteen patients were treated and 17 were evaluable for response. The starting dose was not tolerable (mucositis, fatigue). At dose level (DL) 1, three of six patients discontinued treatment due to toxicity, DL − 1 had no significant toxicity. Panitumumab 6 mg/kg iv q 2 weeks with BKM120 60 mg given 5 out of 7 days per week was declared the RP2D. One patient (5.9%) who was PTEN and PIK3CA negative by IHC had a partial response, seven had stable disease, and nine had disease progression. Conclusion Panitumumab (6 mg/kg iv q 2 weeks) with BKM120 60 mg given 5 out of 7 days per week was declared the RP2D. Toxicities including fatigue, rash and mucositis. There was little evidence of activity in this biomarker unselected cohort.

Introduction Activation of the RAS/RAF/MEK/ERK pathway may confer resistance to chemotherapy in non-small cell lung cancer (NSCLC). Selumetinib (AZD6244, ARRY142886), a MEK1/2 inhibitor combined with chemotherapy in patients with NSCLC was evaluated in two schedules to evaluate efficacy and toxicity. Methods IND.219 was a three-arm study of first line pemetrexed/platinum chemotherapy with two schedules of selumetinib (Arm A: intermittent given on days 2–19; Arm B: continuous given on days 1–21) versus chemotherapy alone (Arm C). The primary endpoint was objective response rate (ORR); secondary objectives were tolerability, progression-free survival (PFS), overall survival (OS). The trial was stopped at the planned interim analysis. Results Arms A/B/C enrolled 20/21/21 patients, ORR was 35% (95% CI 15–59% median duration 3.8 months), 62% (95% CI 38–82%; median duration 6.3 months), 24% (95% CI 8–47%; median duration 11.6 months) respectively. The PFS (months Arm A, B, C) was 7.5, 6.7, 4.0 respectively (hazard ratio (HR) PFS Arm A over Arm C: 0.76 [95% CI, 0.38–1.51, 2-sided p = 0.42]; Arm B over Arm C 0.75 [95% CI 0.37–1.54, p = 0.43]. Skin and gastrointestinal adverse events were more common with the addition of selumetinib. A high incidence of venous thromboembolism was seen in all arms. Conclusions Selumetinib combined with chemotherapy was associated with a higher response rate. Continuous selumetinib appeared to be superior to an intermittent schedule. PFS was prolonged with the addition of selumetinib, however this was not statistically significant.

Purpose:Monalizumab binds CD94/NKG2A, preventing HLA-E inhibition of tumor lymphocytes. A dose-ranging/cohort expansion trial of monalizumab for recurrent gynecologic malignancies was conducted to determine the recommended phase II dose (RP2D) and to explore clinical activity, pharmacokinetics, pharmacodynamics, safety, and immunogenicity.Patients and Methods:Participants (and part 2 expansion cohorts) included (i) platinum-sensitive ovarian, (ii) platinum-resistant ovarian, (iii) squamous cervical (CX), and (iv) epithelial endometrial (END) carcinomas. Part 1 assessed monalizumab at 1, 4, or 10 mg/kg every 2 weeks. In part 2, ≥4 patients/cohort underwent pre- and on-treatment tumor biopsies. Preset criteria determined cohort expansion.Results:A total of 58 participants were evaluable. The RP2D was 10 mg/kg i.v. every 2 weeks. Dose proportionality and 100% NKG2A saturation were observed. Related adverse events were mild: headache, abdominal pain, fatigue, nausea, and vomiting. Grade 3 related adverse events were nausea (1), vomiting (1), dehydration (1), fatigue (2), anorexia (1), dyspnea (1), and proctitis (1). Dose-limiting toxicities were not observed. Hematologic and biochemical changes were mild and not dose related. Best response was SD: part 1, 7 of 18 (39%) [3.4 months (1.4–5.5)], and part 2, 7 of 39 (18%) [1.7 months (CX) to 14.8 months (END)]. Neither a predictive biomarker for SD nor evidence of pharmacodynamic effects was identified. There was a trend to significance between a reduction in lymphocyte HLA-E total score and pharmacodynamics.Conclusions:Monalizumab 10 mg/kg i.v. every 2 week is well tolerated in patients with pretreated gynecologic cancers. Short-term disease stabilization was observed. Future studies should assess combinations with other agents, including immunotherapeutics.

