ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results.

Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (CI): 52-97%) and a specificity of 75% (90% CI: 56.5-88.5%). Median time to ctDNA response was 2.1 months (90% CI: 1.5-2.6), and patients with mR attained longer progression-free survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167 .

Programmed Cell Death Protein 1 Inhibitors and MET Targeted Therapies in NSCLC With MET Exon 14 Skipping Mutations: Efficacy and Toxicity as Sequential Therapies.

Introduction: NSCLC with MET exon 14 skipping mutation (METex14) is associated with poor outcomes. Integration of novel targeted therapies is challenging because of barriers in testing and drug access. We, therefore, sought to characterize the treatment patterns, outcomes, and emerging issues of treatment sequencing in patients with METex14-mutant NSCLC. Methods: We reviewed all NSCLC cases with METex14 alterations between 2014 and 2020 across four Canadian cancer centers. Demographics, disease characteristics, systemic therapy, overall response rates (ORRs), survival, and toxicity were summarized. Results: Among 64 patients with METex14-mutant NSCLC, the median overall survival was 23.1 months: 127.0 months in stage 1, 27.3 months in resected stage 2 and 3, and 16.6 months in unresectable stage 3 or 4 disease, respectively. In patients with advanced disease, 22% were too unwell for systemic treatment. MET tyrosine kinase inhibitors (TKIs) were administered to 28 patients with an ORR of 33%, median progression-free survival of 2.7 months, and 3.8 months for selective TKIs. Programmed cell death protein-1 (PD-1) inhibitors were given to 25 patients-the ORR was 44% and progression-free survival was 10.6 months. No responses were seen with subsequent MET TKIs after initial TKI treatment. Grade 3 or higher toxicities occurred in 64% of patients who received MET TKI after PD-1 inhibitors versus 8% in those who did not receive PD-1 inhibitors. Conclusions: Many patients with advanced METex14 NSCLC were too unwell to receive treatment. PD-1 inhibitors seem effective as an initial treatment, although greater toxicity was seen with subsequent MET TKIs. Thus, timely testing for METex14 skipping and initial therapy are imperative to improving patient survival.

Survival outcomes and predicting intracranial metastasis in stage III non-small cell lung cancer treated with definitive chemoradiation: Real-world data from a tertiary cancer center.

PURPOSE/OBJECTIVE: Around 30% of patients with non-small cell lung cancers (NSCLC) are diagnosed with stage III disease at presentation, of which about 50% are treated with definitive chemoradiation (CRT). Around 65-80% of patients will eventually develop intracranial metastases (IM), though associated risk factors are not clearly described. We report survival outcomes and risk factors for development of IM in a cohort of patients with stage III NSCLC treated with CRT at a tertiary cancer center. MATERIALS/METHODS: We identified 195 patients with stage III NSCLC treated with CRT from January 2010 to May 2021. Multivariable logistic regression was used to generate odds ratios for covariates associated with development of IM. Kaplan-Meier analysis with the Log Rank test was used for unadjusted time-to-event analyses. P-value for statistical significance was set at < 0.05 with a two-sided test. RESULTS: Out of 195 patients, 108 (55.4%) had stage IIIA disease and 103 (52.8%) had adenocarcinoma histology. The median age and follow-up (in months) was 67 (IQR 60-74) and 21 (IQR 12-43), respectively. The dose of radiation was 60 Gy in 30 fractions for148 patients (75.9%). Of the 77 patients who received treatment since immunotherapy was available and standard at our cancer center, 45 (58.4%) received at least one cycle. During follow-up, 84 patients (43.1%) developed any metastasis, and 33 (16.9%) developed IM (either alone or with extracranial metastasis). 150 patients (76.9%) experienced a treatment delay (interval between diagnosis and treatment > 4 weeks). Factors associated with developing any metastasis included higher overall stage at diagnosis (p = 0.013) and higher prescribed dose (p = 0.022). Factors associated with developing IM included higher ratio of involved over sampled lymph nodes (p = 0.001) and receipt of pre-CRT systemic or radiotherapy for any reason (p = 0.034). On multivariate logistical regression, treatment delay (OR 3.9, p = 0.036) and overall stage at diagnosis (IIIA vs. IIIB/IIIC) (OR 2.8, p = 0.02) predicted development of IM. These findings were sustained on sensitivity analysis using different delay intervals. Median OS was not reached for the overall cohort, and was 43.1 months for patients with IM and 40.3 months in those with extracranial-only metastasis (p = 0.968). In patients with any metastasis, median OS was longer (p = 0.003) for those who experienced a treatment delay (48.4 months) compared to those that did not (12.2 months), likely due to expedited diagnosis and treatment in patients with a higher symptom burden secondary to more advanced disease. CONCLUSIONS: In patients with stage III NSCLC treated with definitive CRT, the risk of IM appears to increase with overall stage at diagnosis and, importantly, may be associated with experiencing a treatment delay (> 4 weeks). Metastatic disease of any kind remains the primary life-limiting prognostic factor in these patients with advanced lung cancer. In patients with metastatic disease, treatment delay was associated with better survival. Patients who experience a treatment delay and those initially diagnosed at a more advanced overall stage may warrant more frequent surveillance for early diagnosis and treatment of IM. Healthcare system stakeholders should strive to mitigate treatment delay in patients with locally NSCLC to reduce the risk of IM. Further research is needed to better understand factors associated with survival, treatment delay, and the development of IM after CRT in the immunotherapy era.

