Real-World Safety and Effectiveness of a Bevacizumab Biosimilar (ABP 215) in Metastatic Colorectal Cancer Patients in Canada.

BACKGROUND: ABP 215 is a biosimilar to the reference product, bevacizumab, and was one of the first biosimilars approved by Health Canada for the first-line treatment of metastatic colorectal cancer (mCRC). This study aimed to address gaps in real-world evidence (RWE) including patient characteristics, treatment safety (primary objective), and effectiveness (secondary objective) for first-line ABP 215 therapy in Canadian patients with mCRC. MATERIALS AND METHODS: Retrospective data were collected in 2 waves, at least 1 year (Wave 1) or 2 years (Wave 2) after commercial availability of ABP 215 at each participating site. RESULTS: A total of 75 patients from Wave 1 and 164 patients from Wave 2 treated with a minimum of 1 cycle of ABP 215 were included. At least one safety event of interest (EOI) was recorded for 34.7% of Wave 1 and 42.7% of Wave 2 patients. The median progression free survival (PFS) for Wave 1 and 2 patients were 9.47 (95% confidence interval [CI]: 6.71, 11.90) and 21.38 (95% CI: 15.82, not estimable) months, respectively. Median overall survival was not estimable for Wave 1 and was 26.45 months for Wave 2. CONCLUSION: The safety and effectiveness of ABP 215 observed in this real-world study were comparable to clinical trial findings and to other RWE with longer PFS in the current study.

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). Objective: To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. Design, Setting, and Participants: In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Intervention: Durvalumab plus tremelimumab or best supportive care. Main Outcomes and Measures: Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Results: Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. Conclusions and Relevance: In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

Clinical consensus statement: Establishing the roles of locoregional and systemic therapies for the treatment of intermediate-stage hepatocellular carcinoma in Canada.

BACKGROUND: Hepatocellular carcinoma (HCC) a leading cause of cancer mortality worldwide and approximately one-third of patients present with intermediate-stage disease. The treatment landscape of intermediate-stage HCC is rapidly evolving due to developments in local, locoregional and systemic therapies. Treatment recommendations focused on this heterogenous disease stage and that take into account the Canadian reality are lacking. To address this gap, a pan-Canadian group of experts in hepatology, transplant, surgery, radiation therapy, nuclear medicine, interventional radiology, and medical oncology came together to develop consensus recommendations on management of intermediate-stage HCC relevant to the Canadian context. METHODS: A modified Delphi framework was used to develop consensus statements with strengths of recommendation and supporting levels of evidence graded using the AHA/ACC classification system. Tentative consensus statements were drafted based on a systematic search and expert input in a series of iterative feedback cycles and were then circulated via online survey to assess the level of agreement. RESULTS & CONCLUSION: The pre-defined ratification threshold of 80 % agreement was reached for all statements in the areas of multidisciplinary treatment (n = 4), intra-arterial therapy (n = 14), biologics (n = 5), radiation therapy (n = 3), surgical resection and transplantation (n = 7), and percutaneous ablative therapy (n = 4). These generally reflected an expansion in treatment options due to developments in previously established or emergent techniques, introduction of new and more active therapies and increased therapeutic flexibility. These developments have allowed for greater treatment tailoring and personalization as well as a paradigm shift toward strategies with curative intent in a wider range of disease settings.

Top 10 research priorities for early-stage colorectal cancer: a Canadian patient-oriented priority-setting partnership.

