Development and Validation of a Prognostic Risk Model for Patients with Advanced Melanoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Risk stratification tools for patients with advanced melanoma (AM) treated with immune checkpoint inhibitors (ICI) are lacking. We identified a new prognostic model associated with overall survival (OS). PATIENTS AND METHODS: A total of 318 treatment naïve patients with AM receiving ICI were collected from a multi-centre retrospective cohort study. LASSO Cox regression identified independent prognostic factors associated with OS. Model validation was carried out on 500 iterations of bootstrapped samples. Harrel's C-index was calculated and internally validated to outline the model's discriminatory performance. External validation was carried out in 142 advanced melanoma patients receiving ICI in later lines. RESULTS: High white blood cell count (WBC), high lactate dehydrogenase (LDH), low albumin, Eastern Cooperative Oncology Group (ECOG) performance status ≥1, and the presence of liver metastases were included in the model. Patients were parsed into 3 risk groups: favorable (0-1 factors) OS of 52.9 months, intermediate (2-3 factors) OS 13.0 months, and poor (≥4 factors) OS 2.7 months. The C-index of the model from the discovery cohort was 0.69. External validation in later-lines (N = 142) of therapy demonstrated a c-index of 0.65. CONCLUSIONS: Liver metastases, low albumin, high LDH, high WBC, and ECOG≥1 can be combined into a prognostic model for AM patients treated with ICI.

Comparing the associations between host and tumor factors with survival outcomes with anti-PD-1 immunotherapy in metastatic melanoma.

BACKGROUND: Anti-programmed death-1 (PD-1) immunotherapy has drastically improved survival for metastatic melanoma; however, 50% of patients have progression within 6 months despite treatment. In this study, we investigated host, and tumor factors for metastatic melanoma patients treated with anti-PD-1 immunotherapy. METHODS: Patients treated with the anti-PD-1 immunotherapy between 2014 and 2017 were identified in Alberta, Canada. All patients had Stage IV melanoma. Patient characteristics, investigations, treatment, and clinical outcomes were obtained from electronic medical records. RESULTS: We identified 174 patients treated with anti-PD-1 immunotherapy. At 37.1 months median follow-up time 135 (77.6%) individuals had died and 150 (86.2%) had progressed. An elevated lactate dehydrogenase (LDH) had a response rate of 21.0% versus 41.0% for those with a normal LDH (p = 0.017). Host factors associated with worse median progression-free survival (mPFS) and median overall survival (mOS) included liver metastases, >3 sites of disease, elevated LDH, thrombocytosis, neutrophilia, anemia, lymphocytopenia, and an elevated neutrophil/lymphocyte ratio. Primary ulcerated tumors had a worse mOS of 11.8 versus 19.3 months (p = 0.042). We identified four prognostic subgroups in advanced melanoma patients treated with anti-PD-1 therapy. (1) Normal LDH with <3 visceral sites, (2) normal LDH with ≥3 visceral sites, (3) LDH 1-2x upper limit of normal (ULN), (4) LDH ≥2x ULN. The mPFS each group was 14.0, 6.5, 3.3, and 1.9 months, while the mOS for each group was 33.3, 15.7, 7.9, and 3.4 months. CONCLUSION: Our study reports that host factors measuring the general immune function, markers of systemic inflammation, and tumor burden and location are the most prognostic for survival.

Clinical Course and Treatment Implications of Combination Immune Checkpoint Inhibitor-Mediated Hepatitis: A Multicentre Cohort.