An assessment of extended pembrolizumab dosing in advanced non-small-cell lung cancer in the COVID-19 pandemic.

Background: There are limited clinical data comparing extended dosing (ED) versus standard dosing (SD) of pembrolizumab for metastatic non-small-cell lung cancer. Methods: This retrospective study included patients with metastatic non-small-cell lung cancer and PD-L1 tumor proportion score ≥50% treated with one or more cycles of single-agent pembrolizumab with SD or ED from January 2018 to December 2020. Results: A higher proportion of patients were alive in the ED group (vs SD) at 6 months (94 vs 51%), 12 months (94 vs 33%) and data cutoff (94 vs 26%) (p < 0.001 for all). The rate (44 vs 32%; p = 0.407) and severity of grade ≥3 immune-related adverse events were similar (50 vs 52%); however, ED patients more frequently discontinued treatment due to toxicity (45 vs 15%; p < 0.001). Conclusion: A greater proportion of ED patients were alive at data cutoff, and the rate and severity of immune-related adverse events were similar between groups.

Cancer in the lungs can be treated with drugs that use your immune system to kill cancer. This study showed that patients lived longer when the drugs were given further apart, and that the extended treatment was equally safe as the standard dosing schedule.

Systematic review of technology-mediated peer support interventions in paediatric type 1 diabetes care.

AIMS: There is increasing interest in the role of peer support in diabetes care. However, technology-mediated peer support in paediatric type 1 diabetes remains understudied.We aimed todescribe technology-mediated peer support interventions for children living with type 1 diabetes, their caregivers and healthcare providers. METHODS: CINAHL, Embase and MEDLINE (Ovid) were searched from Jan 2007 to June 2022. We included randomised and non-randomised trials with peer support interventions for children living with diabetes, their caregivers and/or healthcare providers. Studies examining clinical, behavioural or psychosocial outcomes were included. Quality was assessed with the Cochrane risk of bias tool. RESULTS: Twelve of 308 retrieved studies were included, with a study duration range of 3 weeks to 24 months and most were randomised trials (n = 8, 66.67%). Four technology-based interventions were identified: phone-based text messages, video, web portal and social media, or a hybrid peer support model. Most (58.6%, n = 7) studies exclusively targeted children with diabetes. No significant improvement was observed in psychosocial outcomes (quality of life, n = 4; stress and coping, n = 4; social support, n = 2). Mixed findings were observed in HbA1c (n = 7) and 28.5% studies (n = 2/7) reported reduced incidence of hypoglycaemia. CONCLUSIONS: Technology-mediated peer support interventions may have the potential to improve diabetes care and outcomes. However, further well-designed studies are necessary that address the needs of diverse populations and settings, and the sustainability of intervention effects.

Management of perinatal cervical spine injury using custom-fabricated external orthoses: design considerations, narrative literature review, and experience from the Hospital for Sick Children. Illustrative cases.