Background Adrenergic receptor stimulation is involved in the development of hypertension (htn) and has been implicated in cancer progression and dissemination of metastases in various tumours, including colon cancer. Adrenergic antagonists such as beta-blockers (bbs) demonstrate inhibition of invasion and migration in colon cancer cell lines and have been associated with decreased mortality in colorectal cancer (crc). We examined the association of baseline htn and bb use with overall (os) and progression-free survival (pfs) in patients with pretreated, chemotherapy refractory, metastatic crc (mcrc). We also examined baseline htn as a predictor of cetuximab efficacy. Methods Using data from the Canadian Cancer Trials Group co.17 study [cetuximab vs. best supportive care (bsc)], we coded baseline htn and use of anti-htn medications, including bbs, for 572 patients. The chi-square test was used to assess the associations between those variables and baseline characteristics. Cox regression models were used for univariate and multivariate analyses of os and pfs by htn diagnosis and bb use. Results Baseline htn, bb use, and anti-htn medication use were not found to be prognostic for improved os. Baseline htn and bb use were not significant predictors of cetuximab benefit. Conclusions In chemorefractory mcrc, neither baseline htn nor bb use is a significant prognostic factor. Baseline htn and bb use are not predictive of cetuximab benefit. Further investigation to determine whether baseline htn or bb use have a similarly insignificant impact on prognosis in patients receiving earlier lines of treatment remains warranted.

3508 Background: CO.28 (NCT03259035) is a phase II study designed to determine if patients with cT1-T3a/bN0 rectal cancer can be treated with induction chemotherapy (FOLFOX/CAPOX) and organ-preserving surgery. Methods: Patients with MRI staged cT1-3a/bN0 tumors and no pathologic (p) high risk features received 6/4 cycles of FOLFOX/CAPOX, repeat sigmoidoscopy/pelvic MRI and subsequent Transanal Endoscopic Surgery (TES) in the absence of tumor progression. ypT0/T1N0 tumors were treated with observation while ypT2+ or ypN+ stage were recommended Total Mesorectal Excision (TME). The primary endpoint was protocol specified Organ Preservation Rate (psOPR = ypT0/T1N0, no p high risk features) and actual Organ Preservation Rate (aOPR = ypT0/T1N0 stage plus higher yp stage patients who declined TME surgery). The study would be considered negative with an psOPR of 50% or lower (H0) and as promising if it is 65% or higher (H1). Results: Between 08/2017 to 05/2020, 58 eligible patients were accrued in Canada and the United States, median age was 67 years, 71% male. All had well-moderately differentiated, non-mucinous rectal adenocarcinoma and median tumor height was 6 cm (range 0-18). Median follow-up was 15.4 months. Chemotherapy with FOLFOX (32) or CAPOX (26) was administered, 90% completed all planned cycles. A total of 56/58 (97%) proceeded to TES, while one patient was ineligible due to tumor progression (1.7%) and one declined. In the intention to treat analysis, the psOPR was 57% (95% CI 43-70%) while the aOPR was 79% (95% CI 67% to 89%) due to 13/23 declining recommended TME surgery. Of 10 patients who proceeded to recommended TME, a complete R0 TME was performed in 9/10, and no p residual carcinoma was found in 7/10. Crude loco-regional (LR) and distant recurrence rates were 3.5% (95% CI 0.4 to 12%) and 0%, respectively. A recurrence occurred in 1/13 patients who initially declined TME surgery. Conclusions: In select patients with early stage rectal cancer, three months of induction CAPOX/FOLFOX followed by TES resulted in a high OPR without the use of pelvic irradiation. The observed high rate of pathologic downstaging may point to high chemo-responsiveness in early rectal adenocarcinoma with no p high risk features. Further trials to evaluate this approach are justified and updated results will be presented. Clinical trial information: NCT03259035. [Table: see text]

