Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib.

Importance: Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood. Objective: To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. Design, Setting, and Participants: Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017. Main Outcomes and Measures: Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib. Results: Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01). Conclusions and Relevance: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.

Cost and Survival Analysis Before and After Implementation of Dana-Farber Clinical Pathways for Patients With Stage IV Non-Small-Cell Lung Cancer.

PURPOSE: Increasing costs and medical complexity are significant challenges in modern oncology. We explored the use of clinical pathways to support clinical decision making and manage resources prospectively across our network. MATERIALS AND METHODS: We created customized lung cancer pathways and partnered with a commercial vendor to provide a Web-based platform for real-time decision support and post-treatment data aggregation. Dana-Farber Cancer Institute (DFCI) Pathways for non-small cell lung cancer (NSCLC) were introduced in January 2014. We identified all DFCI patients who were diagnosed and treated for stage IV NSCLC in 2012 (before pathways) and 2014 (after pathways). Costs of care were determined for 1 year from the time of diagnosis. RESULTS: Pre- and postpathway cohorts included 160 and 210 patients with stage IV NSCLC, respectively. The prepathway group had more women but was otherwise similarly matched for demographic and tumor characteristics. The total 12-month cost of care (adjusted for age, sex, race, distance to DFCI, clinical trial enrollment, and EGFR and ALK status) demonstrated a $15,013 savings after the implementation of pathways ($67,050 before pathways v $52,037 after pathways). Antineoplastics were the largest source of cost savings. Clinical outcomes were not compromised, with similar median overall survival times (10.7 months before v 11.2 months after pathways; P = .08). CONCLUSION: After introduction of a clinical pathway in metastatic NSCLC, cost of care decreased significantly, with no compromise in survival. In an era where comparative outcomes analysis and value assessment are increasingly important, the implementation of clinical pathways may provide a means to coalesce and disseminate institutional expertise and track and learn from care decisions.

Feasibility of using algorithm-based clinical decision support for symptom assessment and management in lung cancer.

CONTEXT: Distressing symptoms interfere with the quality of life in patients with lung cancer. Algorithm-based clinical decision support (CDS) to improve evidence-based management of isolated symptoms seems promising, but no reports yet address multiple symptoms. OBJECTIVES: This study examined the feasibility of CDS for a Symptom Assessment and Management Intervention targeting common symptoms in patients with lung cancer (SAMI-L) in ambulatory oncology. The study objectives were to evaluate completion and delivery rates of the SAMI-L report and clinician adherence to the algorithm-based recommendations. METHODS: Patients completed a web-based symptom assessment and SAMI-L created tailored recommendations for symptom management. Completion of assessments and delivery of reports were recorded. Medical record review assessed clinician adherence to recommendations. Feasibility was defined as 75% or higher report completion and delivery rates and 80% or higher clinician adherence to recommendations. Descriptive statistics and generalized estimating equations were used for data analyses. RESULTS: Symptom assessment completion was 84% (95% CI=81-87%). Delivery of completed reports was 90% (95% CI=86-93%). Depression (36%), pain (30%), and fatigue (18%) occurred most frequently, followed by anxiety (11%) and dyspnea (6%). On average, overall recommendation adherence was 57% (95% CI=52-62%) and was not dependent on the number of recommendations (P=0.45). Adherence was higher for anxiety (66%; 95% CI=55-77%), depression (64%; 95% CI=56-71%), pain (62%; 95% CI=52-72%), and dyspnea (51%; 95% CI=38-64%) than for fatigue (38%; 95% CI=28-47%). CONCLUSION: The CDS systems, such as SAMI-L, have the potential to fill a gap in promoting evidence-based care.

Radiographic assessment and therapeutic decisions at RECIST progression in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors.

PURPOSE: Advanced NSCLC harboring epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) typically progresses after initial response due to acquired resistance. TKIs are often continued beyond progressive disease by RECIST. We investigated the practice of continuing EGFR-TKIs after RECIST-PD via CT findings. METHODS: Among 101 advanced NSCLC patients with sensitizing EGFR mutations treated with first-line EGFR-TKIs, 70 patients had baseline and at least one follow-up CT for retrospective radiographic assessments using RECIST1.1; 56 patients had experienced PD by the data closure date of June 2011. RESULTS: Among 56 patients experiencing PD, 82% were female, median age was 63 years, 50% were never-smokers, 57% had distant metastasis, 57% had exon 19 deletion, and 89% were treated with erlotinib. 49 patients (88%) continued TKI therapy beyond retrospectively assessed PD. 31/32 (97%) patients who progressed by an increase in their target lesions continued TKI. 13/16 (81%) patients who progressed by appearance of a new lesion remained on TKI. 5/6 (83%) patients with both increase of target lesions and new lesion at PD continued TKI. Two patients with PD in non-target lesions discontinued therapy at PD. In 49 continuing patients, the median time from retrospectively assessed RECIST-PD to termination of TKI was 10.1 months. CONCLUSIONS: 88% of EFGR-mutant NSCLC patients who progressed on first-line TKI continued therapy beyond RECIST-PD, which is not the single determining factor for terminating TKI in EGFR-mutant NSCLC patients. Additional radiographically defined progression criteria are needed for this population.