BACKGROUND: Cervical spine injuries in neonates are rare and no guidelines are available to inform management. The most common etiology of neonatal cervical injury is birth-related trauma. Management strategies that are routine in older children and adults are not feasible due to the unique anatomy of neonates. OBSERVATIONS: Here, the authors present 3 cases of neonatal cervical spinal injury due to confirmed or suspected birth trauma, 2 of whom presented immediately after birth, while the other was diagnosed at 7 weeks of age. One child presented with neurological deficits due to spinal cord injury, while another had an underlying predisposition to bony injury, infantile malignant osteopetrosis. The children were treated with a custom-designed and manufactured full-body external orthoses with good clinical and radiographic outcomes. A narrative literature review further supplements this case series and highlights risk factors and the spectrum of birth-related spinal injuries reported to date. LESSONS: The current report highlights the importance of recognizing the rare occurrence of cervical spinal injury in newborns and provides pragmatic recommendations for management of these injuries. Custom orthoses provide an alternate option for neonates who cannot be fitted in halo vests and who would outgrow traditional casts.

A study of the efficacy and toxicity outcomes of extended durvalumab dosing in patients with stage III unresectable non-small cell lung cancer (NSCLC) during the COVID-19 pandemic.

BACKGROUND: Durvalumab following chemoradiation in unresectable stage III non-small cell lung cancer (NSCLC) has led to improved outcomes. The schedule of administration has been determined by pharmacokinetic studies. This study evaluates real-world efficacy and safety outcomes of extended dosing (ED) vs. standard dosing (SD) of durvalumab. METHODS: Stage III NSCLC patients treated at the Cancer center of Southeastern Ontario with consolidative durvalumab from March 2017-December 2020 were included. Patient characteristics and outcomes were evaluated through retrospective review. Comparisons were made using chi-square and t-tests. Kaplan-Meier curves were used to analyze overall survival (OS). RESULTS: A total of 35 patients were included; 15 (43%) switched to ED. Distant recurrence rates were higher in the ED group (53% vs. 20%, p = 0.07), with no differences in the sites of disease recurrence. A similar proportion of patients were alive in the ED vs. SD group (93% vs. 80%, p = 0.3), with no significant difference in OS. There were less grade 3 or greater immune-related adverse events in the ED group (0% vs. 20%). Treatment discontinuation occurred in 47% vs. 50% in the ED vs. SD groups, respectively, owing to toxicity in 20% of patients in the ED group vs. 40% in the SD group. CONCLUSIONS: Extended dosing has similar efficacy and toxicity to standard dosing; however, there was a higher rate of toxicity necessitating discontinuation in the SD group, which may have impacted the clinical decision-making to switch to ED. Our data is limited by a small sample size and should be further validated in larger cohorts.

Predictors of successful natural sleep MRI for sensorineural hearing loss in infants.

OBJECTIVES: Cochlear implantation (CI) in children with sensorineural hearing loss (SNHL) before 12 months of age (mo) improves language outcomes. MRI is important to assess CI candidacy. Anesthesia before 3 years old may increase risk of neurocognitive delay. Natural sleep MRI (NS-MRI) is an emerging technique to avoid anesthesia in infants, but relies on successful sleep for adequate imaging. Our multidisciplinary team hypothesized the following predictors of successful NS-MRI for CI evaluation: age, distance travelled, comorbidities, primary language, insurance type, HL characteristics, time and duration of MRI. METHODS: We performed retrospective review of children 0-12mo who attempted NS-MRI. The NS-MRI was successful if imaging was sufficient for definitive clinical management per the managing otolaryngologist. RESULTS: Among 26 patients (29 scans), the median age was 3.2mo (range: 1.2-6.8mo), distance travelled was 16.3 miles (range: 0.9 to 365 miles), 12 (46%) children had medical comorbidities. 8 (31%) had public insurance. 10 (38%) had bilateral HL. 52% (15/29) of scans were successful. Patients with comorbidities had significantly lower odds of successful NS-MRI (OR 0.09; 95% CI 0.01-0.54). Success was not associated with age, distance travelled, insurance type, primary language, HL characteristics, time or duration of MRI on univariable analysis. All 11 children who failed NS-MRI underwent hearing-aid fitting and/or imaging with sedation and CI as clinically indicated before 12mo. CONCLUSION: NS-MRI was successful in 52% of infants, regardless of age, demographics, HL or MRI characteristics. Unsuccessful NS-MRI did not result in delayed intervention. NS-MRI is an effective consideration for a broad range of infants with SNHL.