BACKGROUND: Immune-related adverse events can occur after treatment with immune checkpoint inhibitors (ICI), limiting treatment persistence. We aimed to evaluate the clinical course of ICI-mediated hepatitis (IMH) associated with combination ipilimumab and nivolumab treatment. METHODS: A retrospective cohort study including consecutive patients with metastatic melanoma treated with ipilimumab and nivolumab between 2013 and 2018 was conducted at two tertiary care centres. IMH was defined by the Common Terminology Criteria for Adverse Events (CTCAE). We determined the proportion of patients developing IMH, and compared the duration, treatment patterns and outcomes, stratified by hepatitis severity. Kaplan-Meier survival analysis was used to evaluate time to hepatitis resolution, and a linear mixed-effects model was used to compare longitudinal outcomes by treatment. RESULTS: A total of 63 patients were included. Thirty-two patients (51%) developed IMH (34% Grade 1-2, 66% Grade 3-4), at a median of 34 days (IQR 20 to 43.5 days) after the first dose. Baseline FIB4 index ≥1.45 was associated with IMH (OR 3.71 [95% CI: 1.03 to 13.38], P = 0.04). Ninety-four per cent (30/32) of patients had liver enzyme normalization after a median duration of 43 days (IQR 26 to 70 days). Corticosteroid use was not associated with faster IMH resolution or less ICI discontinuation. A total of 24 patients died during the study; no deaths were attributable to hepatitis-related complications. Fifty-three per cent (17/32) of patients resumed anti-PD-1 monotherapy and three patients developed IMH recurrence. CONCLUSIONS: Approximately half of the patients treated with combination ipilimumab and nivolumab developed IMH in this cohort. However, most patients experienced uncomplicated IMH resolution.

Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma.

INTRODUCTION: Objective response rates (ORR) appear to be higher in melanoma patients who develop immune-related adverse events (irAEs), but whether there is a similar association between irAEs and survival remains unknown. MATERIALS AND METHODS: Patients with advanced melanoma treated with single-agent pembrolizumab or nivolumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAEs that occurred while on anti-programmed cell death protein 1 (PD-1) checkpoint inhibitors. The primary objective was to compare overall survival (OS) with patients who developed any irAEs versus those who did not. Secondary outcomes included progression-free survival (PFS) and ORR. RESULTS: Among 186 patients, any-grade and grade ≥3 irAEs occurred in 88 (47%) and 27 (15%) patients, respectively; one patient died of pneumonitis. In a landmark analysis excluding patients who died within the first 12 weeks, the median follow-up was 24 months, 20 months in patients without any irAEs and 26 months in patients with irAEs (p = .006). Median OS was 39 versus 23 months (hazard ratio [HR], 0.46; p = .001) for any irAE and no irAE, respectively, and median OS not reached versus 29 months for grade ≥3 irAEs and no grade ≥3 irAEs, respectively. In multivariate analysis, elevated lactate dehydrogenase correlated with reduced OS (HR, 2.34; p = .001), whereas each additional cycle of treatment received (HR, 0.94; p < .001) and development of grade ≥3 irAEs (HR, 0.29, p = .024) were significantly associated with longer OS. CONCLUSION: Anti-PD-1-associated grade ≥3 irAEs in patients with advanced melanoma is associated with better patient outcomes, including overall survival. IMPLICATIONS FOR PRACTICE: Previous prospective randomized clinical trials demonstrate improved response rates in patients with melanoma who develop select adverse events. The current population-based real-world study in advanced melanoma reports an association with anti-programmed cell death protein 1 (PD-1)-induced grade ≥3 immune-related adverse events (irAEs) and better patient outcomes, including overall survival. These results suggest that irAEs may be a manifestation of a patient's ability to mount a systemic immune response from PD-1-directed therapies, which may be associated with therapeutic benefit. The finding of irAEs coinciding with clinical benefit from these therapies supposes that these events are, by and large, unavoidable, and the critical management of irAEs remains essential for optimizing patient outcomes.

The Lung Immune Prognostic Index Discriminates Survival Outcomes in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of several solid tumor types. However, as patient outcomes are heterogeneous, clinical tools to aid in prognostication are needed. The Lung Immune Prognostic Index (LIPI) correlates with outcomes in patients with non-small cell lung cancer (NSCLC) treated with ICI, but its applicability beyond NSCLC is poorly defined. We sought to determine whether LIPI is associated with overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in a pooled, real-world, retrospective cohort of patients with solid tumors treated with ICI. Of the total pooled cohort (N = 578), 47.2%, 38.2% and 14.5% of patients were stratified into good, intermediate and poor LIPI group, respectively. Median OS were 22.8 (95% CI 17.4-29.5), 7.8 (95% CI 6.6-9.6), and 2.5 months (95% CI 1.4-3.4) (p < 0.0001). Median PFS were 9.9 (95% CI 7.2-11.5), 3.6 (95% CI 2.7-4.3), and 1.4 months (95% CI 1.2-2.2) (p < 0.0001). ORR was also associated with LIPI group (p < 0.001). Intermediate and poor LIPI were independently prognostic of OS compared to good LIPI, with hazard ratios (HR) of 1.8 (95% CI 1.4-2.3, p < 0.001) and 3.6 (95% CI 2.5-5.1, p < 0.001), respectively. These data are the first to suggest that in a real-world setting, the prognostic value of LIPI may be tumor agnostic.

