Safety and efficacy of immune checkpoint blockade in patients with advanced nonsmall cell lung cancer and brain metastasis.

The presence of brain metastases (BM) is a negative prognostic factor for patients with advanced nonsmall cell lung cancer (NSCLC). Their incidence seems to be higher in patients with oncogene-driven tumours, especially those with EGFR-mutated or ALK-rearranged tumours. Although targeted treatments demonstrate significant efficacy regarding BM, they only apply to a minority of NSCLC patients. On the other hand, systemic therapies for nononcogenic-driven NSCLC with BM have shown limited clinical benefit. In recent years, immunotherapy alone or combined with chemotherapy has been adopted as a new standard of care in first-line therapy. This approach seems to be beneficial to patients with BM in terms of efficacy and toxicity. Combined immune checkpoint inhibition as well as the combination of immunotherapy and radiation therapy show promising results with significant, but overall acceptable toxicity. A pragmatic approach of allowing enrolment of patients with untreated or symptomatic BM in randomised trials evaluating immune checkpoint inhibitors strategies, possibly coupled with central nervous system-related endpoints may be needed to generate data to refine treatment for this patient population.

Price trends of reimbursed oncological drugs in Switzerland in 2005-2019: A descriptive analysis.

Increasing oncological treatment costs are a major global concern with the risk of entailing two-tiered health care. Among cost determining factors is the price of individual drugs. In recognition of the central role of this factor, we present a comprehensive overview of the development of monthly prices of oncological drugs introduced over the last 15 years in Switzerland. We identified all oncological drugs newly reimbursed by mandatory health insurance in 2005-2019, and searched public repositories for their package prices, indications with approval dates, and treatment regimens for the calculation of (indication-specific) monthly prices. We found 81 products covering 77 different substances (39.5% protein kinase inhibitors, 21.0% monoclonal antibodies). Most indications related to the topography "blood", followed by "lung and thorax" and "digestive tract". From 2005­2009 to 2015­2019, the median monthly product price over all distinct indications of all products decreased by 7.56% (CHF 5,699 [interquartile range 4,483­7,321] to CHF 5,268 [4,019­6,967]), whereas it increased by 73.7% for monoclonal antibodies. In December 2019, six products had monthly prices over CHF 10,000, all approved for hematological or dermatological cancers. Our analysis suggests that individual price developments of oncological drugs are presently not the major driver of rising cancer treatment costs. However, rising launch prices of some new, mostly hematological drugs are of concern and require continued monitoring.

Fingolimod and tumor-infiltrating lymphocytes in checkpoint-inhibitor treated cancer patients.

Immune checkpoint inhibitors (ICIs) are emerging as the new standard of care for treating various metastatic cancers. It is known that effective anti-tumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes (TILs) in solid tumor tissue. Cancer patients with relapsing-remitting multiple sclerosis (RRMS) are often under continuous treatment with fingolimod, an immune-modulating drug that inhibits lymphocyte egress from secondary lymphatic organs. Little is known about the effect of fingolimod on ICI cancer therapy, as fingolimod may limit the number of TILs. Here we present three patients with RRMS, who developed various cancers during fingolimod treatment. Histology of all tumors consistently showed low numbers of TILs. A second biopsy taken from one of the tumors, a melanoma, revealed a significant increase of TILs after stopping fingolimod and starting pembrolizumab, indicating a surge in the number and re-invigoration of T cells. Our study suggests that fingolimod limits the number of TILs in solid tumors and may, thus, inhibit anti-cancer immune responses.

First-Line Immune Checkpoint Inhibition for Advanced Non-Small-Cell Lung Cancer: State of the Art and Future Directions.