PD-L1 assessment in cytology samples predicts treatment response to checkpoint inhibitors in NSCLC.

BACKGROUND: Testing for tumor programmed death ligand-1 (PD-L1) expression was initially developed with histology specimens in non-small cell lung cancer (NSCLC). However, cytology specimens are widely used for primary diagnosis and biomarker studies in clinical practice. Limited clinical data exist on the predictiveness of cytology-derived PD-L1 scores for response to immune checkpoint inhibitor (ICI) therapy. METHODS: We reviewed all NSCLC specimens clinically tested at the University Health Network (UHN) for PD-L1 with 22C3pharmDx, from 01/2013 to 04/2021. Treatment outcomes in patients treated with single agent ICI therapy were reviewed and compared according to cytology- and histology-derived PD-L1 scores. RESULTS: We identified 494 and 1942 unique patients with cytology- and histology-derived tumor proportion scores, respectively, during the study period. Informative testing rates were 95 % vs 98 % for cytology and histology, respectively. Clinical data were available for 152 patients treated with single agent ICI: 61 cytology and 91 histology. Overall response rates (ORR) were similar for cytology and histology (36 % vs 34 %; p = 0.23), as well as median progression free survival (PFS) (4.9 vs 4.2 months; p = 0.99) and overall survival (23.4 vs 19.7 months; p = 0.99). The results remained similar even after adjusting for PD-L1 expression levels and line of ICI treatment (PFS HR 1.15; 95 %CI 0.78-1.70; p = 0.47). CONCLUSIONS: Treatment outcomes to single agent ICI based on cytology-derived PD-L1 scores were comparable to histology controls. Our results support PD-L1 biomarker testing on both cytology and histology specimens.

Upfront Next Generation Sequencing in Non-Small Cell Lung Cancer.

In advanced non-small cell lung cancer (NSCLC), patients with actionable genomic alterations may derive additional clinical benefit from targeted treatment compared to cytotoxic chemotherapy. Current guidelines recommend extensive testing with next generation sequencing (NGS) panels. We investigated the impact of using a targeted NGS panel (TruSight Tumor 15, Illumina) as reflex testing for NSCLC samples at a single institution. Molecular analysis examined 15 genes for hotspot mutation variants, including AKT1, BRAF, EGFR, ERBB2, FOXL2, GNA11, GNAQ, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA, RET and TP53 genes. Between February 2017 and October 2020, 1460 samples from 1395 patients were analyzed. 1201 patients (86.1%) had at least one variant identified, most frequently TP53 (47.5%), KRAS (32.2%) or EGFR (24.2%). Among these, 994 patients (71.3%) had clinically relevant variants eligible for treatment with approved therapies or clinical trial enrollment. The incremental cost of NGS beyond single gene testing (EGFR, ALK) was CAD $233 per case. Reflex upfront NGS identified at least one actionable variant in more than 70% of patients with NSCLC, with minimal increase in testing cost. Implementation of NGS panels remains essential as treatment paradigms continue to evolve.

Complete response and survival outcomes in patients with advanced cancer on immune checkpoint inhibitors.

Aim: To evaluate overall survival in advanced cancer patients who achieved complete response (CR) with immune checkpoint inhibitor (ICI) therapy. Methods: This retrospective study included patients with advanced unresectable or metastatic cancer who received at least one cycle of palliative-intent ICI. Best overall response was used to define response groups. Results: 21 (7%) of 322 patients achieved CR. Multivariate analysis demonstrated that CR was independently associated with better overall survival compared with disease progression (hazard ratio: 0.012; 95% CI: 0.002-0.090) and stable disease (hazard ratio: 0.063; 95% CI: 0.009-0.464) as well as a nonsignificant trend toward better overall survival compared with partial response (hazard ratio: 0.169; 95% CI: 0.023-1.252) regardless of cancer type, ICI regimen or ICI line. Conclusion: Patients who achieved CR had longer survival compared with patients who did not achieve CR.

Outcomes of Hypofractionated Stereotactic Radiotherapy for Small and Moderate-Sized Brain Metastases: A Single-Institution Analysis.