Cav3.1 overexpression is associated with negative characteristics and prognosis in non-small cell lung cancer.

INTRODUCTION: Voltage-gated calcium channels (VGCC) have been found to be differentially expressed in several different tumor types, but their role in tumor growth, malignant invasion, metastases and impact on clinical outcomes has not been clarified. MATERIALS AND METHODS: From a cohort database of 193 patients with early-stage NSCLC, 163 formalin-fixed paraffin-embedded specimens were available for analysis to construct tissue microarrays. Cav3.1 protein expression was detected using fluorescence immunohistochemistry, and quantified using automated image acquisition and analysis. RESULTS: Among the cohort of 193 NSCLC patients, adenocarcinoma (53.9%) and squamous cell carcinoma (SCC) (30.1%) were the most common histologies. There was no difference between SCC and non-SCC subtypes in overall survival (OS) or relapse-free survival (RFS); 74.2 vs 90.1 months (p = 0.543) and 48.8 vs 52.6 months (p = 0.766), respectively. T-type VGCC 3.1 (Cav3.1) overexpression was assessed by tissue microarray immunohistochemistry analysis from 163 available patient samples. Eighteen (11.0%) NSCLC primaries were found to have Cav3.1 overexpression levels, and were significantly associated with SCC histology (p < 0.001), larger tumor size (p < 0.001) and later stage disease at diagnosis (p = 0.019). Median OS was 48.6 vs 106.7 months for Cav3.1 overexpressing and non-overexpressing patients, respectively (p = 0.032). Regression analysis revealed a significantly negative effect for Cav3.1 overexpression on RFS (Hazard ratio [HR] = 2.02, p = 0.048). CONCLUSIONS: Cav3.1 overexpression is a potential biomarker for poorer patient outcomes. These results bring supportive evidence for calcium channels inducing an aggressive phenotype in NSCLC and potentially may serve as a therapeutic target in overexpressing tumors.

Outcomes and Drug Costs of Sunitinib Regimens for Metastatic Renal Cell Carcinoma: A Provincial Population-Based Study.

BACKGROUND: Conventional sunitinib dosing in metastatic renal cell carcinoma (mRCC) administers 50 mg daily on a 4 weeks on/2 weeks off (4/2) schedule. Not all patients tolerate this regimen and many undergo modifications to schedule, dose, or both. MATERIAL AND METHODS: All patients with mRCC treated with sunitinib by the Saskatchewan Cancer Agency between January 1, 2006, and January 1, 2013, were included. Regimens were categorized as standard intermittent dosing (SID), modified intermittent schedule (MIS), modified intermittent dosing (MID), combination of modified schedule and dosing (MSD), or continuous dosing (CD). The primary objective was to compare overall survival (OS) between regimens. Secondary outcomes included progression-free survival (PFS), discontinuation due to adverse effects (AE), and medication cost. RESULTS: Among 161 patients, 18.0%, 51.6%, and 30.4% had favorable, intermediate, and poor Heng risk prognoses, respectively. A total of 140 (87.0%) received sunitinib as first-line therapy. MID was associated with longer OS compared with SID (estimated median 28.4 vs. 11.2 months). PFS was longer for MID, MSD, and CD compared with SID (estimated median 12.0, 9.0, and 8.0 months vs. 3.0 months, respectively). Adjustment for potential confounders did not negate these associations. SID also had higher average monthly drug costs than MIS, MID, and MSD. Overall discontinuation rate due to AE was high (24%). CONCLUSION: An adjusted-dose sunitinib regimen is associated with improved OS and PFS over SID, with lower costs. The development of toxicities requiring dose reductions serves as a predictive biomarker for better outcomes.