The Role of Angiogenesis Inhibitors in the Era of Immune Checkpoint Inhibitors and Targeted Therapy in Metastatic Non-Small Cell Lung Cancer.

OPINION STATEMENT: The treatment of advanced non-small cell lung cancer (NSCLC) has evolved to include targeted therapy, immunotherapy as well as chemotherapy for selected patients in the first-line setting. Angiogenesis inhibitors have been used in combination with chemotherapy in the first-line and maintenance settings providing improved progression-free survival (PFS) and objective response rate (ORR), as well as overall survival (OS) in selected studies. Biologic rationale exists for combining anti-angiogenic agents with immunotherapy and targeted kinase inhibitors (TKIs). A recent study has demonstrated improved survival when anti-PD-L1 therapy was added to chemotherapy plus bevacizumab. Subgroup analysis of patients with mutations in the epidermal growth factor receptor (EGFR) gene and rearrangements in the anaplastic lymphoma kinase (ALK) gene also demonstrated benefit with combined anti-PD-L1, bevacizumab, and platinum chemotherapy. Further investigation into combination therapy is warranted in the EGFR- and ALK-positive population given this signal. Anti-angiogenics combined with EGFR-targeted treatment in the wild-type population have shown modest PFS benefit with no OS benefit, and their routine use has not been adopted. The combination of EGFR inhibitors plus vascular endothelial growth factor (VEGF) inhibitors in the EGFR mutation-positive population has demonstrated substantial improvements in response and PFS; however, given the higher toxicity and lack of survival benefit to date, combination therapy in this group should be used with caution. At the present time, use of bevacizumab can be recommended with atezolizumab and chemotherapy for the first-line treatment of non-squamous NSCLC patients. Data with other checkpoint inhibitors and anti-angiogenics are too early to make firm recommendations regarding their use.

Optimal primary febrile neutropenia prophylaxis for patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer: a systematic review.

BACKGROUND: Due to the high rate of febrile neutropenia (FN) with docetaxel-cyclophosphamide (DC) chemotherapy, primary FN prophylaxis is recommended. However, the optimal choice of prophylaxis [i.e., granulocyte-colony stimulating factors (G-CSF) or antibiotics] is unknown. A systematic review was performed to address this knowledge gap. METHODS: Embase, Ovid Medline, Pubmed, the Cochrane database of systematic reviews, and Cochrane register of controlled trials were searched from 1946 to April 2016 for studies evaluating primary prophylactic FN treatments in breast cancer patients receiving DC chemotherapy. Outcome measures evaluated included: incidence of FN and treatment-related hospitalizations, chemotherapy dose reduction/delays/discontinuations, and adverse events. Screening and data collection were performed by two independent reviewers. RESULTS: Of 2105 identified records, 7 studies (n = 2535) met the pre-specified eligibility criteria. Seven additional studies (n = 621) were identified from prior systematic reviews. There were 3 randomized controlled trials (RCTs) (n = 2256) and 11 retrospective studies (n = 900). Study sample sizes ranged from 30 to 982 patients (median 99.5), evaluating pegfilgrastim (n = 1274), filgrastim (n = 1758), and oral ciprofloxacin (n = 108). Given the heterogeneity of patients and study design, a narrative synthesis of results was performed. Median FN rates with and without primary prophylaxis were 6.6 % (IQR 3.9-10.6 %) and 31.3 % (IQR 25-33 %), respectively. No FN-related deaths were reported. No RCT directly compared G-CSF with antibiotic interventions. CONCLUSIONS: Primary FN prophylaxis reduces the incidence of FN. Despite considerable cost and toxicity differences between G-CSF and antibiotics, there is insufficient data to make a recommendation of one strategy over another.

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.

A Guide to Implementing Immune Checkpoint Inhibitors within a Cancer Program: Experience from a Large Canadian Community Centre.

The increased use of immune checkpoint inhibitors across cancer programs has created the need for standardized patient assessment, education, monitoring, and management of immune-related adverse events (irAEs). At William Osler Health System in Brampton, Ontario, a practical step-wise approach detailing the implementation of cancer immunotherapy in routine practice was developed. The approach focuses on four key steps: (1) identification of patient educators; (2) development of patient education materials; (3) development of patient monitoring tools; (4) involvement and education of multidisciplinary teams. Here, we provide an in-depth description of what was included in each step and how we integrated the different elements of the program. For each step, resources, tools, and materials that may be useful for patients, healthcare providers, and multidisciplinary teams were developed or modified based on existing materials. At our centre, the program led to improved patient comprehension of irAEs, the ability to act on symptoms (patient self-efficacy), and low rates of emergency room visits at first presentation for irAEs. We recognize that centres may need to tailor the approaches to their institutional policies and encourage centres to adapt and modify the forms and tools according to their needs and requirements.