Background: Stereotactic radiosurgery (SRS) is the standard treatment for limited intracranial metastases. With the advent of frameless treatment delivery, fractionated stereotactic radiotherapy (FSRT) has become more commonly implemented given superior control and toxicity rates for larger lesions. We reviewed our institutional experience of FSRT to brain metastases without size restriction. Methods: We performed a retrospective review of our institutional database of patients treated with FSRT for brain metastases. Clinical and dosimetric details were abstracted. All patients were treated in 3 or 5 fractions using LINAC-based FSRT, did not receive prior cranial radiotherapy, and had at least 6 months of MRI follow-up. Overall survival was estimated using the Kaplan-Meier method. Local failure and radionecrosis cumulative incidence rates were estimated using a competing risks model with death as the competing risk. Univariable and multivariable analyses using Fine and Gray's proportional subdistribution hazards regression model were performed to determine covariates predictive of local failure and radionecrosis. Results: We identified 60 patients and 133 brain metastases treated at our institution from 2016 to 2020. The most common histologies were lung (53%) and melanoma (25%). Most lesions were >1 cm in diameter (84.2%) and did not have previous surgical resection (88%). The median duration of imaging follow-up was 9.8 months. The median survival for the whole cohort was 20.5 months. The local failure at 12 months was 17.8% for all lesions, 22.1% for lesions >1 cm, and 13.7% for lesions ≤1 cm (p = 0.36). The risk of radionecrosis at 12 months was 7.1% for all lesions, 13.2% for lesions >1 cm, and 3.2% for lesions ≤1 cm (p = 0.15). Conclusions: FSRT is safe and effective in the treatment of brain metastases of any size with excellent local control and toxicity outcomes. Prospective evaluation against single-fraction SRS is warranted for all lesion sizes.

A Real-World Evaluation of Atezolizumab Plus Platinum-Etoposide Chemotherapy in Patients With Extensive-Stage SCLC in Canada.

INTRODUCTION: The real-world data evaluating treatment outcomes of atezolizumab plus carboplatin-etoposide chemotherapy (atezolizumab) for extensive-stage SCLC (ESCLC) are lacking. Our objective was to evaluate real-world outcomes of ESCLC treated with atezolizumab. METHODS: A retrospective analysis of provincial patients with ESCLC who started first-line (1L) systemic treatment was conducted. We primarily evaluated the progression-free survival (PFS) and overall survival (OS) outcomes in association with atezolizumab compared with platinum-etoposide chemotherapy (chemotherapy) while adjusting for relevant demographic and clinical factors. Adverse events (AEs) during 1L were evaluated. RESULTS: A total of 67 patients were identified. Of the 34 patients who received atezolizumab, 24% had Eastern Cooperative Oncology Group performance status greater than or equal to 2, approximately 50% were more than or equal to 65 years, 21% received cisplatin-etoposide chemotherapy before atezolizumab, and 12% had thoracic radiation (tRT).Within the atezolizumab versus chemotherapy group, the median PFS equals to 6.0 versus 4.3 months (p = 0.03) whereas OS = 12.8 versus 7.1 months (p = 0.01). Relative to chemotherapy, the hazard ratio (95% confidence interval) for PFS was 0.53 (0.28-1.02) and OS was 0.42 (0.20-0.88) with atezolizumab. tRT compared with no tRT receipt correlated with reduced death risk (hazard ratio [95% confidence interval] = 0.33 [0.13-0.88]).AE-related treatment withdrawal with atezolizumab was 32% and 15% with chemotherapy (p = 0.02). Within the tRT subgroup, 25% versus 20% in atezolizumab versus chemotherapy group, respectively, discontinued 1L owing to AE. CONCLUSIONS: This is the first real-world study revealing comparable survival with that in the IMpower133 trial. Treatment discontinuation from AEs was higher with atezolizumab among Canadian patients with ESCLC. Our data suggest safe use of tRT and chemoimmunotherapy, but its efficacy for ESCLC warrants further study.

Prognostic and predictive effect of KRAS gene copy number and mutation status in early stage non-small cell lung cancer patients.