BACKGROUND: Colorectal cancer, one of the most commonly diagnosed cancers, is now being detected earlier and treatments are improving, which means that patients are living longer. Partnering with Canadian clinicians, patients and researchers, we aimed to determine research priorities for those living with early-stage colorectal cancer in Canada. METHODS: We followed the well-established priority-setting partnership outlined by the James Lind Alliance to identify and prioritize unanswered questions about early-stage (i.e., stages I-III) colorectal cancer. The study was conducted from September 2018 to September 2020. We surveyed patients, caregivers and clinicians from across Canada between June 2019 and December 2019. We categorized the responses using thematic analysis to generate a list of unique questions. We conducted an interim prioritization survey from April 2020 to July 2020, with patients, caregivers and clinicians, to determine a shorter list of questions, which was then reviewed at a final meeting (involving patients, caregivers and clinicians) in September 2020. At that meeting, we used a consensus-based process to determine the top 10 priorities. RESULTS: For the initial survey, 370 responses were submitted by 185 individuals; of the 98 individuals who provided demographic information, 44 (45%) were patients, 16 (16%) were caregivers, 7 (7%) were members of an advocacy group, 26 (27%) were health care professionals and 5 (5%) were categorized as "other." The responses were refined to create a list of 66 unique unanswered questions. Twenty-five respondents answered the interim prioritization survey: 13 patients (52%), 2 caregivers (8%), 3 advocacy group members (12%) and 7 health care professionals (28%). This led to a list of the top 30 questions. The final consensus meeting involved 20 individuals (10 patients [50%], 3 caregivers [15%] and 7 health care professionals [35%]), who agreed to the top 10 research priorities. The priorities covered a range of topics, including screening, treatment, recurrence, management of adverse effects and decision-making. INTERPRETATION: We determined the top research priorities for early-stage colorectal cancer using a collaborative partnership of stake-holders from across Canada. The priorities covered a broad range of topics that could be addressed by future research, including improved screening practices, the role of personalized medicine, the management of adverse effects of treatment, decision-making and prevention of recurrence.

Evaluating the impact of universal Lynch syndrome screening in a publicly funded healthcare system.

PURPOSE: Referrals for Lynch syndrome (LS) assessment have traditionally been based on personal and family medical history. The introduction of universal screening practices has allowed for referrals based on immunohistochemistry tests for mismatch repair (MMR) protein expression. This study aims to characterize the effect of universal screening in a publicly funded healthcare system with comparison to patients referred by traditional criteria, from January 2012 to March 2017. METHODS: Patient files from the time of initiation of universal screening from 2012 to 2017 were reviewed. Patients were sorted into two groups: (a) universally screened and (b) referred by traditional methods. Mutation detection rates, analysis of traditional testing criteria met, and cascade carrier testing were evaluated. RESULTS: The mutation detection rate of the universal screening group was higher than the traditionally referred group (45/228 (19.7%) vs 50/390 (12.5%), P = .05), though each were able to identify unique patients. An analysis of testing criteria met by each patient showed that half of referred patients from the universal screening group could not meet any traditional testing criteria. CONCLUSION: The implementation of universal screening in a publicly funded system will increase efficiency in detecting patients with LS. The resources available for genetic testing and counseling may be more limited in public systems, thus inclusion of secondary screening with BRAF and MLH1 promoter hypermethylation testing is key to further optimizing efficiency.

Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study.

Importance: Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H). Objective: To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC. Design, Setting, and Participants: A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease. Interventions: We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio. Main Outcomes and Measures: The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB). Results: Of 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004). Conclusions and Relevance: This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02870920.

A predictive analysis of the SP120 and 10D7G2 antibodies for human equilibrative nucleoside transporter 1 (hENT1) in pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine.

Expression of human equilibrative nucleoside transporter 1 (hENT1) in pancreatic ductal adenocarcinoma (PDAC) has been postulated to be a marker of sensitivity to gemcitabine. However, heterogeneity in the studies attempting to quantify hENT1 expression in patients with PDAC treated with gemcitabine has yielded inconclusive results that impede the adoption of hENT1 expression as a predictive biomarker. Tissue microarrays consisting of PDAC specimens from 227 patients acquired between 1987 and 2013 annotated with treatment and outcome information were subjected to staining with two antibodies for hENT1 (10D7G2 and SP120) on a single automated platform and scored by two independent pathologists blinded to treatment and outcome. The resultant scores were subjected to individual predictive disease-specific survival analysis and to unsupervised hierarchical clustering to generate a multi-marker classification. Tumour cell staining prevalence using either SP120 or 10D7G2 was predictive of gemcitabine sensitivity (p = 0.02; p = 0.01). When combined, three groups emerged, classified as SP120Low_10D7G2Low, SP120Low_10D7G2High, and SP120High_10D7G2High, in which adjuvant gemcitabine conferred median survival differences of 0.2, 0.8, and 1.5 (p = 0.76, p = 0.06, p = 0.01) years, respectively. These results were largely replicated in multivariable analysis with the P value for the SP120Low_10D7G2High cluster achieving statistical significance (p = 0.03). These data suggest that either antibody for hENT1 can be used to predict gemcitabine sensitivity in resected PDAC. However, using both antibodies adds valuable information that enables the stratification of patients who can expect to have a good, intermediate, and poor response to adjuvant gemcitabine.