Point of Care Molecular Testing: Community-Based Rapid Next-Generation Sequencing to Support Cancer Care.

Purpose: Biomarker data are critical to the delivery of precision cancer care. The average turnaround of next-generation sequencing (NGS) reports is over 2 weeks, and in-house availability is typically limited to academic centers. Lengthy turnaround times for biomarkers can adversely affect outcomes. Traditional workflows involve moving specimens through multiple facilities. This study evaluates the feasibility of rapid comprehensive NGS using the Genexus integrated sequencer and a novel streamlined workflow in a community setting. Methods: A retrospective chart review was performed to assess the early experience and performance characteristics of a novel approach to biomarker testing at a large community center. This approach to NGS included an automated workflow utilizing the Genexus integrated sequencer, validated for clinical use. NGS testing was further integrated within a routine immunohistochemistry (IHC) service, utilizing histotechnologists to perform technical aspects of NGS, with results reported directly by anatomic pathologists. Results: Between October 2020 and October 2021, 578 solid tumor samples underwent genomic profiling. Median turnaround time for biomarker results was 3 business days (IQR: 2-5). Four hundred eighty-one (83%) of the cases were resulted in fewer than 5 business days, and 66 (11%) of the cases were resulted simultaneously with diagnosis. Tumor types included lung cancer (310), melanoma (97), and colorectal carcinoma (68), among others. NGS testing detected key driver alterations at expected prevalence rates: lung EGFR (16%), ALK (3%), RET (1%), melanoma BRAF (43%), colorectal RAS/RAF (67%), among others. Conclusion: This is the first study demonstrating clinical implementation of rapid NGS. This supports the feasibility of automated comprehensive NGS performed and interpreted in parallel with diagnostic histopathology and immunohistochemistry. This novel approach to biomarker testing offers considerable advantages to clinical cancer care.

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.

Integrating comprehensive genomic sequencing of non-small cell lung cancer into a public healthcare system.

OBJECTIVES: Standard molecular testing for patients with stage IV non-small cell lung cancer (NSCLC) in the Canadian publicly funded health system includes single gene testing for EGFR, ALK, and ROS-1. Comprehensive genomic profiling (CGP) may broaden treatment options for patients. This study examined the impact of CGP in a publicly funded health system. METHODS: Consenting patients with stage IV NSCLC without known targetable alterations underwent CGP on diagnostic samples. Patients that had progressed on targeted therapy were also eligible. The CGP assay was a hybrid capture next generation sequencing (NGS) panel (Oncomine Comprehensive Assay Version 3, ThermoFisher). The number of actionable alterations, changes in treatment, clinical trial eligibility and costs as a result of CGP were evaluated and patient willingness-to-pay. RESULTS: Of 182 screened patients,134 (74%) had successful CGP testing. Twenty percent had received prior targeted therapy. Incremental actionable alterations were identified in 31% of patients. The most common novel targets identified were mutations in ERBB2 (exon 20 insertions), MET (exon 14 skipping) and KRAS (G12C). At data cut off (31/12/2020), 16% of patients had a change in treatment as a result of CGP. Additional clinical trial options were identified for 75% of patients. The incremental direct laboratory cost for CGP beyond public reimbursement for single gene tests was $747 CAD/case. CONCLUSION: CGP identifies additional actionable targets beyond single gene tests with a direct impact on patient treatment and increased clinical trial eligibility. These benefits highlight the value of CGP in patients with NSCLC in public health systems.

The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer.

The management of Stage III non-small cell lung cancer (NSCLC) is complex and requires multidisciplinary input. Since the publication of the PACIFIC trial (consolidative durvalumab post concurrent chemotherapy and radiation in Stage III disease) which showed improved survival for patients in the immunotherapy arm, there has been much interest in the use of immunotherapy in the Stage III setting. In this review, we explore the biologic and clinical rationale for the use of immunotherapy in Stage III NSCLC, present previously published and upcoming data in the neoadjuvant, adjuvant, and concurrent realms of Stage III management, and discuss unanswered questions and challenges moving forward.

Second and later-line erlotinib use in non-small cell lung cancer: real world outcomes and practice patterns overtime in Canada.