BACKGROUND: In the current analysis, we characterize the prognostic significance of KRAS mutations with concomitant copy number aberrations (CNA) in early stage non-small cell lung cancer (NSCLC), and evaluate the ability to predict survival benefit from adjuvant chemotherapy. METHODS: Clinical and genomic data from the LACE (Lung Adjuvant Cisplatin Evaluation)-Bio consortium was utilized. CNAs were categorized as Gain (CN ≥2) or Neutral (Neut)/Loss; KRAS status was defined as wild type (WT) or mutant (MUT). The following groups were compared in all patients and the adenocarcinoma subgroup, and were correlated to survival endpoints using a Cox proportional hazards model: WT + Neut/Loss (reference), WT + Gain, MUT + Gain and MUT + Neut/Loss. A treatment-by-variable interaction was added to evaluate predictive effect. RESULTS: Of the 946 (399 adenocarcinoma) NSCLC patients, 41 [30] had MUT + Gain, 145 [99] MUT + Neut/Loss, 125 [16] WT + Gain, and 635 [254] WT + Neut/Loss. A non-significant trend towards worse lung cancer-specific survival (LCSS; HR =1.34; 95% CI, 0.83-2.17, P=0.232), DFS (HR =1.34; 95% CI, 0.86-2.09, P=0.202) and OS (HR =1.59; 95% CI, 0.99-2.54, P=0.055) was seen in KRAS MUT + Gain patients relative to KRAS WT + Neut/Loss patients. A negative prognostic effect of KRAS MUT + Neut/Loss was observed for LCSS (HR =1.32; 95% CI, 1.01-1.71, P=0.038) relative to KRAS WT + Neut/Loss on univariable analysis, but to a lesser extent after adjusting for covariates (HR =1.28; 95% CI, 0.97-1.68, P=0.078). KRAS MUT + Gain was associated with a greater beneficial effect of chemotherapy on DFS compared to KRAS WT + Neut/Loss patients (rHR =0.33; 95% CI, 0.11-0.99, P=0.048), with a non-significant trend also seen for LCSS (rHR =0.41; 95% CI, 0.13-1.33, P=0.138) and OS (rHR =0.40; 95% CI, 0.13-1.26, P=0.116) in the adenocarcinoma subgroup. CONCLUSIONS: A small prognostic effect of KRAS mutation was identified for LCSS, and a trend towards worse LCSS, DFS and OS was noted for KRAS MUT + Gain. A potential predictive effect of concomitant KRAS mutation and copy number gain was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require validation.

Assessment Of Tumour Infiltrating Lymphocytes And Pd-l1 Expression In Adenoid Cystic Carcinoma Of The Salivary Gland.

PURPOSE: Early phase clinical studies are ongoing to evaluate the role of immune checkpoint inhibitors in adenoid cystic carcinoma (ACC) despite a paucity of information on the immune microenvironment. This study aims to better characterize the immune microenvironment of ACC tumours and evaluate survival outcomes based on tumour infiltrating lymphocyte (TIL) and programmed death-ligand 1 (PD-L1) expression. METHODS: Patient characteristics, treatment and outcome data were collected for 24 ACC patients. The CD8+(cluster of differentiation 8) TIL and PD-L1 expression were quantified by immunohistochemistry. Marker expression and survival outcomes were evaluated by Kaplan-Meier analysis. RESULTS: All cases were negative for PD-L1 expression; four cases had focal high, eight cases had focal moderate and 12 cases had low TIL expression. Based on TIL expression, there was no difference in disease-free or overall survival. CONCLUSION: Adenoid cystic carcinoma tumours were found to be associated with a poor immunogenic microenvironment, with absent PD-L1 expression and low CD8+ TILs. There was no association between TIL expression and survival. These data suggest that PD-L1 and TIL expression are unlikely to be useful as predictive biomarkers for response to immunotherapy.

A single institution study evaluating outcomes of PD-L1 high KRAS-mutant advanced non-small cell lung cancer (NSCLC) patients treated with first line immune checkpoint inhibitors.

