Faculty Bibliography

Many decades in the making, immunotherapy has demonstrated its ability to produce durable responses in several cancer types. In the last decade, immunotherapy has shown itself to be a viable therapeutic approach for non-small cell lung cancer (NSCLC). Several clinical trials have established the efficacy of immune checkpoint blockade (ICB), particularly in the form of anti-programmed death 1 (PD-1) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies and anti-programmed death 1 ligand (PD-L1) antibodies. Many trials have shown progression free survival (PFS) and overall survival (OS) benefit with either ICB alone or in combination with chemotherapy when compared to chemotherapy alone. The identification of biomarkers to predict response to immunotherapy continues to be evaluated. The future of immunotherapy in lung cancer continues to hold promise with the development of combination therapies, cytokine modulating therapies and cellular therapies. Lastly, we expect that innovative advances in technology, such as artificial intelligence (AI) and machine learning, will begin to play a role in the future care of patients with lung cancer.

INTRODUCTION:Programmed death-ligand 1 (PD-L1) is used as a biomarker for anti-programmed cell death protein-1 (PD-1) or anti-PD-L1 immunotherapies in NSCLC. We report here the results of population-based PD-L1 testing using the 22C3 IHC pharmDx Assay (Agilent Technologies) in a large Canadian regional reference pathology laboratory. METHODS:Testing was conducted reflexively on biopsies and resections for NSCLC during an 8-month period. Tumor proportion score (TPS) cutoffs for low and high expression were 1% and 50%, respectively. RESULTS:area (p < 0.026). Concordance among 27 patients with paired primary lung and metastatic tumor biopsies revealed only weak concordance (κ = 0.48). CONCLUSIONS:Intratumoral heterogeneity of PD-L1 expression may result in misclassification of PD-L1 status in a substantial proportion of PD-L1-negative small biopsy samples. Biopsy of metastatic site may increase proportion of patients with high PD-L1 expression.

INTRODUCTION:The efficacy of immune checkpoint inhibitors (ICIs) is low among EGFR-mutated non-small-cell lung cancer (NSCLC), although prolonged responses have occasionally been reported. We investigated the association between mutation subtypes and ICI outcomes among HER2- and EGFR-mutated NSCLC. PATIENTS AND METHODS:This retrospective single-center study analyzed patients with EGFR- and HER2-mutated advanced NSCLC who received at least 1 cycle of ICI between 2013 and 2019. Patient characteristics, mutation subtype, and ICI outcomes. RESULTS:Among 48 patients with advanced NSCLC, 14 (29%) had HER2 mutations and 34 (71%) had EGFR mutations. EGFR mutations included 16 (47%) exon 19 deletion, 7 (21%) L858R, 5 (15%) uncommon, and 6 (18%) exon 20 insertion. Compared to EGFR-sensitizing mutations (ESMs), HER2 and EGFR exon 20 mutations were associated with a trend toward better response (respectively, ESM, HER2, and EGFR exon 20: 11%, 29%, and 50%; P = .07) and significantly better disease control rates (respectively, 18%, 57%, and 67%; P = .008). Compared to ESM, HER2 mutations (adjusted hazard ratio, 0.35; P = .02) and EGFR exon 20 mutations (adjusted hazard ratio, 0.37; P = .10 trend) were also associated with improved PFS. Programmed death ligand 1 (PD-L1) expression remained an independent predictor of PFS (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23-0.76; P = .004). The 6-month PFS rates were 29% (HER2), 33% (EGFR exon 20), and 4% (ESM). ICIs were generally well tolerated in this population. Importantly, no immune-related toxicity was observed in 10 patients who received a tyrosine kinase inhibitor (TKI) as the immediate next line treatment after ICI. CONCLUSION:HER2 and EGFR exon 20 mutations derive greater benefit from ICIs with comparable PFS to wild-type historical second/third-line unselected cohorts. ICIs remain a treatment option for this genomic subgroup, given the absence of approved targeted therapies for these rare mutations.

