Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial.

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.

Canadian Consensus Recommendations for the Management of Operable Stage II/III Non-Small-Cell Lung Cancer: Results of a Modified Delphi Process.

The treatment paradigm for patients with stage II/III non-small-cell lung cancer (NSCLC) is rapidly evolving. We performed a modified Delphi process culminating at the Early-stage Lung cancer International eXpert Retreat (ELIXR23) meeting held in Montreal, Canada, in June 2023. Participants included medical and radiation oncologists, thoracic surgeons and pathologists from across Quebec. Statements relating to diagnosis and treatment paradigms in the preoperative, operative and postoperative time periods were generated and modified until all held a high level of consensus. These statements are aimed to help guide clinicians involved in the treatment of patients with stage II/III NSCLC.

Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.

BACKGROUND: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma. METHODS: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual. FINDINGS: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. INTERPRETATION: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. FUNDING: The Canadian Cancer Society and Merck & Co.

Canadian Consensus Recommendations on the Management of Extensive-Stage Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive, neuroendocrine tumour with high relapse rates, and significant morbidity and mortality. Apart from advances in radiation therapy, progress in the systemic treatment of SCLC had been stagnant for over three decades despite multiple attempts to develop alternative therapeutic options that could improve responses and survival. Recent promising developments in first-line and subsequent therapeutic approaches prompted a Canadian Expert Panel to convene to review evidence, discuss practice patterns, and reach a consensus on the treatment of extensive-stage SCLC (ES-SCLC). The literature search included guidelines, systematic reviews, and randomized controlled trials. Regular meetings were held from September 2022 to March 2023 to discuss the available evidence to propose and agree upon specific recommendations. The panel addressed biomarkers and histological features that distinguish SCLC from non-SCLC and other neuroendocrine tumours. Evidence for initial and subsequent systemic therapies was reviewed with consideration for patient performance status, comorbidities, and the involvement and function of other organs. The resulting consensus recommendations herein will help clarify evidence-based management of ES-SCLC in routine practice, help clinician decision-making, and facilitate the best patient outcomes.

Canadian Consensus Recommendations on the Management of KRAS G12C-Mutated NSCLC.

Activating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS), in particular, a point mutation leading to a glycine-to-cysteine substitution at codon 12 (G12C), are among the most frequent genomic alterations in non-small cell lung cancer (NSCLC). Several agents targeting KRAS G12C have recently entered clinical development. Sotorasib, a first-in-class specific small molecule that irreversibly inhibits KRAS G12C, has since obtained Health Canada approval. The emergence of novel KRAS-targeted therapies warrants the development of evidence-based consensus recommendations to help clinicians better understand and contextualize the available data. A Canadian expert panel was convened to define the key clinical questions, review recent evidence, and discuss and agree on recommendations for the treatment of advanced KRAS G12C-mutated NSCLC. The panel agreed that testing for KRAS G12C should be performed as part of a comprehensive panel that includes current standard-of-care biomarkers. Sotorasib, the only approved KRAS G12C inhibitor in Canada, is recommended for patients with advanced KRAS G12C-mutated NSCLC who progressed on guideline-recommended first-line standard of care for advanced NSCLC without driver alterations (immune-checkpoint inhibitor(s) [ICIs] +/- chemotherapy). Sotorasib could also be offered as second-line therapy to patients who progressed on ICI monotherapy that are not candidates for a platinum doublet and those that received first-line chemotherapy with a contraindication to ICIs. Preliminary data indicate the activity of KRAS G12C inhibitors in brain metastases; however, the evidence is insufficient to make specific recommendations. Regular liver function monitoring is recommended when patients are prescribed KRAS G12C inhibitors due to risk of hepatotoxicity.

Lorlatinib Effectiveness and Quality-of-Life in Patients with ALK-Positive NSCLC Who Had Failed Second-Generation ALK Inhibitors: Canadian Real-World Experience.