BACKGROUND: In Canada, epidermal growth factor receptor (EGFR) inhibitor therapies in advanced non-small cell lung cancer (NSCLC) were initially approved regardless of EGFR status. The purpose of this study is to characterise the use of second or later-line erlotinib therapy in Ontario, Canada from 2007-2016, as well as evaluate the impact of erlotinib therapy on survival and emergency department (ED) visits in a real-world population. METHODS: This is a retrospective cohort study derived at ICES (formerly known as the Institute for Clinical and Evaluative Sciences) of advanced NSCLC patients diagnosed from 2007-2016 in Ontario, Canada, over the age of 65, who received at least one dose of first-line chemotherapy. The exposure of interest was receipt of second or later-line erlotinib. The primary outcome was the hazard ratio for mortality evaluated using a Cox proportional hazards model, and the secondary outcome, ED visits, was evaluated using a Poisson model. RESULTS: First-line chemotherapy was administered in 30.4% of stage IV NSCLC patients. Of these patients, 19.7% received second or later-line erlotinib. The proportion of patients prescribed second or later-line erlotinib decreased over the course of the study (P<0.0001). Unadjusted median overall survival in the entire cohort was 325 days (95% CI: 314-337 days), 513 days (95% CI: 485-539 days) in the erlotinib cohort, and 282 days (95% CI: 270-291 days) in the non-erlotinib cohort. Despite this, the adjusted hazard ratio for death was 1.89 (95% CI: 1.73-2.07, P<0.0001) for patients on erlotinib. Patients receiving erlotinib also had a marginally higher relative rates of ED visits with an adjusted relative risk of 1.10 (95% CI: 1.02-1.19, P=0.013). CONCLUSIONS: This study highlights the importance of using EGFR targeted treatments in NSCLC patients with a predictive biomarker, and suggests that treatment with erlotinib therapy is unlikely to benefit unselected patients with advanced NSCLC.

Primary Febrile Neutropenia Prophylaxis for Patients Who Receive FEC-D Chemotherapy for Breast Cancer: A Systematic Review.

PURPOSE: Despite widespread use of fluorouracil, epirubicin, cyclophosphamide, docetaxel (FEC-D) chemotherapy in breast cancer, the optimal strategy for primary febrile neutropenia (FN) prophylaxis remains unknown. A systematic review was therefore performed. METHODS: Embase, Ovid MEDLINE, PubMed, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials, and conference proceedings were searched from 1946 to April 2016 for trials that reported the effectiveness of primary FN prophylaxis with FEC-D chemotherapy. Outcome measures were incidence of FN; treatment-related hospitalizations; chemotherapy dose delays, reductions, and discontinuations; and adverse events from prophylaxis. RESULTS: Of 2,205 identified citations, eight studies (n = 1,250) met our eligibility criteria. Three additional studies (n = 293) were identified from a prior systematic review. Three randomized controlled trials (n = 576), one phase IV single-arm trial (n = 69), one prospective observational study (n = 37), and six retrospective studies (n = 861) were identified. Agents investigated were pegfilgrastim (n = 108), filgrastim (n = 1,119), and ciprofloxacin (n = 89). The heterogeneity of studies meant that a narrative synthesis of results was performed. Median FN rates for patients who received FEC-D with and without primary prophylaxis were 10.1% (interquartile range [IQR], 3.9% to 22.6%) and 23.9% (IQR, 9.2% to 27.3%), respectively. In the absence of primary prophylaxis, FN was more common during docetaxel than during FEC. Data from six studies showed a median rate of dose reductions and delays of 6.1% (IQR, 3.1% to 14.3%) and 19.3% (IQR, 10.5% to 32.8%), respectively, that occurred as a consequence of FN. Toxicity from prophylaxis itself was rarely reported. CONCLUSION: Primary FN prophylaxis is effective in patients who receive FEC-D chemotherapy. The paucity of prospective data makes optimal recommendations about the choice and timing of prophylaxis challenging.

Splenosis involving the gastric fundus, a rare cause of massive upper gastrointestinal bleeding: a case report and review of the literature.

Splenosis, the autotransplantation of splenic tissue following splenic trauma, is uncommonly clinically significant. Splenosis is typically diagnosed incidentally on imaging or at laparotomy and has been mistakenly attributed to various malignancies and pathological conditions. On the rare occasion when splenosis plays a causative role in a pathological condition, a diagnostic challenge may ensue that can lead to a delay in both diagnosis and treatment. The following case report describes a patient presenting with a massive upper gastrointestinal bleed resulting from arterial enlargement within the gastric fundus secondary to perigastric splenosis. The cause of the bleeding was initially elusive and this case highlights the importance of a thorough clinical history when faced with a diagnostic challenge. Treatment options, including the successful use of transarterial embolization in this case, are also presented.