Canadian Cancer Trials Group Research Articles

467 (PB455): IND.241: A Canadian Cancer Trials Group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER +/HER2- metastatic breast cancer

467 (PB455): IND.241: A Canadian Cancer Trials Group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER +/HER2- metastatic breast cancer

A Phase II Study of Neoadjuvant Opnurasib KRAS G12C Inhibitor in Patients With Surgically Resectable Non-Small Cell Lung Cancer (CCTG IND.242A): A Substudy of the IND.242 Platform Master Protocol

Molecularly targeted agents are increasingly being studied in the treatment of early-stage non-small cell lung cancer (NSCLC) to try and improve cure. However, phase 3 data on neoadjuvant therapy have largely been conducted in a biomarker agnostic manner with inconsistent exclusion of EGFR and ALK alterations. Our objective was to develop IND.242 as a large-scale neoadjuvant platform trial to introduce novel agents into the preoperative window for molecularly-defined NSCLC patient populations. Given that KRAS G12C mutations are common in the overall NSCLC patient population, ranging from 9.4% to 13% of cases across different cohorts, and may be associated to worse prognosis, the initial IND.242A Substudy was designed to test neoadjuvant JDQ443 (opnurasib), a selective KRAS G12C inhibitor. This current trial report describes the multicenter, Canadian Cancer Trials Group (CCTG)-led IND.242 neoadjuvant phase 2 platform master protocol and its first Substudy (IND.242A) of neoadjuvant opnurasib KRAS G12C inhibitor for patients with surgically resectable NSCLC (AJCC 8th edition stage IA2 to IIIA). In IND.242A, a maximum of 27 patients will be accrued in participating Canadian sites. The primary objective is the rate of major pathological response (MPR) following neoadjuvant opnurasib. Secondary objectives include safety and tolerability of the treatment regimen, objective response rate (ORR) by RECIST 1.1 for the neoadjuvant treatment period, pathological complete response (pCR) rate, event-free survival (EFS) at 2 years, and surgical outcomes. Exploratory objectives are to explore patient related outcomes (PROs) and identify potential predictive biomarkers of response and mechanisms of resistance on tissue and peripheral blood samples.

Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.

ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.

Kinetic Profiling of RAS Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of RAS Mutations in Neo-RAS-Wildtype Metastatic Colorectal Cancer Is Transient.

In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable. CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression. Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00). We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.

Rolling the DICEP on lymphoma salvage treatments? Choose wisely.

Although immunotherapy is rapidly changing the treatment approach to r/r diffuse large B cell lymphoma, there is still a place for autologous stem cell transplantation in some patients. The report by Stewart etal. focuses on induction therapy and the importance of the pretransplantation phase. Commentary on: Stewart etal. Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-Outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19555.

Impact of concurrent antibiotics on survival with immunotherapy in metastatic colorectal and pancreatic cancer.