Lorlatinib is the only targeted therapy approved in Canada to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) whose tumor has progressed despite treatment with second-generation ALK tyrosine kinase inhibitor (TKI), a patient population with high unmet need and lack of publicly reimbursed targeted treatments in Canada. We prospectively examined the real-world effectiveness and impact of lorlatinib on quality-of-life in 59 lorlatinib-treated patients, characterized as: median age of 62.0 years; 47.5% were female; 32.2% had central nervous system metastases; 50.8% had 2+ prior ALK TKI lines; and alectinib was the most common ALK TKI (72.9%) administered before lorlatinib, including 44.1% who received first-line alectinib. With a median follow-up of 15.3 months (IQR: 6.2-19.2), median time-to-treatment discontinuation of lorlatinib was 15.3 months (95% CI: 7.9-not reached), with 54.2% (95% CI: 40.8-65.9%) of patients without treatment discontinuation at 12 months. At baseline, the mean health utility score (HUS) was 0.744 (SD: 0.200). At 3 months, patients receiving lorlatinib demonstrated a 0.069 (95% CI: 0.020-0.118; p = 0.007) average HUS increase over baseline; HUS was maintained at 6 and 12 months. Thus, patients with ALK-positive NSCLC post second-generation ALK TKI remained on lorlatinib for a meaningful duration of time while their quality-of-life was preserved.

A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors.

BACKGROUND: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. OBJECTIVE: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles. PATIENTS AND METHODS: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1-3 and 8-10 of a 21-day treatment cycle. RESULTS: Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified). CONCLUSION: Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02482311; registered June 2015.

Targeting Mesothelin in Solid Tumours: Anti-mesothelin Antibody and Drug Conjugates.

PURPOSE OF REVIEW: This review aims to summarise the pathobiological role of mesothelin and the current data on therapeutic antibodies targeting mesothelin in solid tumours. RECENT FINDINGS: High mesothelin expression is restricted to the pericardium, pleura, peritoneum and tunica vaginalis. Mesothelin does not seem to have any normal biological function in adult normal tissues. Mesothelin is highly expressed in mesothelioma, serous ovarian cancer, pancreatic cancer and some gastric cancer and adenocarcinoma of the lung and is responsible for tumour proliferation, metastasis, resistance to chemotherapy or radiation and evasion of immune system. To date, antibody, antibody drug conjugates and bispecific antibodies with immune checkpoints have been investigated in mesothelin expressing malignancies. After a couple of decades of clinical investigation in antibody targeting mesothelin, the therapeutic benefit is relatively modest. Novel delivery of mesothelin targeting agents, more potent payload in antibody drug conjugates and immune checkpoint inhibitor, may improve therapeutic benefit.

Brief Report: Canadian Cancer Trials Group IND.227: A Phase 2 Randomized Study of Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma (NCT02784171).

Immune checkpoint inhibitors have activity in mesothelioma. IND.227 was a phase 2 trial (120 patients planned) comparing progression-free survival of standard platinum and pemetrexed (CP) versus CP + pembrolizumab (pembro) versus pembro. Accrual to the pembro arm was discontinued on the basis of interim analysis (IA-16 wk disease control rate). CP + pembro was tolerable, with progression-free survival similar between arms and median survival and overall response rate higher than those of CP alone (19.8 mo [95% confidence interval or CI: 8.4-41.36] versus 8.9 mo [95% CI: 5.3-12.8] and 47% [95% CI: 24%-71%] versus 19% [95% CI: 5%-42%], respectively). The subsequent phase 3 trial has completed accrual; results are expected in 2023.

BMS-986012, an Anti-Fucosyl-GM1 Monoclonal Antibody as Monotherapy or in Combination With Nivolumab in Relapsed/Refractory SCLC: Results From a First-in-Human Phase 1/2 Study.

Introduction: Fucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1. Methods: CA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival. Results: Patients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 [90%]). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval [CI]) was higher with BMS-986012 plus nivolumab (38% [20.7%-57.7%]) than with monotherapy (4% [0.8%-11.0%]). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4-not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%-20.7%) and 39.3% (21.7%-56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0-7.3) and 18.7 (8.2-37.3) months, respectively. Conclusions: BMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880).