e15581 Background: The randomized phase II CCTG CO.26 clinical trial investigated the use of combined durvalumab and tremelimumab vs. best supportive care (BSC) for patients with mCRC and suggested an increase in overall survival (OS). The largest benefit was seen in patients who were microsatellite stable (MSS) with a pTMB ≥ 28 variants per megabase. Considering significantly higher adverse event rates and costs associated with durvalumab and tremelimumab, it is important to evaluate its cost-effectiveness. Accordingly, we performed a cost-utility analysis of durvalumab and tremelimumab compared to BSC in the intention-to-treat (ITT) and biomarker-enriched populations using CO.26 trial data. Methods: We developed a 4-state microsimulation model to evaluate the expected health outcomes in life-years (LYs), quality-adjusted life-years (QALYs) and costs of the treatment group compared to BSC over a lifetime horizon (5 years). The incremental cost-utility ratio (ICUR) was used to compare treatment strategies. Direct trial data from CO.26 were used to inform model inputs, including OS curves, progression-free survival (PFS) curves, and adverse event rates. As health state utilities were not collected in CO.26, values from the CORRECT trial, a multi-centre randomized placebo-controlled phase III study for regorafenib in mCRC, were used. Costs of therapy, hospitalization due to adverse events, end-of-life care, and physician costs were derived from the literature and publicly available sources (in 2020 Canadian dollars). Since the monthly price of tremelimumab was unavailable, it was approximated with the price of another CTLA-4 inhibitor, ipilimumab. The base-case analysis evaluated these treatment strategies in the ITT population. Scenario analyses evaluated the cost-effectiveness in biomarker-enriched populations. Costs and effects were discounted at 1.5% as per Canadian guidelines. Results: In the base-case, expected LYs for combined durvalumab and tremelimumab and BSC were 0.75 and 0.51 (incremental (Δ) 0.24) respectively. Expected QALYs were 0.47 and 0.33 (Δ 0.14). Expected lifetime costs were $60 500 and $15 500 (Δ $45 000) for an ICUR of $320 000/QALY. In the biomarker-enriched subgroup, the expected LYs were 0.67 and 0.33 (Δ 0.34), expected QALYs were 0.43 and 0.22 (Δ 0.21), and expected lifetime costs were $62 000 and $15 200 (Δ $47 000). This represents an increase in the incremental QALYs by 50% and costs by 5% for an ICUR 30% lower than the base case at $220 000/QALY. Conclusions: Combined durvalumab and tremelimumab is not considered cost-effective in refractory mCRC under conventional willingness-to-pay thresholds. Cost-effectiveness is improved with biomarker enrichment for high pTMB, driven by the greater derived health outcomes in this subgroup.

4135 Background: PA.7 evaluated whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases efficacy. A previous analysis of the PA.7 data demonstrated high plasma based TMB (≥9 mut/Mb) was associated with improved OS in the Gem, Nab-P, D+T arm. DNA repair pathway aberrations beyond mismatch repair have been associated with potential immune sensitivity. We assessed the predictive value of germline ATM mutations in the PA.7 trial. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs. GEM and Nab-P (arm B) in patients (pts) with mPDAC (n = 180). The primary endpoint was overall survival (OS). Pre-treatment plasma was sequenced with the Predicine ATLAS next generation assay (600 gene, 2.4 Mb panel). 2-sided alpha set at 0.1. Results: 180 pts were randomized (119 to arm A and 61 to arm B) There was no significant difference in OS (9.8 months in arm A vs. 8.8 months in arm B, p-value 0.72) or PFS (5.5 months and 5.4 months respectively, HR 0.98, p-value 0.91). Plasma analysis was performed on 174/180 pts with available samples. 16/174 (9.2%) pts had germline ATM mutations, 12 in arm A and 4 in arm B. GEM, Nab-P, D+T was associated with improved OS in patients with ATM mutations (HR 0.10, 90% CI 0.03-0.37; median OS 13.9 months vs. 4.9 months) while no activity was seen in pts with ATM Wild Type (HR 0.99, 90% CI 0.73-1.33; median OS 9.79 months vs. 10.2 months); interaction p = 0.014. Germline ATM mutation status was independent of plasma TMB levels (Wilcoxon p = 0.76). Conclusions: Germline ATM mutation appeared predictive of benefit from the addition of dual immune checkpoint inhibitors (D and T) to Gem and Nab-P, with a significant interaction p-value. In addition to previous data from this trial regarding the predictive value of high plasma TMB (≥9 mut/Mb), this data further supports that there may be independent subgroups of PDAC, beyond MSI-H, that may benefit from immunotherapy, and trials evaluating immunotherapy in subgroups of PDAC with these profiles are warranted. Clinical trial information: NCT02879318.