BACKGROUND:Immune checkpoint inhibitors (ICIs) have excellent systemic activity and are standard first line treatment in EGFR/ALK wild type metastatic non-small cell lung cancer (NSCLC). However, their role in patients with brain metastases, which affects over 20% of patients and cause significant morbidity, is less clear. METHODS:We reviewed patients with EGFR/ALK wild-type mNSCLC with CNS metastases. Serial MRIs were reviewed to determine the time to intracranial progression (iPFS). Multivariate regression was performed to adjust for the disease-specific graded prognostic score (ds-GPA). RESULTS:We identified 36 ICI- and 33 chemotherapy-treated patients with baseline CNS metastases and available serial MRIs (average frequency:3.5 months). Baseline radiation was given except for 2 chemotherapy-treated patients with asymptomatic solitary metastasis. The CNS burden of disease was higher in the ICI-treated group (ICI:22% vs. chemotherapy:0% had >10 lesions; p = 0.02), but the utilization of WBRT was not (ICI:31% vs. chemotherapy:45%; p = 0.09). At the time of progression, CNS involvement was identified in 30 % of ICI-treated patients compared to 64 % of chemotherapy controls (p = 0.02). ICI-treated patients had superior iPFS (13.5 vs 8.4 months) that remained significant in multivariate analysis (HR 1.9; 95%CI 1.1--3.4). Superior CNS outcomes in ICI-treated patients were driven by the PD-L1 high subgroup where the 12-month cumulative incidence rate of CNS progression was 19% in ICI-treated PD-L1 ≥ 50%, 50% in ICI-treated PD-L1 < 50% and 58% in chemotherapy-treated patients (p = 0.03). CONCLUSIONS:Remarkable CNS disease control is seen with baseline RT plus ICIs in patients with PD-L1 ≥ 50%. Strategies for delaying WBRT should be investigated in this subgroup of patients.

BACKGROUND:The PACIFIC trial demonstrated that durvalumab therapy following chemoradiation (CRT) was associated with improved overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC). It is unclear whether the results obtained as part of randomised controlled trials are a reflection of real-world (RW) data. Several questions remain unanswered with regard to RW durvalumab use, such as optimal time to durvalumab initiation, incidence of pneumonitis and response in PD-L1 subgroups. METHODS:In this multicentre retrospective analysis, 147 patients with stage III NSCLC treated with CRT followed by durvalumab were compared with a historical cohort of 121 patients treated with CRT alone. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test in univariate analysis. Multivariate analysis was performed to evaluate the effect of standard prognostic factors for durvalumab use. RESULTS:Median OS was not reached in the durvalumab group, compared with 26.9 months in the historical group (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.37-0.85, p = 0.001). In the durvalumab group, our data suggest improved 12-month OS in patients with PD-L1 expression ≥50% (100% vs 86%, HR: 0.25, 95% CI: 0.11-0.58, p = 0.007). There was no difference in OS between patients with a PD-L1 expression of 1-49% and patients with PD-L1 expression <1%. Delay in durvalumab initiation beyond 42 days did not impact OS. Incidence of pneumonitis was similar in the durvalumab and historical groups. In the durvalumab group, patients who experienced any-grade pneumonitis had a lower 12-month OS than patients without pneumonitis (85% vs 95%, respectively; HR: 3.3, 95% CI: 1.2-9.0, p = 0.006). CONCLUSIONS:This multicentre analysis suggests that PD-L1 expression ≥50% was associated with favourable OS in patients with stage III NSCLC treated with durvalumab after CRT, whereas the presence of pneumonitis represented a negative prognostic factor.