AIM: This study aimed to evaluate the impact of KRAS status on the efficacy of first-line immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced incurable or metastatic NSCLC with PD-L1 ≥50% treated with palliative-intent, single-agent PD-1/PD-L1 inhibitors at the Cancer Centre of Southeastern Ontario were included. KRAS mutation status was determined via massively parallel sequencing. Primary study outcome was median overall survival (mOS). RESULTS: Seventy-eight patients (59 non-squamous, 19 squamous) were identified; only non-squamous patients were included in KRAS mutation analyses. Thirty patients (51%) were KRAS-MT (mutant), with G12C (19%), G12V (15%), and G12D (13%) accounting for the most common KRAS mutation subtypes. There was no difference in mOS between KRAS-MT and KRAS-WT (wild-type) patients (12.9 vs. 19.3 months, p = 0.879). There was a non-significant trend towards worse mOS in KRAS G12C patients compared to non-G12C and KRAS-WT patients (11.4 vs. 44.9 vs. 19.3 months, p = 0.772). On multivariable analysis, KRAS-MT status was not associated with mOS (HR 0.901, 95%CI 0.417-1.946, p = 0.791). ECOG≥2 was an independent prognostic factor for worse mOS (HR 2.853, 95%CI 1.237-6.583, p = 0.014). Immune-related adverse events did not differ between KRAS-MT and KRAS-WT groups (48% vs. 52%, p = 1.000). CONCLUSIONS: KRAS mutation status did not have a significant impact on ICI efficacy or safety. However, a non-significant trend towards worse survival was noted in patients treated with ICI whose tumours harboured the KRAS G12C variant. This study provides valuable information for comparative analysis in the future.

CXCR4 expression in lung carcinogenesis: Evaluating gender-specific differences in survival outcomes based on CXCR4 expression in early stage non-small cell lung cancer patients.

INTRODUCTION: Evidence suggests that the expression of certain cytokine receptors increases with lung cancer evolution. Overexpression of the cytokine receptor CXCR4 is associated with poor outcomes in stage IV non-small cell lung cancer (NSCLC), with shorter survival in females with high CXCR4 expression. This study quantifies CXCR4 expression in early stage disease and evaluates its association with gender-specific recurrence-free (RFS) and overall survival (OS) in resected stage I-III NSCLC patients. METHODS: Patient characteristics and clinical outcomes were obtained from the Glans-Look Lung Cancer (G-LLC) database for early stage NSCLC patients diagnosed between 2003-2006 at the Tom Baker Cancer Centre (TBCC). CXCR4 expression was quantified on tissue microarrays (TMA). Median RFS and OS were evaluated by gender using Kaplan-Meier analyses. CXCR4 expression and outcome data were analyzed using Cox proportional hazards (PH) and multi-state models (MSM). RESULTS: 176 stage I-III NSCLC patients were identified. CXCR4 expression was lower in early stage NSCLC patients, with a mean CXCR4 expression of 1729 (SD 1083) compared to 2640 (SD 1541) in stage IV patients. On Kaplan-Meier, median RFS by gender was similar (male 52.8 months vs. female 54.5 months) as was median OS (male 80.9 months vs. female 89.0 months), and there was no significant difference in RFS (p = 0.60) or OS (p = 0.30) by gender and CXCR4 groups over follow-up. By multivariable analysis, CXCR4 expression was not prognostic for RFS (Hazard Ratio (HR) = 1.00, p = 0.73) or OS (HR = 1.00, p = 0.44), and no gender difference was observed. CONCLUSIONS: CXCR4 expression increases with stage progression in NSCLC but is not prognostic in early stage NSCLC patients of either gender. Mechanisms by which CXCR4 expression increases during lung carcinogenesis warrant further exploration and testing in clinical trials.

A real-world comparison of cisplatin vs cetuximab used concurrently with radiation in the treatment of locally advanced oropharyngeal carcinoma.

BACKGROUND: This population-based retrospective study compares the efficacy of cisplatin (cis-RT) vs cetuximab (cetux-RT) with concurrent radiation as definitive treatment in patients with oropharyngeal carcinoma (OPC). METHODS: Patients with OPC treated in Alberta with cis-RT or cetux-RT between 2006 and 2016 were evaluated. Median disease-free survival (DFS) and overall survival (OS) were assessed using the Kaplan-Meier method. Multivariable analysis (MVA) was completed with a Cox proportional hazards model. RESULTS: Among 546 patients with OPC, 431 (78.9%) received cis-RT and 115 (21.1%) cetux-RT. Patients treated with cetux-RT were more likely to develop a recurrence after treatment compared to cis-RT (25% vs 15%, P = .01). On MVA, current smoking, human papillomavirus (HPV)-negative status, higher Charlson comorbidity index (CCI), T-stage, and cetux-RT predicted for worse DFS and OS. Outcomes in older patients with a higher CCI still favored cis-RT. CONCLUSIONS: Our data reaffirm results from randomized studies showing better survival outcomes with cis-RT compared to cetux-RT even among those who are >65 with CCI ≥3.