411 Background: PA.7 evaluated whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases efficacy as first line therapy in mPDAC. High TMB is associated with immunotherapy sensitivity, with a threshold of ≥10 mut/Mb receiving FDA accelerated approved for pembrolizumab in a tissue agnostic setting. We assessed the predictive value of plasma TMB in the PA.7 trial. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs. GEM and Nab-P (arm B) in patients (pts) with mPDAC (n = 180). The primary endpoint was overall survival (OS). Pre-treatment plasma was sequenced with the CLIA-certified PredicineATLAS cfDNA next generation assay (600 genes, 2.4 Mb panel). A pre-specified cut point of 5 mut/MB was selected based on distribution of TMB in the trial. 2-sided alpha set at 0.1. Results: 180 pts were randomized (119 to arm A and 61 to arm B). There was no significant difference in OS (9.8 months in arm A vs. 8.8 months in arm B, p-value 0.72) or PFS (5.5 months and 5.4 months respectively, HR 0.98, p-value 0.91). Plasma TMB analysis was performed on 174/180 pts with available samples, and tumor derived variants were detected in 173/174 pts (99.4%). 172 pts were microsatellite stable and 1 pt was microsatellite high (MSI-H) (plasma TMB 52.9 muts/Mb). Using the pre-specified cut-point of 5 mut/Mb there was no significant predictive value from plasma TMB (interaction p = 0.91). Using a minimum p-value approach, a cut-point of 9 mut/MB appeared predictive (p-interaction = 0.064; significant at pre-specified p = 0.1). 8/174 (4.6%) pts had a plasma TMB ≥9 mut/Mb (5/115 (4.4%) in arm A and 3/59 (5%) in arm B). GEM, Nab-P, D+T was associated with improved OS in patients with plasma TMB ≥9 mut/Mb (HR 0.30, 90% CI 0.06-1.37) while no activity was seen in pts with < 9 mut/Mb, (HR 0.97, 90% CI 0.73-1.29). TMB cut-point analysis revealed a clear trend for a decreasing HR favoring the GEM, Nab-P, D and T arm above the selected cut point, with no benefit in the low TMB group. Conclusions: Plasma TMB analysis was successful in over 99% of pts with available samples. Plasma TMB ≥9 mut/Mb was predictive of benefit from the addition of dual immune checkpoint inhibitors (D and T) to Gem and Nab-P, with a significant interaction p-value. While only present in a subgroup of pts (4.6%), this data defines a group beyond MSI-H PDAC that may benefit from immunotherapy. The optimal cut-point for high TMB in this setting requires validation. A clinical trial specifically assessing the role of chemotherapy combined with immune checkpoint inhibition in high TMB mPDAC is warranted. Clinical trial information: NCT02879318.

61 Background: Pembrolizumab was recently granted tissue agnostic FDA accelerated approval for metastatic cancers with TMB≥10 mut/Mb. However, limited data supports immunotherapy in microsatellite stable (MSS) mCRC with TMB≥10 mut/Mb. We assessed tissue TMB and contrasted it to plasma derived TMB in the CO.26 trial. Methods: CO.26 was a phase 2 trial (2-sided ⍺ = 0.1 and 80% power) that randomized 180 patients (pts) 2:1 to D+T or BSC in refractory mCRC. Pre-treatment plasma was sequenced with the GuardantOMNI assay and archival tissue underwent exome sequencing with TMB assessed per the TMB harmonization project. MSI-H cases were excluded. For plasma TMB, we used a previously published cut point (≥28). Results: Overall survival (OS) but not progression free survival (PFS) was improved with D+T in the entire population. Of 180 pts, 163 were evaluable for plasma and 110 for tissue TMB. Median time between archival tissue and plasma collection was 3.1 yrs (IQR 1.9-5.1). Median tissue TMB was 6.6 muts/Mb (IQR 4.1-12.0), while median plasma TMB was 16.3 muts/Mb (IQR 9.4-25.9). Tissue and plasma TMB (r = -0.039, P = 0.69) were not correlated. Tissue TMB≥10 was not prognostic in the BSC arm (HR 1.01, 90%CI 0.52-1.92, P = 0.99) and OS was not improved in pts with tissue TMB≥10 (32/110 pts) following D+T vs BSC. A test of interaction suggested this threshold was not predictive (P = 0.85). Using a minimum P-value approach, no threshold supported high tissue TMB as predictive in MSS mCRC. In fact, the optimal cut point suggested low tissue TMB ( < 4.1 muts/Mb) had the greatest benefit from D+T (P-interaction = 0.048) and pts with TMB ≥4.1 mut/Mb (HR 0.50, 90%CI 0.26-0.96, P = 0.083) trended to better OS in the BSC arm. In contrast, 35/163 pts (21%) were identified in a high plasma TMB group associated with worse OS (HR 2.56, 90%CI 1.45-4.54, P = 0.007) in the BSC arm but improved OS following D+T compared to BSC with P-interaction = 0.082. Only 1 response was noted following D+T in a pt with tissue TMB = 16 mut/Mb and plasma TMB = 13 mut/Mb. Conclusions: Archival tissue TMB≥10 mut/Mb does not appear predictive of D+T benefit in MSS mCRC. Plasma derived TMB may better reflect evolutionary changes following intervening therapy than archival tissue. Clinical trial information: NCT02870920. [Table: see text]