The advent of PD-(L)1 and CTLA-4 immune check point inhibitors (CPIs) has dramatically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC). For up to a quarter of patients with advanced NSCLC, CPIs have the potential to induce durable responses with long-term survival outcomes. Since the approval of first-line pembrolizumab for patients whose tumors express a PD-L1 ≥ 50%, several pivotal first-line CPI-based phase 3 studies have been conducted investigating combination treatments combining CPIs with chemotherapy (ChT) or combining different CPIs with or without ChT. As a result, there has been an increase in front-line treatment options for advanced NSCLC, and treatment algorithms are changing very quickly. In fit patients with advanced NSCLC, combination treatments including CPI and ChT are considered the new standard of care with improved clinical outcomes. CPI combination treatments are well tolerated and quality of life also seems to be better when CPIs are implemented in the first-line setting. The aim of this review is to provide a summary of the recently published first-line phase 3 studies investigating CPIs as monotherapy or in combination with other CPIs or ChT in advanced NSCLC, and to suggest possible treatment algorithms.

Targeted Therapy For RET-Rearranged Non-Small Cell Lung Cancer: Clinical Development And Future Directions.

Approximately 1-2% of unselected patients with Non-small Cell Lung Cancer (NSCLC) harbor RET rearrangements resulting in enhanced cell survival and proliferation. The initial treatment strategy for RET rearranged NSCLC has been multi-target tyrosine kinase inhibition. With overall response rates (ORR) of 16-53% and a median progression-free survival (PFS) of 4.5-7.3 months these outcomes are clearly inferior to the efficacy outcomes of selective tyrosine kinase inhibitors (TKI) in other oncogene-addicted NSCLC. Additionally, multi-kinase inhibition in RET-driven NSCLC patients showed concerning rates of high-grade toxicity, mainly induced by anti-VEGFR-kinase activity. Novel selective RET inhibitors like BLU-667, LOXO-292 and RXDX-105 have been recently investigated in early phase clinical trials showing promising efficacy with a manageable toxicity profile.

First-line immune checkpoint blockade for advanced non-small-cell lung cancer: Travelling at the speed of light.

The development of PD-1, PD-L1 and CTLA-4 immune checkpoint inhibitors (CPI) has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC). The potential of immunotherapy (IO) to induce durable responses for a subset of patients represents a therapeutic milestone. After the approval of front-line single agent pembrolizumab, IO-based combinations are rapidly entering clinical practice resulting in a fast change of treatment algorithms for advanced NSCLC. We hereby summarize the recent first-line phase 3 trials evaluating PD-(L)1 blockade plus chemotherapy (ChT) and PD-1 plus CTLA-4 CPI for advanced NSCLC and provide potential treatment recommendations.

Risk score for non-small cell lung cancer patients starting checkpoint inhibitor treatment.

BACKGROUND: Prognosis of metastatic non-small cell lung cancer significantly improved with the availability of checkpoint inhibitors (anti-PD-1/PD-L1). Unfortunately, reliable biomarkers to predict treatment benefit are lacking. PATIENTS AND METHODS: We prospectively collected clinical and laboratory data of 56 non-small cell lung cancer patients treated with a checkpoint inhibitor. The aim was to identify baseline parameters correlating with worse outcome and to create a risk score that enabled to stratify patients into different risk groups. As inflammation is known to promote tumor growth, we focused on inflammation markers in the blood. Disease control (DC) was defined as complete response, partial response, and stable disease on CT scan according to RECIST 1.1. RESULTS: Half of the patients achieved DC. Four parameters differed significantly between the DC group and the no disease control group: Eastern Cooperative Oncology Group performance status (P=0.009), number of organs with metastases (P=0.001), lactate dehydrogenase (P=0.029), and ferritin (P=0.005). A risk score defined as the number of these parameters (0= no risk factor) exceeding a threshold (Eastern Cooperative Oncology Group performance status ≥2, number of organs with metastases ≥4, lactate dehydrogenase ≥262U/L, and ferritin ≥241 µg/L) was associated with overall survival and progression-free survival. Overall survival at 6 and 12 months is as follows: Scores 0-1: 95% and 95%; Score 2: 67% and ≤33%; Scores 3-4: 15% and 0%. Progression-free survival at 6 and 12 months is as follows: Scores 0-1: 81% and 50%; Score 2: 25% and ≤25%; Scores 3-4: 0% and 0%. CONCLUSION: We propose an easy-to-apply risk score categorizing patients into different risk groups before treatment start with a PD-1/PD-L1 antibody.