Consensus Recommendations to Optimize Testing for New Targetable Alterations in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) has historically been associated with a poor prognosis and low 5-year survival, but the use of targeted therapies in NSCLC has improved patient outcomes over the past 10 years. The pace of development of new targeted therapies is accelerating, with the associated need for molecular testing of new targetable alterations. As the complexity of biomarker testing in NSCLC increases, there is a need for guidance on how to manage the fluid standard-of-care in NSCLC, identify pragmatic molecular testing requirements, and optimize result reporting. An expert multidisciplinary working group with representation from medical oncology, pathology, and clinical genetics convened via virtual meetings to create consensus recommendations for testing of new targetable alterations in NSCLC. The importance of accurate and timely testing of all targetable alterations to optimize disease management using targeted therapies was emphasized by the working group. Therefore, the panel of experts recommends that all targetable alterations be tested reflexively at NSCLC diagnosis as part of a comprehensive panel, using methods that can detect all relevant targetable alterations. In addition, comprehensive biomarker testing should be performed at the request of the treating clinician upon development of resistance to targeted therapy. The expert multidisciplinary working group also made recommendations for reporting to improve clarity and ease of interpretation of results by treating clinicians and to accommodate the rapid evolution in clinical actionability of these alterations. Molecular testing of all targetable alterations in NSCLC is the key for treatment decision-making and access to new therapies. These consensus recommendations are intended as a guide to further optimize molecular testing of new targetable alterations.

COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non-Small-Cell Lung Cancer.

PURPOSE: Durvalumab significantly improves overall survival for patients with unresectable stage III non-small-cell lung cancer and no progression after concurrent chemoradiotherapy (cCRT). Building upon that standard of care, COAST is a phase II study of durvalumab alone or combined with the anti-CD73 monoclonal antibody oleclumab or anti-NKG2A monoclonal antibody monalizumab as consolidation therapy in this setting. METHODS: Patients with unresectable stage III non-small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and no progression after cCRT were randomly assigned 1:1:1, ≤ 42 days post-cCRT, to durvalumab alone or combined with oleclumab or monalizumab for up to 12 months, stratified by histology. The primary end point was investigator-assessed confirmed objective response rate (ORR; RECIST v1.1). RESULTS: Between January 2019 and July 2020, 189 patients were randomly assigned. At this interim analysis (data cutoff, May 17, 2021), median follow-up was 11.5 months (range, 0.4-23.4 months; all patients). Confirmed ORR was numerically higher with durvalumab plus oleclumab (30.0%; 95% CI, 18.8 to 43.2) and durvalumab plus monalizumab (35.5%; 95% CI, 23.7 to 48.7) versus durvalumab (17.9%; 95% CI, 9.6 to 29.2). Progression-free survival (PFS) was prolonged with both combinations versus durvalumab (plus oleclumab: hazard ratio, 0.44; 95% CI, 0.26 to 0.75; and plus monalizumab: hazard ratio, 0.42; 95% CI, 0.24 to 0.72), with higher 12-month PFS rates (plus oleclumab: 62.6% [95% CI, 48.1 to 74.2] and plus monalizumab: 72.7% [95% CI, 58.8 to 82.6] v durvalumab alone: 33.9% [95% CI, 21.2 to 47.1]). All-cause grade ≥ 3 treatment-emergent adverse events occurred in 40.7%, 27.9%, and 39.4% with durvalumab plus oleclumab, durvalumab plus monalizumab, and durvalumab, respectively. CONCLUSION: Both combinations increased ORR and prolonged PFS versus durvalumab alone. Safety was similar across arms with no new or significant safety signals identified with either combination. These data support their further evaluation in a phase III trial.

Lifestyle factors and lung cancer risk among never smokers in the Canadian Partnership for Tomorrow's Health (CanPath).