117 Background: Previous studies have identified MAPK and PIK3CA/AKT/mTOR pathways as common mechanisms of acquired resistance to anti-EGFR antibodies (EGFRab) in mCRC. However, such alterations do not account for all patients that become treatment resistant. Using paired whole-exome (WES; tissue) and circulating tumor DNA (ctDNA; plasma) sequencing, we performed characterization of the EGFRab resistance landscape in patients with mCRC. Methods: Post-treatment (ctDNA; plasma) sequencing was performed for 169 patients with mCRC, with 112 (66%) patients also receiving pre-treatment (WES; primary tumor) sequencing as part of the CO.26 trial. 66 (39%) patients received EGFRab previously at a median of 132.0 days prior to plasma sampling. Using bespoke bioinformatics pipelines (WES) coupled with the GuardantOMNI assay (plasma), we compared somatic mutation (SNV/indel, CNV and fusion) frequencies between pre- and post-EGFRab timepoints, and contrasted results between the two groups. Results: Significant increases in de novo acquisition of EGFR (p = 5.6e-4), KRAS (p = 0.011), ZNF217 (p = 0.0022), MAP2K1 (p = 0.0078) and LRP1B (p = 0.017) SNV/indels were unique to the EGFRab group and often occurred as multiple, low allele frequency events in the same patient. De novo copy number amplification of known resistance genes EGFR/ BRAF/ MET were observed in EGFRab-treated patients (p < 0.05), along with SMO (p = 6.8e-7), PTEN inhibitory gene PREX2 (p = 5.6e-4), FLT3 (p = 2.0e-5), NOTCH4 (p = 6.3e-5), ERBB2 (7.4e-4), KMT2A (p = 3.7e-4) and ARID1B (p = 0.0014). Genes impacted by fusion events in EGFRab-treated patients included BRAF-KIAA1549 (1 patient) and MET-CAV1 (1 patient), and these events were not detected in matched pre-treatment samples. EGFRab-treated patients were found to acquire a combination of multiple (≥5) mutation events (SNV/indel, CNV or fusion) at much higher frequency compared to non-EGFRab-treated patients (67% versus 25% of patients, p = 8.7e-8). Tumor mutation burden (TMB) was not significantly different (p = 0.71) between treatment groups prior to therapy initiation, while post-treatment TMB was significantly higher (p = 1.8e-7) in EGFRab-treated patients (median 25.4 versus 13.1 mut/mb). Conclusions: In addition to previously established resistance pathways, we identified acquired alterations in additional genes such as SMO, PREX2 and epigenetic modifiers KMT2A/ARID1B in EGFRab-treated patients . Moreover, we highlight the phenomenon by which EGFRab-treated tumors acquire multiple concurrent resistance mutations and heightened TMB. Our analysis provides novel insight into the landscape of resistance mechanisms to EGFRab in mCRC while highlighting the potential role for immunotherapy post-EGFRab. Clinical trial information: NCT02870920.

Canadian Cancer Society Research Institute [021039, 015469]; National Cancer Institute [CA180888, CA189953, CA180828, CA13612, CA37981, CA077202, CA180863, CA67753, CA189805, CA16116, CA180802]; Canadian Cancer Trials Group [CA077202, CA180863]; ECOG-ACRIN Cancer Research Group [CA180820, CA21115]; Novartis Pharmaceuticals; Avon Foundation; AstraZeneca; Pfizer; Roche; Amgen; Novartis; Glaxo-SmithKline; Eisai; Genomic Health; NanoString; Genentech; BioMarin

