Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer.

BACKGROUND: Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non-small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG. MATERIALS AND METHODS: Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. RESULTS: One hundred twenty-nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression-free survival (PFS) in the unselected intent-to-treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37-1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16-0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97-4.76; p = .059, HRG-by-treatment interaction, p value = .0016). CONCLUSION: The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). IMPLICATIONS FOR PRACTICE: The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.

Lung Cancer Screening, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology.

Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings.

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.

Delay of treatment change after objective progression on first-line erlotinib in epidermal growth factor receptor-mutant lung cancer.

BACKGROUND: Erlotinib is a highly active epidermal growth factor receptor (EGFR) kinase inhibitor that is approved for first-line use in lung cancers harboring EGFR mutations. Anecdotal experience suggests that this drug may provide continued disease control after patients develop objective progression of disease (PD), although this has not been systematically studied to date. METHODS: Patients who had Response Evaluation Criteria In Solid Tumors-defined PD who were participating in 3 prospective trials of first-line erlotinib in advanced lung cancer were studied retrospectively, and the progression characteristics were compared between patients with and without EGFR-sensitizing mutations. Factors were studied that influenced the time until treatment change (TTC), defined as the time from PD to the start of a new systemic therapy or death. The rate of tumor progression was assessed by comparing tumor measurements between the computed tomography scan obtained at the time of PD and the preceding scan. RESULTS: In total, 92 eligible patients were studied, including 42 with and 50 without an EGFR-sensitizing mutation. The EGFR-mutant cohort had a slower rate of progression (P = .003) and a longer TTC (P < .001). Among the patients with EGFR-mutant cancers, 28 (66%) continued single-agent erlotinib after PD, and 21 (50%) were able to delay a change in systemic therapy for >3 months; only 2 patients received local debulking therapy during that period. Multivariate analysis of the patients with EGFR-mutant tumors demonstrated that a longer time to progression, a slower rate of progression, and a lack of new extrathoracic metastases were associated with a longer TTC. CONCLUSIONS: A change in systemic therapy commonly can be delayed in patients with EGFR-mutant lung cancer who objectively progress on first-line erlotinib, particularly in those with a longer time to progression, a slow rate of progression, and a lack of new extrathoracic metastases.

Lung cancer screening, version 1.2015: featured updates to the NCCN guidelines.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide recommendations for selecting individuals for lung cancer screening, and for evaluation and follow-up of nodules found during screening, and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights focus on the major updates to the 2015 NCCN Guidelines for Lung Cancer Screening, which include a revision to the recommendation from category 2B to 2A for one of the high-risk groups eligible for lung cancer screening. For low-dose CT of the lung, the recommended slice width was revised in the table on "Low-Dose Computed Tomography Acquisition, Storage, Interpretation, and Nodule Reporting."

Volumetric tumor growth in advanced non-small cell lung cancer patients with EGFR mutations during EGFR-tyrosine kinase inhibitor therapy: developing criteria to continue therapy beyond RECIST progression.

BACKGROUND: The objective of this study was to define the volumetric tumor growth rate in patients who had advanced nonsmall cell lung cancer (NSCLC) with sensitizing epidermal growth factor receptor (EGFR) mutations and had initially received treatment with EGFR-tyrosine kinase inhibitor (TKI) therapy beyond progression. METHODS: The study included 58 patients with advanced NSCLC who had sensitizing EGFR mutations treated with first-line gefitinib or erlotinib, had baseline computed tomography (CT) scans available that revealed a measurable lung lesion, had at least 2 follow-up CT scans during TKI therapy, and had experienced volumetric tumor growth. The tumor volume (in mm3) of the dominant lung lesion was measured on baseline and follow-up CT scans during therapy. In total, 405 volume measurements were analyzed in a linear mixed-effects model, fitting time as a random effect, to define the growth rate of the logarithm of tumor volume (log(e)V). RESULTS: A linear mixed-effects model was fitted to predict the growth of log(e)V, adjusting for time in months from baseline. Log(e)V was estimated as a function of time in months among patients whose tumors started growing after the nadir: log(e)V = 0.12*time + 7.68. In this formula, the regression coefficient for time, 0.12/month, represents the growth rate of log(e)V (standard error, 0.015/month; P < .001). When adjusted for baseline volume, log(e)V0, the growth rate was also 0.12/month (standard error, 0.015/month; P < .001; log(e)V = 0.12*months + 0.72 log(e)V0 + 0.61). CONCLUSIONS: Tumor volume models defined volumetric tumor growth after the nadir in patients with EGFR-mutant, advanced NSCLC who were receiving TKI, providing a reference value for the tumor growth rate in patients who progress after the nadir on TKI therapy. The results can be studied further in additional cohorts to develop practical criteria to help identify patients who are slowly progressing and can safely remain on EGFR-TKIs.

Chemotherapy with Erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors.