Survival of older patients with cancer in the Veterans Health Administration versus fee-for-service Medicare.

PURPOSE: The Veterans Health Administration (VHA) provides high-quality preventive chronic care and cancer care, but few studies have documented improved patient outcomes that result from this high-quality care. We compared the survival rates of older patients with cancer in the VHA and fee-for-service (FFS) Medicare and examined whether differences in the stage at diagnosis, receipt of guideline-recommended therapies, and unmeasured characteristics explain survival differences. PATIENTS AND METHODS: We used propensity-score methods to compare all-cause and cancer-specific survival rates for men older than age 65 years who were diagnosed or received their first course of treatment for colorectal, lung, lymphoma, or multiple myeloma in VHA hospitals from 2001 to 2004 to similar FFS-Medicare enrollees diagnosed in Surveillance, Epidemiology, and End Results (SEER) areas in the same time frame. We examined the role of unmeasured factors by using sensitivity analyses. RESULTS: VHA patients versus similar FFS SEER-Medicare patients had higher survival rates of colon cancer (adjusted hazard ratio [HR], 0.87; 95% CI, 0.82 to 0.93) and non-small-cell lung cancer (NSCLC; HR, 0.91; 95% CI, 0.88 to 0.95) and similar survival rates of rectal cancer (HR, 1.05; 95% CI, 0.95 to 1.16), small-cell lung cancer (HR, 0.99; 95% CI, 0.93 to 1.05), diffuse large-B-cell lymphoma (HR, 1.02; 95% CI, 0.89 to 1.18), and multiple myeloma (HR, 0.92; 95% CI, 0.83 to 1.03). The diagnosis of VHA patients at earlier stages explained much of the survival advantages for colon cancer and NSCLC. Sensitivity analyses suggested that additional adjustment for the severity of comorbid disease or performance status could have substantial effects on estimated differences. CONCLUSION: The survival rate for older men with cancer in the VHA was better than or equivalent to the survival rate for similar FFS-Medicare beneficiaries. The VHA provision of high-quality care, particularly preventive care, can result in improved patient outcomes.

Quality of care for older patients with cancer in the Veterans Health Administration versus the private sector: a cohort study.

BACKGROUND: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States. Studies suggest that the VHA provides better preventive care and care for some chronic illnesses than does the private sector. OBJECTIVE: To assess the quality of cancer care for older patients provided by the VHA versus fee-for-service Medicare. DESIGN: Observational study of patients with cancer that was diagnosed between 2001 and 2004 who were followed through 2005. SETTING: VHA and non-VHA hospitals and office-based practices. PATIENTS: Men older than 65 years with incident colorectal, lung, or prostate cancer; lymphoma; or multiple myeloma. MEASUREMENTS: Rates of processes of care for colorectal, lung, or prostate cancer; lymphoma; or multiple myeloma. Rates were adjusted by using propensity score weighting. RESULTS: Compared with the fee-for-service Medicare population, the VHA population received diagnoses of colon (P < 0.001) and rectal (P = 0.007) cancer at earlier stages and had higher adjusted rates of curative surgery for colon cancer (92.7% vs. 90.5%; P < 0.010), standard chemotherapy for diffuse large B-cell non-Hodgkin lymphoma (71.1% vs. 59.3%; P < 0.001), and bisphosphonate therapy for multiple myeloma (62.1% vs. 50.4%; P < 0.001). The VHA population had lower adjusted rates of 3-dimensional conformal or intensity-modulated radiation therapy for prostate cancer treated with external-beam radiation therapy (61.6% vs. 86.0%; P < 0.001). Adjusted rates were similar for 9 other measures. Sensitivity analyses suggest that if patients with cancer in the VHA system have more severe comorbid illness than other patients, rates for most indicators would be higher in the VHA population than in the fee-for-service Medicare population. LIMITATION: This study included only older men and did not include information about performance status, severity of comorbid illness, or patient preferences. CONCLUSION: Care for older men with cancer in the VHA system was generally similar to or better than care for fee-for-service Medicare beneficiaries, although adoption of some expensive new technologies may be delayed in the VHA system. PRIMARY FUNDING SOURCE: Department of Veterans Affairs.