BACKGROUND:Tobacco exposure contributes to over 80 % of lung cancer cases. Smoking is associated with programmed death-ligand 1 (PD-L1) tumor expression and better outcomes from anti-programmed cell death protein 1 (anti-PD-1) therapy in patients with advanced non-small cell lung cancer (NSCLC). PD-L1 tumor expression is now routinely used to predict benefit from anti-PD-1 therapy in patients with advanced NSCLC. In this study, we explored the impact of smoking status on patient outcomes with anti-PD-1 therapy in addition to PD-L1 tumor expression. METHODS:A prospective real-world cohort of 268 patients with advanced NSCLC treated with anti-PD-1 monotherapy at the Princess Margaret Cancer Centre (PMCC) was used for this analysis. Logistic regression was performed to test factors associated with treatment response (RECIST v1.1), including PD-L1 tumour proportion score (TPS) and smoking status. RESULTS:Overall response rates (ORR) to immunotherapy were significantly higher in current and former smokers than never smokers (36 % vs 26 % vs 14 %; p = 0.02). In patients with PD-L1 tumour proportion score (TPS) ≥50 %, current smokers continued to experience better ORR to anti-PD-1 therapy than never smokers (58 % vs 19 %; p = 0.03). Current smoking was associated with higher response even after adjusting for level of PD-L1 TPS expression (adjusted odds ratio 5.9, 95 % CI 1.6-25.0, p = 0.03). Exploratory analysis demonstrated higher 1-year survival rates in smokers compared to never smokers (p = 0.003). CONCLUSIONS:Smoking remains an important factor associated with response to anti-PD-1 monotherapy. Advanced NSCLC patients with positive PD-L1 expression are more likely to respond to anti-PD-1 monotherapy if they are current smokers compared to never smokers.

INTRODUCTION:Second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) appear superior to first-generation TKIs in clinical trials, but at the cost of greater toxicity. It is unclear whether real-world patients, who often suffer worse outcomes, experience similar survival benefits. Using population-based data, we aim to characterize outcome differences by type of treatment. PATIENTS AND METHODS:We reviewed all patients with advanced non-small-cell lung cancer who initiated treatment with an EGFR TKI at BC Cancer between 2010 and 2015. A propensity score was generated to account for imbalances in patient characteristics between treatment groups. A Cox proportional hazards model based on the propensity score was then used to estimate effects of treatment on survival. RESULTS:A total of 484 patients were identified for analysis. Patients in the second-generation cohort were younger (62 vs. 67 years), had less baseline central nervous system metastases (9% vs. 22%), and more uncommon EGFR mutations (13% vs. 7%). Patients receiving a second-generation TKI had an improved overall survival (hazard ratio, 0.69; P = .05), driven by the subgroup with an EGFR exon 19 deletion. Patients with a L858R mutation did not appear to derive benefit from a second-generation TKI (hazard ratio, 0.91; P = .74). Overall, 40% of patients receiving a second-generation TKI required a dose reduction, but only 1% required discontinuation. CONCLUSIONS:Second-generation TKIs tended to be chosen over first-generation TKIs as frontline therapy in younger patients with uncommon EGFR mutations and without central nervous system metastases. The survival benefit of a second-generation TKI seen in clinical trials appeared to be generalizable to real-world patients and is a reasonable first-line therapy.

INTRODUCTION:Financial distress has been established as a clinically relevant patient-reported outcome associated with worse mortality and quality of life. Our goal was to define factors associated with financial burden (FB) in a public health care system. MATERIALS AND METHODS:Patients with advanced lung cancer were recruited from outpatient clinics at the Princess Margaret Cancer Centre (Toronto, Canada). FB was measured with the validated Comprehensive Score for Financial Toxicity (COST) instrument, a 12-item survey scored from 0 to 44, with lower scores reflecting worse financial well-being. Data on patient and treatment characteristics, total out-of-pocket costs (OOP), and private insurance coverage were collected. Multivariable logistic regression models were fit for COST score and each variable, to determine factors associated with greater FB (COST < 21). RESULTS:Of 251 patients approached, 200 (80%) participated. The median age of the cohort was 65 years; 56% were female. The median total OOP ranged between $1000 and $5000 CAD. The median COST score was 21 (range, 0-44). FB was associated with age, with patients < 65 years reporting greater FB than older patients (COST, 18.0 vs. 24.0; P < .0001). In multivariable logistic regression analysis, younger age was associated with greater FB, when adjusting for income, employment status, OOP, and private insurance coverage (odds ratio, 3.6; 95% confidence interval, 1.5-9.1; P < .0001). CONCLUSION:Age is significantly associated with FB in the Canadian (Ontario) public health care system, with younger patients with lung cancer reporting greater financial distress. This study highlights priority patient populations where FB should be routinely assessed and appropriate resources for support offered.