2609 Background: The interplay between antibiotics and the microbiome has been hypothesized to modify the immune response to cancer and may negatively affect immune checkpoint inhibitor (ICI) efficacy. Methods: We retrospectively reviewed concurrent antibiotics received in the randomized phase II Canadian Cancer Trials Group (CCTG) CO.26 and PA.7 clinical trials. CO.26 evaluated dual programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition (with durvalumab and tremelimumab) versus best supportive care only (BSC) in metastatic refractory colorectal cancer (CRC). PA.7 evaluated gemcitabine and nab-paclitaxel +/- durvalumab and tremelimumab in metastatic pancreatic ductal adenocarcinoma. In CO.26, T cell receptor sequencing (TCR-seq) was available at baseline and week 8. Results: In CO.26 (n=180), median (range) age was 65 (36-87) years, 33% (n=59) were female, and 29% (n=50) were ECOG 0. Concurrent exposure to antibiotics was associated with improved overall survival (OS) (7.4 vs 6.2 months, adjusted hazard ratio (aHR) 0.66 (95% confidence interval (CI) 0.46-0.93), p=0.018) in patients with metastatic CRC who received ICIs, but not in patients who received BSC (3.5 vs 4.5 months, HR 1.49 (95% CI 0.81-2.73), p= 0.20); (p-interaction=0.094). In antibiotic class analysis, concurrent exposure of ICIs to fluoroquinolones (9.4 vs 6.2 months, aHR 0.50 (95% CI 0.30-0.82), p=0.0067), but not penicillins or cephalosporins, was associated with improved OS. There was no difference in RAS/RAF status or tumor mutation burden in patients who received antibiotics/fluoroquinolones or not. The results were consistent when also controlling for TMB (antibiotics aHR 0.63 (0.44, 0.91), p=0.013; fluoroquinolones aHR 0.51 (0.31, 0.84), p=0.009). Patients treated with antibiotics did not have a different TCR diversity or clonality between baseline and 8 weeks (p=0.37 and p=0.47) compared to those who did not receive antibiotics (p=0.26 and p=0.60). In PA.7 (n=180), median (range) age was 65 (29-84) years, 48% (n=87) were female, and 24% (n=44) were ECOG 0. Antibiotics were not associated with OS in patients who did/did not receive ICIs (9.7 vs 10.8 months, HR 0.97 (95% CI 0.64, 1.46), p=0.87; 7.4 vs 10.3 months HR 1.22 (95% CI 0.72, 2.09), p=0.46, respectively). Fluoroquinolones were also not associated with OS regardless of whether or not the patient received ICI therapy (10.9 vs 9.8 months, HR 0.74 (95% CI 0.47, 1.15), p=0.18; 7.2 vs 10.2 months, HR 1.18 (95% CI 0.62, 2.27), p=0.62). Conclusions: Concurrent exposure to antibiotics, and specifically fluoroquinolones during ICI therapy was associated with a statistically significant improvement in OS in patients with metastatic CRC, but not metastatic pancreatic cancer. This is discrepant from prior reports in other tumor types and suggests that the gut microbiome may impact ICI efficacy uniquely in patient with CRC. Clinical trial information: NCT02870920 , NCT02879318 .

Artemin and immune checkpoint inhibitor (ICI) efficacy in metastatic colorectal cancer (mCRC): A correlative analysis of the Canadian Cancer Trials Group (CCTG) CO.26 trial.

Artemin and immune checkpoint inhibitor (ICI) efficacy in metastatic colorectal cancer (mCRC): A correlative analysis of the Canadian Cancer Trials Group (CCTG) CO.26 trial.

Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP.

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

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). To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. 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. Durvalumab plus tremelimumab or best supportive care. 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). 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. 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.

Canadian Cancer Trials Group SC.26 - Emotion and Symptom-Focused Engagement (EASE): A Multi-Site Randomized Controlled Trial of an Intervention for Individuals with Acute Leukemia