Purpose New onset symptoms on adjuvant aromatase inhibitors for hormone receptor positive early breast cancer may associate with clinical outcomes. We performed this exploratory analysis of the association of new onset musculoskeletal (MSK) and vasomotor (VM) symptoms with clinical outcomes in the NCIC CTG MA.17 trial 5 years of extended adjuvant endocrine therapy with letrozole after tamoxifen. Methods Symptoms were collected at baseline, 1, 6, and every 12 months on study. Multivariate Cox Models adjusting for age, nodal status, duration of tamoxifen and prior chemotherapy were used to compare disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) based on data collected before, and after, the unblinding between women with VM or MSK symptoms and those without. Results Data post-unblinding showed new VM symptoms on extended letrozole significantly improved DFS and DDFS when occurring 1 month (DFS HR 0.52, 95% CI, 0.28–0.96; p = 0.04; DDFS HR 0.49, 95% CI, 0.24–0.99; p = 0.046) and 6 months (DFS HR 0.43, 95% CI, 0.24–0.78; p = 0.006; DDFS HR 0.44, 95% CI, 0.22–0.85; p = 0.02) after treatment initiation. Those with new VM symptoms at 12 months also had a significantly better DFS (HR 0.47, 95% CI 0.26, 0.84; P = 0.01) and a trend in improved DDFS. Only a trend to improved OS was found for those with VM symptoms 6 month after treatment. No significant improvement was found for those with new MSK symptoms at any time point or for any endpoint. Conclusions New onset VM symptoms with extended letrozole may be useful in predicting treatment benefit.

Background: There is strong interest in testing lifestyle interventions to improve cancer outcomes; however, the optimal methods for achieving behavior change in large-scale pragmatic trials are unknown. Here, we report the 1-year feasibility results for exercise behavior change in the Canadian Cancer Trials Group CO.21 (CHALLENGE) Trial. Methods: Between 2009 and 2014, 273 high-risk stage II and III colon cancer survivors from 42 centers in Canada and Australia were randomized to a structured exercise program (SEP; n = 136) or health education materials (HEM; n = 137). The primary feasibility outcome in a prespecified interim analysis was a difference between randomized groups of ≥5 metabolic equivalent task (MET)-hours/week in self-reported recreational physical activity (PA) after at least 250 participants reached the 1-year follow-up. Secondary outcomes included health-related fitness. Results: The SEP group reported an increase in recreational PA of 15.6 MET-hours/week compared with 5.1 MET-hours/week in the HEM group [mean difference = +10.5; 95% confidence interval (CI) = +3.1–+17.9; P = 0.002]. The SEP group also improved relative to the HEM group in predicted VO2max (P = 0.068), 6-minute walk (P < 0.001), 30-second chair stand (P < 0.001), 8-foot up-and-go (P = 0.004), and sit-and-reach (P = 0.08). Conclusions: The behavior change intervention in the CHALLENGE Trial produced a substantial increase in self-reported recreational PA that met the feasibility criterion for trial continuation, resulted in objective fitness improvements, and is consistent with the amount of PA associated with improved colon cancer outcomes in observational studies. Impact: The CHALLENGE Trial is poised to determine the causal effects of PA on colon cancer outcomes. Cancer Epidemiol Biomarkers Prev; 25(6); 969–77. ©2016 AACR.

Background Women with breast cancer and diabetes mellitus (DM) have poorer survival. Mechanisms include insulin dysregulation and/or DM related co-morbidities (CM). In MA.17 adjuvant letrozole (LET) after 5 years of tamoxifen (TAM) reduced the risk of recurrence and improved survival. We evaluated DM, hypertension (HTN), and coronary artery disease (CAD) as prognostic and predictive factors in MA.17. Patients and methods Disease free survival, distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: in women treated by placebo (PLAC) based on the presence or absence of baseline DM (n = 462), HTN (n = 1627), CAD (n = 604) or any one of these CM (n = 2049), and between LET and PLAC groups in each CM. Analyses based on nodal status were performed. Results DM was neither prognostic nor predictive for women on extended LET. Women with one CM had similar outcomes on LET compared to women free of CM. For node positive women, the difference between LET and PLAC in DDFS was greater among women with one CM (hazard ratio [HR] = 0.30 [0.15–0.60], p = 0.001) compared to those without CM (HR = 0.72 [0.45–1.16], p = 0.17, p interaction = 0.04). Women on PLAC with HTN trended towards lower DDFS (HR = 1.50 [0.98–2.3], p = 0.06) and OS (HR = 1.61 [0.95–2.72], p = 0.08) than non-HTN women. HTN women had better DDFS on LET than non-HTN women. Women with one CM on PLAC had lower OS (HR = 2.10 [1.26–3.51], p = 0.004) than those free of CM. Conclusions DM was not prognostic or predictive of outcomes. Women with CM who remain disease free after 5 years of TAM should be offered LET. HTN trended towards a negative prognosticator and outcomes among this group were improved on LET. More studies are needed to assess impact of adrenergic stimulation as a possible link to poorer breast cancer outcomes.