BACKGROUND: Although smoking is the primary risk factor for lung cancer, 15-25% of lung cancers occur in never smokers. Emerging evidence suggests lifestyle factors are associated with lung cancer risk, but few studies among never smokers exist. METHODS: A case-control study of never smokers within the Canadian Partnership for Tomorrow's Health was conducted. At recruitment, participants provided data on lifestyle, health history and sociodemographic factors. Incident lung cancers were identified through linkage with administrative health records. Cases (n = 190) were matched to controls (n = 760) on age, sex, and follow-up time. Logistic regression analyses, adjusted for matching factors and annual income, were used to identify associations between lifestyle factors and lung cancer risk. RESULTS: Consumption of < 5 servings of fruits and vegetables/day was associated with higher risk of lung cancer (OR 1.50, 95% CI 1.03-2.17). Short or long sleep (≤ 6 or > 9 h/night) was also associated with increased risk of lung cancer (OR 1.52, 95% CI 1.01-2.29). No associations were observed for obesity measures, alcohol consumption, or physical activity. CONCLUSION: Our findings provide evidence of a potential role between sleep, fruits and vegetable consumption, and lung cancer risk in a pan-Canadian, non-smoking population. However, the sample size is modest, and further investigation is needed.

Present and Emerging Biomarkers in Immunotherapy for Metastatic Non-Small Cell Lung Cancer: A Review.

Targeting the immune system, especially the PDL-1/PD-1 axis, has significantly improved the outcomes of metastatic lung cancer patients. However, only a portion of patients will benefit significantly from PD(L)1 therapeutics alone or in combination with either chemotherapy or anti-CTLA4 antibody. It is therefore important to study predictive biomarkers to help select the patients who will experience the most benefit from immunotherapy. In this paper, the current status of PDL-1 expression on tumour cells, the smoking status of patients, tumour mutational burden, gut microbiome and STK11 and KEAP1 mutations in the tumour as predictive biomarkers for PD(L)-1-based immunotherapy are summarized.

Application of liquid biopsy-based targeted capture sequencing analysis to improve the precision treatment of non-small cell lung cancer by tyrosine kinase inhibitors.

BACKGROUND: Targeted therapy of patients with non-small cell lung cancer (NSCLC) who harbour sensitising mutations by tyrosine kinase inhibitors (TKIs) has been found more effective than traditional chemotherapies. However, target genes status (eg, epidermal growth factor receptor (EGFR) TKIs sensitising and resistant mutations) need to be tested for choosing appropriate TKIs. This study is to investigate the performance of a liquid biopsy-based targeted capture sequencing assay on the molecular analysis of NSCLC. METHODS: Plasma samples from patients with NSCLC who showed resistance to the first/second-generation EGFR TKIs treatment were collected. The AVENIO ctDNA Expanded Kit is a 77 pan-cancer genes detection assay that was used for detecting EGFR TKIs resistance-associated gene mutations. Through comparison of the EGFR gene testing results from the Cobas EGFR Mutation Test v2, and UltraSEEK Lung Panel, the effectiveness of the targeted capture sequencing assay was verified. RESULTS: A total of 24 plasma cell-free DNA (cfDNA) samples were tested by the targeted capture sequencing assay. 33.3% (8/24) cfDNA samples were positive for EGFR exon 20 p.T790M which leads to EGFR dependent TKIs resistance. 8.3% (2/24) and 4.2% (1/24) samples were positive for mesenchymal-epithelial transition gene amplification and B-Raf proto-oncogene, serine/threonine kinase exon 15 p.V600E mutations which lead to EGFR independent TKIs resistance. The median value of the p.T790M variant allele fraction and variant copy numbers was 2% and 36.10 copies/mL plasma, respectively. The next-generation sequencing test showed higher than 90% concordance with either MassArray or qPCR-based methods for detecting either EGFR TKIs sensitising or resistance mutations. CONCLUSION: The targeted capture sequencing test can support comprehensive molecular analysis needed for TKIs treatment, which is promising to be clinically applied for the improved precision treatment of NSCLC.

Bilateral Lung Transplant for Treatment of Idiopathic Pulmonary Fibrosis With Undetected Lung Adenocarcinoma: A Case Report.