Background: Despite the rapid onset and life-threatening nature of acute leukemia (AL) and its treatment, there is a lack of research on its psychological and physical consequences and even less on interventions to alleviate them [Bryant 2016]. A longitudinal study of individuals with newly diagnosed or recently relapsed AL showed substantial physical and psychological distress in this population [Rodin 2013; Zimmermann 2013]. Based on these findings, an integrated psychosocial and early palliative care intervention, Emotion And Symptom-focused Engagement (EASE), was developed for patients with AL [Rodin 2015]. A phase II randomized pilot trial of EASE vs. usual care demonstrated feasibility and showed promising positive effects on traumatic stress symptoms (primary outcome) and other secondary outcomes, including depressive symptoms, number and severity of physical symptoms and related distress, pain, quality of life (QOL), satisfaction with care, and attachment security [Rodin 2020]. Study design and methods:The Canadian Cancer Trials Group SC.26 (NCT04224974) randomized phase III trial is underway to test the effectiveness and cost-effectiveness of the EASE intervention in AL. EASE is a novel manualized intervention that combines psychological support with routine symptom screening plus triggered referral to palliative care for symptom control. The goal is to reduce psychological distress and symptom burden, and enhance QOL and satisfaction with care in individuals with newly diagnosed AL undergoing induction therapy. Participants are randomized in a 1:1 unblinded ratio to usual care (UC) or UC and EASE (EASE). EASE consists of two components: the psychotherapy intervention (EASE-psy) and triggered early palliative care (EASE-phys). EASE-psy involves tailored supportive psychotherapy delivered by trained therapists over the initial 8 weeks following hospital admission for treatment of AL. It combines elements of relational support, affect regulation, and trauma-informed cognitive behavioural therapy. All patients randomized to EASE receive weekly symptom screening during the initial inpatient treatment period with triggered referral to early palliative care (EASE-phys). Subjects are stratified by centre, age (≤60 vs. &amp;gt;60) and type of acute leukemia (acute myeloid leukemia vs. acute lymphoblastic leukemia). For patients diagnosed with a mixed phenotype acute leukemia, the dominant sub-type is used for stratification purposes. Patients are ≥18 years, newly diagnosed and recruited within 2 weeks of hospital admission, and receiving or expected to receive induction therapy with curative intent. Current exclusion criteria include major communication difficulties at the time of recruitment; receipt of on-site psychological/psychiatric counselling or palliative care services at the time of recruitment; a diagnosis of acute promyelocytic leukemia or acute leukemia of ambiguous lineage. The two primary outcomes reflect the dual nature of the physical and psychosocial components of the EASE intervention: Mean severity of traumatic stress symptoms at 4 weeks using the 30-item Stanford Acute Stress Reaction Questionnaire (SASRQ) [Cardeña 1996] updated to be DSM-5-concordant [American Psychiatric Association 2013] and mean physical symptom severity at 4 weeks using the Memorial Symptom Assessment Scale (MSAS) [Portenoy 1994]. Hypotheses will be tested using multilevel modeling with maximum likelihood estimation, conducted as intention-to-treat analyses. Economic analysis will be conducted to measure the cost-effectiveness of the EASE intervention. Utilities will be derived from the EQ-5D-5L [Herdman 2011] and FACIT-Sp [Webster 2003] questionnaires. The planned sample size of this study is 266. Since January 2022, 53 patients at 4 Canadian centres have undergone randomization. Conclusion: The information obtained from this study will inform clinicians and decision makers of the value of implementing the EASE intervention in adults with AL.

An Update of Stereotactic Body Radiotherapy (SBRT) for the Palliation of Unirradiated Mucosal Head and Neck Squamous Cell Carcinoma (SCC)

We report the treatment outcomes of palliative Stereotactic Body Radiation Therapy (SBRT) in patients with primary mucosal head and neck cancer (HNC) who were not eligible to receive conventional radiation therapy (RT). This is a retrospective study that reviewed the medical records of patients with primary SCC mucosal HNC who were treated with SBRT between 2011 and 2022. Patients with other histologies, skin cancer, parotid tumors, or recurrent previously irradiated tumors were excluded from the study. A total of 74 patients and 77 tumors were treated with SBRT in this cohort. The median age in the study was 81 (52-97) years and the median follow-up was 7.2 months. The most common site of HNC was the oral cavity (62%), followed by the oropharynx (18%), hypopharynx (8%), larynx (5%), nasal cavity/sinonasal cancer (3%), and unknown primary (1%). T3-4 lesions were found in most patients (76%). SBRT doses ranged from 35-50 Gy in 5 fractions, and the most common prescription dose was ≥45 Gy in 5 fractions (60%) for the GTV prescription. An elective nodal volume of 25 Gy in 5 fractions was infrequently (17%) used. Most patients (81%) who were treated twice a week completed in ≤14 days. The predominant symptoms at presentation were: pain (41%), mass effect (39%), dysphagia/odynophagia (14%), headache/nasal obstruction (1.4%), bleeding (1.4%), stridor (1.4%), asymptomatic (1.4%), and unknown (1.4%). 84% of patients had symptomatic response to treatment with 24% of them having complete symptom response. Cumulative incidence of local failure (LF) was 6.7% and at 6 months and 17.9% at 12 months, respectively. Cumulative incidence of distant metastasis was 7.3% and 10.5% at 6 and 12 months. Cancer was the most common cause of death in 29 patients (51%). The median overall survival (OS) was 8 months with 6 and 12-month OS rates of 67% and 36%, respectively. 39% of patients developed acute G3 toxicity, including 30% with G3 mucositis, 5% with G3 dysphagia, and 4% with G3 dermatitis. A crude rate of late G ≥3 toxicity was observed in 11% of patients including (5%, n = 4) with osteoradionecrosis, and a single case of dysphagia, soft tissue necrosis, supraglottic ulceration, and mucosal necrosis. This study highlights the feasibility of SBRT as a treatment option for primary mucosal head and neck cancer patients who are not eligible for conventional radiation therapy. The results indicate that SBRT was effective in achieving local control and symptom relief, but larger prospective studies are needed to confirm the findings. The Canadian Cancer Trials Group has endorsed HN-13, a randomized control trial comparing HN SBRT to palliative RT.