The prognostic value of signet ring cell histology in stage I/II colon cancer-a population-based, propensity score-matched analysis.

BACKGROUND: Previous research associated signet ring cell histology in colon cancer patients with poor survival outcomes. The aim of this study was to analyze the prognostic significance of signet ring cell histology on overall and cancer-specific survival in patients with localized colon cancer. METHODS: Stage I and II colon cancer patients treated with surgical resection between 2004 and 2015 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were assessed using risk-adjusted Cox proportional hazards regression models and propensity score methods. RESULTS: Eighty-eight thousand nine hundred fifty-eight stage I-II colon cancer patients were identified. Overall, 446 (0.5%) showed signet ring cell histology. In unadjusted analyses, the 5-year OS and CSS rates of patients with signet ring cell histology were 65.8 and 83.1%, respectively, compared with 74.3 and 88.7% in patients with non-signet ring cell adenocarcinoma (p values: OS, p < 0.001; CSS, p < 0.001). Neither in risk-adjusted Cox proportional hazard regression analysis (OS: hazard ratio (HR), 0.96 (95% CI, 0.82-1.12%) p = 0.616; CSS: HR, 1.01 (95% CI, 0.79-1.28%) p = 0.946) nor with propensity score matching (OS: HR, 0.96 (95% CI, 0.82-1.14%) p = 0.669 and CSS: HR: 1.09 (95% CI: 0.84-1.40%) p = 0.529), a survival disadvantage was found for signet ring cell histology. CONCLUSION: This is the first propensity score-adjusted population-based investigation on exclusively stage I and II colon cancer patients providing compelling evidence that signet ring cell histology does not negatively impact survival in stage I and II colon cancer after risk-adjusting for known prognostic factors. Therefore, standard treatment strategies can be applied in these patients.

Lower hospital volume is associated with higher mortality after oesophageal, gastric, pancreatic and rectal cancer resection.

BACKGROUND: In various countries, the association of lower hospital volume and higher mortality after oesophageal, gastric, pancreatic and rectal cancer resection has been clearly demonstrated. However, scientific evidence regarding the volume-outcomes relationship for high-risk visceral surgical procedures in Switzerland is lacking. The a priori hypothesis of this retrospective population-based cohort study analysis was that low-volume hospitals in Switzerland have a higher rate of postoperative mortality after oesophageal, gastric, pancreatic and rectal cancer resection. METHODS: Patients undergoing elective resection of oesophageal, gastric, pancreatic and rectal cancer between 1999 and 2012 were identified in the inpatient database of the Swiss Federal Statistical Office. Nonparametric correlation analyses were used to assess time trends. Mortality was assessed in univariable and risk-adjusted conditional logistic regression analyses with stratification for year of surgery. RESULTS: A total of 1487 oesophageal, 4404 gastric, 2668 pancreatic and 9743 rectal cancer patients were identified. For all cancer entities, significant treatment centralisation was observed over the time period (all p <0.001). The rate of mortality was inversely related to the annual number of patients treated at a certain hospital. The decrease of postoperative mortality from low-volume to high-volume hospitals was 6.3% to 3.3% for oesophageal cancer (p = 0.019), 4.9% to 3.3% for gastric cancer (p = 0.023), 5.4% to 2.0% for pancreatic cancer (p = 0.037), and 2.4% to 1.6% for rectal cancer (p = 0.008). These results were confirmed in risk-adjusted analyses with a decreased odds of pos-operative death by 49% for oesophageal (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.22-1.18; p = 0.085), 32% for gastric (OR 0.68, 95% CI 0.48-0.98; p = 0.032), 68% for pancreatic (OR 0.32, 95% CI 0.11-0.89; p = 0.011) and 29% for rectal cancer (OR 0.71, 95% CI 0.52-0.98; p = 0.033). CONCLUSION: This population-based analysis - the first of its kind in the literature - demonstrates a higher postoperative mortality in low-volume hospitals for patients undergoing oesophageal, gastric, pancreatic and rectal cancer resection in Switzerland. Hence, such operations should preferably be performed in high-volume hospitals.