BACKGROUND: Lung transplant has become a curative therapy for various forms of progressive lung disease refractory to medical management. Idiopathic pulmonary fibrosis (IPF) is a rare condition characterized by accumulation of activated fibroblasts and secretion of extracellular matrices within the lung parenchyma. End-stage IPF is a fatal condition, with limited medical therapies other than lung transplantation. IPF has been demonstrated as a known risk factor for the development of lung cancer, and current lung transplant standards define history of malignancy within the past five years as an absolute exclusion criterion. CASE REPORT: We present the case of a patient with biopsy-confirmed idiopathic pulmonary fibrosis treated with bilateral lung transplant, discovered to have stage four lung adenocarcinoma in the explanted lungs. The patient subsequently received pseudoadjuvant chemotherapy and remained recurrence-free until 23 months post-transplant. CONCLUSION: This case highlights the challenge of ruling out malignancy in patients with end-stage lung disease. There remains a paucity of clinical studies on lung transplantation for lung cancer and more evidence is required before supporting this clinical decision.

Risk stratification of gastrointestinal stromal tumors by Nanostring gene expression profiling.

PURPOSE: The risk assessment classification schemes for gastrointestinal stromal tumors (GIST) include tumor site, size, mitotic count and variably tumor rupture. Heterogeneity in high-risk GIST poses limitations for current classification schemes. This study aims to demonstrate the clinical utility of risk stratification by gene expression profiling (GEP) using Nanostring technology. METHODS: Fifty-six GIST cases were analyzed using a 231 gene expression panel. GEP results were correlated with clinical and pathological data. The prognostic performance was assessed in 34 patients with available survival data using ROC curves, Kaplan-Meier survival curves and compared with traditional risk assessment schemes. Volcano plot analysis identified seven genes with significantly higher expression (FDR < .0.05) in high-risk than in non-high-risk tumors, namely TYMS, CDC2, TOP2A, CCNA2, E2F1, PCNA, and BIRC5. Together, these transcripts exhibited significantly higher expression in high-risk tumors than in intermediate (P < 0.01), low (P < 0.001), and very low (P = 0.01) risk tumors. Receiver-operating characteristic curve analysis demonstrated area under the curve (AUC) to be 0.858 for the separation of high-risk and non-high-risk tumors. Kaplan-Meier survival analysis demonstrated improved risk stratification (log-rank test P < 0.001) compared to the current risk assessment classification (P = 0.231). CONCLUSION: In addition to current clinical and histology-based risk classification for patients with GIST, gene expression may offer complementary prognostic information.

Rapid Unmasking of Immune-related Adverse Events After Discontinuation of Chemotherapy in Chemo-immunotherapy Regimens.

Pembrolizumab is an immune-checkpoint inhibitor (ICI) of programmed cell death protein 1 (PD-1), which restores T-cell-mediated antitumor immune activity and therefore enhances the body's immune response to cancer cells. Due to the nature of this therapy, immune-related adverse events (irAE) can manifest in nearly every organ system. Chemo-immunotherapy regimens are now considered first-line treatment for several cancers, with recent literature suggesting there are higher rates of certain irAEs with ICI monotherapy when compared with chemo-immunotherapy combinations. In certain regimens chemo-immunotherapy induction is followed by ICI maintenance monotherapy, and data regarding irAE incidence in this transition period are very limited. We report 3 cases of patients on pembrolizumab in combination with cytotoxic chemotherapy who developed an irAE shortly following discontinuation of a chemotherapy agent. Cases were identified in the Rheumatology in Immuno-Oncology clinic at the University of Alberta and clinical data were extracted by retrospective chart review after obtaining written consent from individual patients. These findings demonstrate that chemotherapy may suppress irAEs in patients using ICIs, and that when chemotherapy agents in combined regimens are discontinued, irAEs can be "unmasked" within the following 6 weeks. Clinicians should be aware of this risk and monitor for irAE development during this critical time period. To the best of the authors' knowledge, this has not been previously reported in the literature.