Power and sample size calculation for incremental net benefit in cost effectiveness analyses with applications to trials conducted by the Canadian Cancer Trials Group

BackgroundHistorically, a priori power and sample size calculations have not been routinely performed cost-effectiveness analyses (CEA), partly because the absence of published cost and effectiveness correlation and variance data, which are essential for power and sample size calculations. Importantly, the empirical correlation between cost and effectiveness has not been examined with respect to the estimation of value-for-money in clinical literature. Therefore, it is not well established if cost-effectiveness studies embedded within randomized-controlled-trials (RCTs) are under- or over-powered to detect changes in value-for-money. However, recently guidelines (such as those from ISPOR) and funding agencies have suggested sample size and power calculations should be considered in CEAs embedded in clinical trials.MethodsWe examined all RCTs conducted by the Canadian Cancer Trials Group with an embedded cost-effectiveness analysis. Variance and correlation of effectiveness and costs were derived from original-trial data. The incremental net benefit method was used to calculate the power of the cost-effectiveness analysis, with exploration of alternative correlation and willingness-to-pay values.ResultsWe identified four trials for inclusion. We observed that a hypothetical scenario of correlation coefficient of zero between cost and effectiveness led to a conservative estimate of sample size. The cost-effectiveness analysis was under-powered to detect changes in value-for-money in two trials, at willingness-to-pay of $100,000. Based on our observations, we present six considerations for future economic evaluations, and an online program to help analysts include a priori sample size and power calculations in future clinical trials.ConclusionThe correlation between cost and effectiveness had a potentially meaningful impact on the power and variance of value-for-money estimates in the examined cost-effectiveness analyses. Therefore, the six considerations and online program, may facilitate a priori power calculations in embedded cost-effectiveness analyses in future clinical trials.

Implications of Contact Days in the Treatment of Relapsed Refractory Diffuse Large B-Cell Lymphoma.

This commentary remarks on a recently published study assessing clinic contact days for patients enrolled in the Canadian Cancer Trials Group LY.12 clinical trial.

IND227 phase III (P3) study of cisplatin/pemetrexed (CP) with or without pembrolizumab (pembro) in patients (pts) with malignant pleural mesothelioma (PM): A CCTG, NCIN, and IFCT trial.

LBA8505 Background: The vast majority of pts with PM have unresectable disease, due to co-morbidities and/or advanced stage. In unresectable PM, standard first line treatment has been C(or carboplatin)P for 20 years but it is usually only moderately efficient, mostly on epithelioid (E)PM, with a global median overall survival (mOS) around 12 months (m), an improved quality-of-life (QoL), and mild toxicity. Trial CM743 demonstrated a significant improvement in mOS for nivolumab/ipilimumab (NI) over CP (18.1 versus 14.1 m), particularly for non-EPM, but 30% NI pts experienced &gt; grade 3 toxicity. Thus, alternative therapies to improve mOS and tolerability are needed. Methods: Canadian Cancer Trials Group (CCTG) IND 227 is an academic, open-label, randomized P3 study of the CCTG, National Cancer Institute of Naples (NCIN) and Intergroupe Francophone de Cancérologie Thoracique (IFCT). The study was supported by grants to CCTG (Canadian Cancer Society -707213); Merck &amp; Co. Inc provided pembrolizumab (pembro) and a grant to support study conduct. Untreated unresectable PM pts ≥ 18 years with ECOG performance status 0-1, adequate hematological, renal and hepatic function, no active autoimmune disease, brain metastases, interstitial lung disease or other active co-morbidities, were randomized 1:1 to CP with or without pembro and stratified by histology (E vs. non-E). Carboplatin was allowed if C contraindicated. Radiological review (BICR) and PD-L1 testing was centralised. mOS was the primary endpoint; median progression-free survival (PFS) and response rate (RR), QoL (EORTC QLQ-C30 + QLQ-LC13) and economic analysis were secondary. Results: A total 440 PM pts were randomized; 218 to CP and 222 to CP-pembro. Data cut-off was 16 September 2022 when the required events was observed. All pts were included in the analyses. Arms were well balanced. Seven pts opted not to receive CP. Median exposure of CP was comparable between arms. Subsequent treatment with chemotherapy was similar in both arms, while 59 pts in CP arm (vs 17 CP-pembro pts) received immunotherapeutics. Using a stratified log rank test, mOS was 17.3m vs 16.1m for CP-pembro vs CP (HR 0.79 95%CI 0.64-0.98; p=0.0324), mPFS was 7.13m vs 7.16m (HR 0.80, 95%CI 0.65-0.99, p=0.0372). BOR was significantly higher for CP-pembro (63% vs 40%, p &lt; 0.0001). Grade 3 or higher pembro related adverse events (AEs) occurred in 19% of patients (88% were grade 3; the most common were fatigue (5%) and diarrhea, pneumonitis and irAE (2% each)), and 16% of pts discontinued pembro per protocol for related AEs (most commonly diarrhea and pneumonitis). Conclusions: With a statistically significant improvement in mOS and acceptable tolerability. CP-pembro is an option for treatment naïve, unresectable PM. Clinical trial information: NCT02784171 .

