Anne C. Chiang

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.

BACKGROUND Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING Merck and the Yale Cancer Center.

Patient-Reported Outcome Performance Measures in Oncology

Patient self-reporting affords the opportunity to better understand the impact of care processes on how patients feel.

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.Significance: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1420-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.

Possible Interaction of Anti–PD-1 Therapy with the Effects of Radiosurgery on Brain Metastases

Patients undergoing stereotactic radiosurgery for brain metastases may show unexpected effects in the lesions after treatment with antibodies to PD-1. Assessments of clinical and radiologic changes need accurate interpretation in this growing patient population. Delayed radiation-induced vasculitic leukoencephalopathy related to stereotactic radiosurgery (SRS) of brain metastases has been reported to manifest clinically 9 to 18 months after treatment. Immune-modulating therapies have been introduced to treatment regimens for malignancies with metastatic predilection to the brain. The interaction of these systemic therapies with other modalities of treatment for brain metastases, namely, SRS, has not been fully characterized. We report two patients with metastatic malignancies to the brain who received SRS followed by immunotherapy with monoclonal antibodies (mAb) to programmed death 1 (PD-1). Both patients appeared to have early clinical and radiologic progression of their treated lesions, which was highly suspicious for tumor progression. Both patients underwent surgical resection of their lesions and the material was submitted for histopathologic examination. Pathologic examination in both cases showed predominantly radiation-induced changes characterized by reactive astrocytosis and vascular wall infiltration by T lymphocytes. The accelerated response to SRS in these two patients was temporally related to the initiation of immunotherapy. We propose a possible biologic interaction between SRS and the PD-1 mAbs. Additionally, awareness of this potential occurrence is critical for accurate interpretation and proper management of clinical and radiologic findings in these patients. Cancer Immunol Res; 4(6); 481–7. ©2016 AACR.

Qualitative analysis of practicing oncologists' attitudes and experiences regarding collection of patient-reported outcomes

PURPOSE There is growing interest in incorporating routine collection of patient-reported outcomes (PROs) into cancer care. Practicing oncologists are a stakeholder group whose views are not well characterized. METHODS We developed an interview guide after literature review and in-depth interviews with leaders in the field. We conducted 45-minute semistructured interviews with a diverse sample of medical oncologists identified through affiliation with the Quality Oncology Practice Initiative or a minority-based Community Clinical Oncology Program until thematic saturation. Multiple analysts independently reviewed and thematically coded verbatim transcripts. RESULTS Seventeen interviews were conducted with oncologists from 15 states. Emergent themes included variable understanding and experience with PROs. There was enthusiasm for the potential of PROs to improve the efficiency and thoroughness of the patient encounter. Fundamental concerns included information overload, possibility of identifying problems without access to intervention, depersonalization of the physician-patient encounter, cost, and inefficiency. Barriers identified included the need for buy-in from other stakeholders in the practice, lack of appropriate referral resources, staffing needs, and technology concerns. Few identified patient compliance, data sharing/privacy, or medical liability as a major barrier to implementation. CONCLUSION Practicing oncologists had variable understanding of the details of PROs but, when introduced to the concept, recognized utility in improving the efficiency and thoroughness of the patient encounter if implemented properly. The time is right to begin pilot testing such measures with community oncologists so they can lend their expertise to national discussions on which measures to use and how best to use them.

Incorporating Patient-Reported Outcomes to Improve Emotional Distress Screening and Assessment in an Ambulatory Oncology Clinic

PURPOSE Assessment of distress and well-being of patients with cancer is not always documented or addressed in a clinical visit, reflecting a need for improved psychosocial screening. METHODS A multidisciplinary team completed process mapping for emotional distress assessment in two clinics. Barriers were identified through cause-and-effect analysis, and an intervention was chosen. Patient-reported outcomes were collected over 6 months using the validated National Comprehensive Cancer Network Emotional Distress Thermometer (EDT) paper tool. The American Society of Clinical Oncology Quality Oncology Practice Initiative (QOPI) measures were compared before and after intervention. RESULTS During 6 months, a total of 864 tools were collected from 1,344 patients in two ambulatory clinics (64%). Electronic medical record documentation of distress increased from 19.2% to 34% during the 6 months before and after intervention. QOPI measures showed an increase in emotional well-being documentation. Of 29 new and 835 return patients, 62% indicated mild distress (EDT, 0 to 3), 18% moderate (EDT, 4 to 6), and 11% severe (EDT, 7 to 10). The average distress score of new patients was significantly higher than that of return patients (5.39 [n = 26] v 2.52 [n = 754]; P < .001). The top problems for patients with moderate and severe distress were worry, fatigue, pain, and nervousness; depression and sadness were particularly noted in patients reporting severe distress. Eleven percent of patients were referred to the social worker on site. CONCLUSION A pilot intervention collecting Patient-reported outcomes in two ambulatory clinics led to increase in psychosocial distress screening followed by sustained improvement, indicated by both process and QOPI measures.

Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non–Small Cell Lung Cancer in the Community Oncology Setting

Importance Broad-based genomic sequencing is being used more frequently for patients with advanced non–small cell lung cancer (NSCLC). However, little is known about the association between broad-based genomic sequencing and treatment selection or survival among patients with advanced NSCLC in a community oncology setting. Objective To compare clinical outcomes between patients with advanced NSCLC who received broad-based genomic sequencing vs a control group of patients who received routine testing for EGFR mutations and/or ALK rearrangements alone. Design, Setting, and Participants Retrospective cohort study of patients with chart-confirmed advanced NSCLC between January 1, 2011, and July 31, 2016, and who received care at 1 of 191 oncology practices across the United States using the Flatiron Health Database. Patients were diagnosed with stage IIIB/IV or unresectable nonsquamous NSCLC who received at least 1 line of antineoplastic treatment. Exposures Receipt of either broad-based genomic sequencing or routine testing (EGFR and/or ALK only). Broad-based genomic sequencing included any multigene panel sequencing assay examining more than 30 genes prior to third-line treatment. Main Outcomes and Measures Primary outcomes were 12-month mortality and overall survival from the start of first-line treatment. Secondary outcomes included frequency of genetic alterations and treatments received. Results Among 5688 individuals with advanced NSCLC (median age, 67 years [interquartile range, 41-85], 63.6% white, 80% with a history of smoking); 875 (15.4%) received broad-based genomic sequencing and 4813 (84.6%) received routine testing. Among patients who received broad-based genomic sequencing, 4.5% received targeted treatment based on testing results, 9.8% received routine EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. Unadjusted mortality rates at 12 months were 49.2% for patients undergoing broad-based genomic sequencing and 35.9% for patients undergoing routine testing. Using an instrumental variable analysis, there was no significant association between broad-based genomic sequencing and 12-month mortality (predicted probability of death at 12 months, 41.1% for broad-based genomic sequencing vs 44.4% for routine testing; difference −3.6% [95% CI, −18.4% to 11.1%]; P = .63). The results were consistent in the propensity score–matched survival analysis (42.0% vs 45.1%; hazard ratio, 0.92 [95% CI, 0.73 to 1.11]; P = .40) vs unmatched cohort (hazard ratio, 0.69 [95% CI, 0.62 to 0.77]; log-rank P < .001). Conclusions and Relevance Among patients with advanced non–small cell lung cancer receiving care in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.

Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non–Small Cell Lung Cancer

Introduction: With expanding indications for programmed death 1 (PD‐1) axis inhibitors in non–small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD‐1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. Methods: Patients with NSCLC who developed AR to PD‐1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune‐related response criteria. Results: Twenty‐six patients with AR to PD‐1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2‐year survival rate from AR was 70% (95% confidence interval: 0.53–0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN‐only progression. Twenty‐three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD‐1 axis inhibitor therapy beyond progression. Three patients were re‐challenged with the same PD‐1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD‐1 axis inhibitor after local therapy. The 2‐year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77–1). Conclusions: Acquired resistance to PD‐1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD‐1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD‐1 axis inhibitor, re‐challenge can again lead to tumor regression.

Management of Small Cell Lung Cancer: Progress and Updates.

AbstractSmall cell lung cancer (SCLC) remains a major public health problem and accounts for 10% to 15% of all lung cancers. It has unique clinical features such as rapid growth, early metastatic spread, and widespread dissemination. A platinum-etoposide combination is the backbone treatment of SCLC; addition of thoracic and prophylactic cranial irradiation has been shown to improve outcome in limited-stage SCLC and in subgroups of extensive-stage SCLC. Over the last decade, significant progress has been made in characterizing the SCLC tumor biology and its developmental pathways. Most recently, efforts have focused not only on molecular targets, but also on the development of novel drugs targeting tumor evolution and immune escape mechanisms; these approaches are promising and offer opportunities that may finally improve the outcomes of SCLC.

Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials

Importance The US Food and Drug Administration (FDA) is increasing its pace of approvals for novel cancer therapeutics, including for immune checkpoint inhibitors of programmed cell death 1 protein (anti–PD-1 agents). However, little is known about how quickly anti–PD-1 agents agents reach eligible patients in practice or whether such patients differ from those studied in clinical trials that lead to FDA approval (pivotal clinical trials). Objectives To assess the speed with which anti–PD-1 agents agents reached eligible patients in practice and to compare the ages of patients treated in clinical practice with the ages of those treated in pivotal clinical trials. Design, Setting, and Participants This retrospective cohort study, performed from January 1, 2011, through August 31, 2016, included patients from the Flatiron Health Network who were eligible for anti–PD-1 agents treatment of selected cancer types, which included melanoma, non–small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Main Outcomes and Measures Cumulative proportions of eligible patients receiving anti–PD-1 agents treatment and their age distributions. Results The study identified 3089 patients who were eligible for anti–PD-1 agents treatment (median age, 66 [interquartile range, 56-75] years for patients with melanoma, 66 [interquartile range, 58-72] years for patients with RCC, and 67 [interquartile range, 59-74] years for patients with NSCLC; 1742 male [56.4%] and 1347 [43.6%] female; 2066 [66.9%] white). Of these patients, 2123 (68.7%) received anti–PD-1 agents treatment, including 439 eligible patients with melanoma (79.1%), 1417 eligible patients with NSCLC (65.6%), and 267 eligible patients with RCC (71.2%). Within 4 months after FDA approval, greater than 60% of eligible patients in each cohort had received anti–PD-1 agents treatment. Overall, similar proportions of older and younger patients received anti–PD-1 agents treatment during the first 9 months after FDA approval. However, there were significant differences in age between clinical trial participants and patients receiving anti–PD-1 agents treatment in clinical practice, with more patients being older than 65 years in clinical practice (range, 327 of 1365 [60.6%] to 46 of 72 [63.9%]) than in pivotal clinical trials (range, 38 of 120 [31.7%] to 223 of 544 [41.0%]; all P < .001). Conclusions and Relevance Anti-PD-1 agents rapidly reached patients in clinical practice, and patients treated in clinical practice differed significantly from patients treated in pivotal clinical trials. Future actions are needed to ensure that rapid adoption occurs on the basis of representative trial evidence.