An international randomized phase III trial comparing radical hysterectomy and pelvic node dissection (RH) vs simple hysterectomy and pelvic node dissection (SH) in patients with low-risk early-stage cervical cancer (LRESCC): A Gynecologic Cancer Intergroup study led by the Canadian Cancer Trials Group (CCTG CX.5-SHAPE).

LBA5511 Background: In the last 2 decades, there has been a trend towards less radical surgery in patients with low-risk cervical cancer. Retrospective data suggested that less radical surgery may be safe and associated with less morbidity. The objective of this non-inferiority phase III prospective randomized trial was to compare RH to SH in women with LRESCC. Methods: Women with LRESCC defined as stage 1A2 or 1B1 with lesion ≤ 2cm were randomized to RH or SH after stratification by cooperative group, intended use of sentinel node mapping, stage, histological type, and tumour grade. The primary endpoint was pelvic recurrence rate at 3 years (PRR3). Non-inferiority of SH to RH is claimed when the 95% upper one-sided confidence limit (95% UCL) for the difference in PRR3 of SH to RH (DPRR3), calculated by the Kaplan-Meier method for pelvic-relapse free survival, is lower than or equal to 4%. Primary intention to treat (ITT) analysis included all patients randomized. Per-protocol (PP) analysis included patients eligible at baseline and without evidence of more advanced disease found at the time of surgery or final pathology, based on treatment received. Secondary endpoints included extrapelvic relapse-free survival (ERFS), overall survival (OS), and quality of life (QoL). Results: 700 women (12 countries, 130 centers) were enrolled from December 2012 to November 2019. Patient characteristics were well balanced: median age was 44 (24-80); 91.7% were stage 1B1 and 61.7% had squamous histology. 50% of the hysterectomies were done laparoscopically (56% SH vs. 44% RH), 25% robotically (24% vs. 25%) and 23% abdominally (17% vs. 29%). 4.4% of patients had lymph node metastasis (4.1% SH and 5.1% RH) and 3.1% had extrauterine extension (2.6% SH and 3.7% RH). A total of 8.8% of women received post-surgical adjuvant therapy (9.2% SH and 8.4% RH). With a median follow-up of 4.5 years, 21 pelvic recurrences were identified (11 SH and 10 RH). The PRR3 was 2.5% with SH and 2.2% with RH (DPRR3 0.35% with 95% UCL 2.32%) in ITT analysis; 2.8% with SH and 2.3% with RH (DPRR3 0.42% with 95% UCL 2.56%) in PP analysis. The 3-year ERFS and OS were respectively 98.1% and 99.1% with SH; 99.7% and 99.4% with RH. RH had significantly higher surgery related incidence of urinary incontinence (11.0% vs. 4.7% with SH; p=0.003) and urinary retention (9.9% vs. 0.6% with SH; p&lt;0.0001) during follow-up. QoL scales with significant difference between the two groups over time were all in favor of SH. Conclusions: The pelvic recurrence rate at 3 years in women with low risk early-stage cervical cancer who underwent a simple hysterectomy is not inferior to those who received a radical hysterectomy. Fewer surgical complications and better quality of life were observed with SH. Clinical trial information: NCT01658930 .

Accrual of adolescents and young adults (AYA) into cancer clinical trials in Canada.

e13598 Background: Historically, accrual rates of AYA (aged 16-39) to cancer clinical trials have been low. This is suggested to contribute to lesser improvements in their outcomes compared with older and younger populations. We sought to describe the impact of collaborative initiatives launched by the Canadian Cancer Trials Group (CCTG), NCTN and C17 to address this. Methods: All CCTG trials open to accrual from 01/01/2004 to 31/12/2022 were evaluated. Trials with eligibility criteria limited to age &gt; 39, or for which CCTG did not have access to individual patient data on age, were excluded. Accrual rates were assessed by age (&lt;30, 30-39, &gt;40 yrs), cancer type, and compared with 2022 Canadian Cancer Society (CCS) prevalence data. Results: 379 studies were open to accrual. 21 trials were excluded as they had no patients aged 16-39 within their inclusion criteria. 2 trials were excluded as they were either COVID related or a trial sub-study. 230 trials were excluded owing to patient age data being unavailable to CCTG. 126 CCTG and NCTN led trials were included. They involved the following disease sites: brain (3), breast (13), GI (12), GU (11), gynecology (6), head &amp; neck (3), hematology (10), lung (11), melanoma (4), sarcoma (2) novel investigational agents (45) and symptom control (6) – the latter two spanned multiple tumor types. Patients aged 16-18 were excluded from many trials limiting accrual opportunities in this subgroup. AYA patients were recruited into trials at a higher level than expected by prevalence data except for brain, lung and head &amp; neck patients. This may be due to younger, fitter patients being recruited onto trials. GU trials, hematology and sarcoma trials recruited better than expected as there were trials geared to diseases common in younger individuals (e.g. germ cell cancers) and incorporating intensive therapy e.g. stem cell transplantation in lymphoma. 3.5% of patients accrued on trials were &lt;40 in 2004-2013 c.f. 8.7% of patients 2014-2022. Conclusions: Limited data is available on AYA aged 16-18 due to trial entry criteria. Currently, most CCTG trials include patients aged ≥14. Trial accrual in the AYA population was higher than predicted by CCS data indicating that clinical trials are acceptable to AYA patients. This supports ongoing efforts to improve trial access to AYA. [Table: see text]

A phase II study of durvalumab re-treatment +/- prednisone in patients who discontinued prior checkpoint therapy due to immune related toxicity (CCTG IND.238A).

TPS2673 Background: Up to 18% of patients permanently discontinue immune checkpoint blockade (ICB) therapy following G3/G4 immune-related adverse events (irAEs) even if reversible / easily managed with replacement therapy or steroids. Safety concerns exist with ICB re-treatment. Given the potential benefit of ICB and evidence that patients with irAEs may exhibit greater efficacy, there is interest in ICB rechallenge following successful management of G3/G4 irAEs in patients who have had benefit, and trials to prospectively investigate ways to prevent irAE recurrence are needed. Durvalumab is a human monoclonal antibody of IgG1κ subclass that binds to PD-L1. Canadian Cancer Trials Group (CCTG) IND.238A is a phase 2, open label, multicentre study of durvalumab +/- prednisone rechallenge in patients who were benefitting from prior ICB but discontinued due to irAEs. Methods: Eligible patients have received prior anti-PD-(L)1 ICB alone or in combination with anti-CTLA-4 ICB, with or without chemotherapy/targeted therapy, and experienced either: 1) G3 or selected G4 irAEs (i.e. endocrinopathies manageable with replacement therapy; hematologic toxicity) that required drug discontinuation; 2) prolonged G2 irAEs where therapy was discontinued due to poor tolerability. Prior irAE must have resolved to ≤G1, patients must have completed steroid therapy and have documented RECIST 1.1 CR, PR, or prolonged SD (≥8 weeks) to initial ICB. Patients with prior (neo)adjuvant/consolidation ICB are eligible provided there has been ≥6-month treatment free interval before enrollment. Based on prior irAE, patients are allocated into either: 1) the High Risk cohort, receiving durvalumab (1500mg IV Q4W in all cohorts) + prednisone 0.5mg/kg/day for C1-2, or; 2) the Standard Risk cohort, where they are randomized to receive either durvalumab + prednisone 10mg/day for C1-2 (Cohort 2A) or durvalumab alone (Cohort 2B). Three to 6 patients are enrolled into each cohort initially, then each cohort expands up to a total of 60 evaluable patients (20 per cohort). Safety review takes place following enrollment of the 1st, 3rd, 6th and 10th patient in each cohort. Safety review occurs 4 weeks after the 1st patient treated on each cohort and subsequently once the last patient has been followed for at least 4 weeks. The primary endpoint is the incidence of treatment-related AEs (CTCAE v5.0), estimated as percentages of patients with each AE (90% exact CI will be calculated). Secondary objectives are ORR (RECIST 1.1 and iRECIST) and efficacy of corticosteroids in preventing recurrent or new ≥G2 irAEs (90% exact CI will be calculated). Exploratory endpoints include PFS / iPFS by Kaplan-Meier method, exploration of blood- and stool-based irAE biomarkers and PD-L1 expression. As of January 30, 2023, 12 of planned 60 patients have been enrolled. Clinical trial information: NCT03847649 .

CCTG EN10: A phase II study of tailored adjuvant therapy in POLE-mutated and p53-wildtype/NSMP early-stage endometrial cancer (EC)—RAINBO BLUE and TAPER.

TPS5632 Background: Molecular classification of EC provides an opportunity to personalize treatment for patients with early disease based on prognosis. We hypothesize that de-escalated adjuvant treatment in patients with early-stage POLE-mutated ( POLEmut) or p53wt/NSMP (p53 wildtype/no specific molecular profile) EC is feasible and associated with favourable disease control, QOL and health economics. Methods: EN.10 is a Canadian Cancer Trials Group led phase II trial that enrolls two independent cohorts of patients with early stage EC based on tumour molecular status: POLEmut (substudy A) and p53wt/NSMP (substudy B). The primary objective is to estimate the 3-year rate of pelvic recurrence. Secondary objectives include estimated 3-year isolated vaginal recurrence, para-aortic recurrence, distant metastasis, survival (recurrence-free, EC-specific, overall survival) and to describe the patient decisional conflict and fear of recurrence. Tertiary objectives: QOL, economic evaluation and interrogation/discovery of additional prognostic biomarkers. Statistical Design: Registration to Substudy A or B is based on molecular classification. Treatment will be deescalated in both substudies; to surveillance-only (all early stage POLEmut, and a proportion of NSMP), or vaginal brachytherapy (proportion of NSMP), with NSMP stratification based on histological grade, and lymphovascular invasion. Substudy A can enroll endometrioid, serous, clear cell, un/dedifferentiated and carcinosarcomas whereas Substudy B is confined to endometrioid histotype. Both arms require ECOG 0-2 and hysterectomy+BSO with nodal assessment required for stage II and grade 3 EC. A total of 120 patients with POLEmut (Sub-study A) and 180 with p53wt/NSMP ER+ (Sub-study B) EC will be recruited in 3 years. If the upper 95% confidence limit is less than 5% in either of Substudy A, Cohort A1 and Sub-study B or both, it will be concluded that patients in one or both groups have an acceptable low risk of pelvic recurrence at 3 years with molecularly-tailored de-escalated adjuvant treatment An additional estimated 25 patients with higher risk POLEmut EC will be enrolled for an exploratory analysis. Conduct to Date: Study activation Dec 19 2022. Enrollment January 31, 2023: 36 Supported by Canadian Cancer Society, Canadian Institutes of Health Research, Gynecologic Cancer Initiative, BC Cancer Foundation. Clinical trial information: NCT05640999 .

CCTG HN11: SPECT-CT guided elective contralateral neck treatment (SELECT) for patients with lateralized oropharyngeal cancer—A phase III randomized controlled trial.

TPS6114 Background: Lymphatic mapping identifies neck lymph nodes at risk for cancer spread in patients with lateralized oropharyngeal (OPC) squamous cell carcinoma. We hypothesize that a lymphatic mapping guided approach to radiotherapy (RT) treatment of the contralateral neck will enable safe de-escalation of therapy with acceptable disease control with potential benefits in RT related toxicity, QOL, swallowing function and economics. Methods: HN.11 is a Canadian Cancer Trials Group international multi-centre, non-inferiority randomized phase III trial comparing a lymphatic mapping-guided approach for management of the contralateral neck (experimental) vs. bilateral neck radiation therapy (RT) (control). The primary objective is to determine if a lymphatic mapping-guided approach for management of the contralateral neck has a non-inferior disease-free survival (DFS) compared to bilateral neck RT. Secondary objectives: To compare swallowing related QOL, xerostomia, isolated contralateral neck failure, overall survival, loco-regional failure, distant metastases, RT-related toxicities, patient reported adverse events (PRO CTCAE), gastrostomy tube usage, and economics indicators (resource utilization, lost productivity, financial toxicity, EQ5D). Exploratory objectives: Swallowing function using video fluoroscopic swallow studies, head and neck-cancer specific QOL, patterns of lymphatic drainage, radiomic prediction of contralateral lymphatic drainage, correlation of tumour somatic mutations and ctDNA with disease recurrence. Statistical Design: The target sample size is 510 patients. The experimental arm will be considered non-inferior if the upper limit of the one sided 95% confidence interval (CI) of the estimated hazard ratio (HR) does not exceed 1.46 (non-inferiority margin of 6.5% for 2-year DFS). In the primary intention-to-treat (ITT) analysis, the study has 81% power, with a one-sided type I error rate of 5%, assuming 5 years of accrual, 3-years of follow up to observe 178 DFS events, and a 5% loss to follow up. If non-inferiority is demonstrated in the ITT analysis, a secondary per-protocol analysis will be performed, analyzing those patients treated as per their allocation, with 80% power to detect non-inferiority of the experimental arm assuming a conservative 10% cross-over from the experimental to the control arm (i.e. failed lymphatic mapping). Conduct to Date: Study activation September 29, 2022. First enrollment was February 10, 2023. Supported by Canadian Cancer Society, Canadian Institutes of Health Research, National Cancer Trials Network (NCTN). Clinical trial information: NCT05451004 .

Comparing the time toxicity of cancer treatments in the CCTG LY.12 trial.

12135 Background: When different cancer treatments have similar oncologic outcomes, their respective time-related burdens can aid patient-oncologist decision-making regarding which treatment approach to pursue. We have previously developed a pragmatic and patient-centered metric of these time burdens-- which we term ‘’time toxicity’’-- as any day with physical healthcare system contact. This includes outpatient (e.g., bloodwork, scans, clinician, etc.) and emergency room visits, and overnight stays in a healthcare facility. Herein we sought to assess time toxicity in a completed RCT. Methods: We conducted a secondary analysis of the Canadian Cancer Trials Group LY.12 RCT that evaluated 2-3 outpatient cycles of gemcitabine, dexamethasone, and cisplatin (GDP) vs. dexamethasone, cytarabine, and cisplatin (DHAP) in 619 patients with relapsed/refractory lymphoma prior to stem cell transplant. Primary analyses reported similar response rates, transplantation rates, event-free-survival, and overall survival across arms. We calculated patient-level time toxicity by analyzing RCT forms. The study period was the date of assignment to the date of progression or the day before stem cell transplant. We considered days without healthcare contact as ‘’home days’’. We compared time measures across arms. Results: The median study duration was longer in the GDP arm (50, vs. 47 days in the DHAP arms, p=0.007). Median time toxic days were comparable in both arms (18 vs 19 days, p=0.79), but median home days were higher in the GDP arm (33 vs 28 days, p&lt;0.001). The proportion of time toxic days (time toxic days divided by study duration) was lower in the GDP arm (34%, vs. 38%, p=0.009). The GDP arm experienced more time toxicity related to planned outpatient chemotherapy (median, 10 vs. 8 days), but the DHAP arm experienced many more hospitalization days (median, 11 vs. 0 days) (Table). Conclusions: This study demonstrates that measures of time toxicity can be extracted from RCTs. These measures can add clinical insight into patient burdens. In LY.12, despite broadly comparable short- and long-term oncologic outcomes, the GDP arm experienced less time toxicity. Such information can guide decision-making for patients with aggressive hematological cancers, who already spend a significant portion of time with healthcare contact. Clinical trial information: NCT00078949 . [Table: see text]