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer has an oncogene-addicted biology that confers sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Published data suggest that EGFR addiction persists after development of TKI acquired resistance, leading many clinicians to continue TKI with subsequent chemotherapy; however, this strategy has not been formally evaluated. Methods. We retrospectively reviewed an institutional database to identify patients with advanced EGFR mutation with acquired resistance who subsequently received chemotherapy. Patients were classified as receiving chemotherapy with continued erlotinib or chemotherapy alone. We assessed differences in outcomes between the two strategies. Results. Seventy-eight patients were included, 34 treated with chemotherapy and erlotinib and 44 treated with chemotherapy alone. Objective response rate was evaluable in 57 patients and was 41% for those treated with chemotherapy and erlotinib and 18% for those treated with chemotherapy alone. After adjusting for chemotherapy regimen and length of initial TKI course, the odds ratio for the response rate was 0.20 (95% confidence interval: 0.05-0.78; p = .02) favoring treatment with chemotherapy and erlotinib. The median progression-free survival was 4.4 months on chemotherapy and erlotinib and 4.2 months on chemotherapy alone (adjusted hazard ratio = 0.79; 95% confidence interval: 0.48-1.29; p = .34). There was no difference in overall survival. Conclusion. This is the first study, to our knowledge, to demonstrate that continuation of EGFR TKI with chemotherapy in patients with acquired resistance improves outcomes compared with chemotherapy alone. We observed an improved response rate but no difference in progression-free survival or overall survival. A larger prospective clinical trial is needed to evaluate this promising strategy further.

RECIST 1.1 in NSCLC patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors: comparison with RECIST 1.0.

OBJECTIVE: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 has been rapidly accepted in clinical trials as a standard measure to assess tumor response to therapy and is expected to improve response assessment, especially in genomically defined patients. The impact of RECIST 1.1 was compared with RECIST 1.0 in non-small cell lung cancer (NSCLC) patients with sensitizing epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors. MATERIALS AND METHODS: Seventy patients with advanced NSCLC harboring sensitizing EGFR mutations treated with a first-line EGFR tyrosine kinase inhibitor were retrospectively studied. Tumor measurements and response assessment were performed using RECIST 1.0 and RECIST 1.1. The number of target lesions, the percentage change at the initial follow-up, best response, and time to progression were compared between RECIST 1.1 and RECIST 1.0. RESULTS: The number of target lesions identified using RECIST 1.1 was significantly lower compared with that using RECIST 1.0 (mean, 2.7 and 2.0, respectively; p < 0.0001; paired Student t test), with a decrease in 31 patients (44%). The initial proportional changes of the target lesion measurements had high correlation between the two criteria (R(2) = 0.8070), with concordant response assessment in 66 patients (94%). The best response showed almost perfect agreement (κw = 0.970). Time to progression (TTP) did not differ between the two criteria in 52 patients (74%), was longer by RECIST 1.1 in 15 patients (21%), and was shorter by RECIST 1.1 in three patients (4%). CONCLUSION: RECIST 1.1 provided highly concordant response assessment with a decreased number of target lesions compared with RECIST 1.0 in advanced NSCLC patients harboring sensitizing EGFR mutations treated with an EGFR tyrosine kinase inhibitor. RECIST 1.1 altered TTP in 25% of patients compared with RECIST 1.0.

Early Findings on the Use of Clinical Pathways for Management of Unwarranted Variation in Cancer Care.

Clinical pathways have the potential to improve complex clinical decision-making in cancer care. The authors implemented pathways with customized content to assist oncologists to select treatments, aiming for an on-pathway rate of 70%-85%. Treatment decisions were captured as on or off pathway, and metrics were shared monthly with users. Oncologists were categorized into quintiles based on on-pathway performance during the first 90 days of use. On-pathway rates were then calculated for days 91-360 (N = 121). Median on-pathway quintile rates varied from 50% to 100% in the initial 90-day period. During follow-up, median on-pathway rates shifted into the prespecified goal range for all groups. Clinical pathways resulted in greater uniformity in medical oncology practice. Monthly feedback about usage, familiarity with the electronic platform, and regular content updates are some factors that may influence on-pathway rates. Clinical pathways hold promise to manage unwarranted variation in cancer care.

Outcomes after combined modality therapy for EGFR-mutant and wild-type locally advanced NSCLC.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations identify a unique biological subtype of non-small cell lung cancer (NSCLC). Treatment outcomes for EGFR-mutant locally advanced NSCLC patients have not been well described. METHODS: We retrospectively examined outcomes after combined modality therapy including thoracic radiation therapy (RT) in 123 patients with locally advanced NSCLC and known EGFR mutation status. Outcomes were compared using Kaplan-Meier analysis, the log-rank test, and multivariate Cox regression models. RESULTS: All 123 patients underwent thoracic RT; 25% had tumors with EGFR mutations and 94% had stage III disease. Overall, 81% received chemotherapy concurrent with RT and 55% underwent surgical resection. With a median follow-up of 27.5 months, the overall survival (OS) rate was significantly higher in patients with EGFR-mutant tumors than in those with wild-type EGFR tumors (2-year estimate: 92.6% versus 69.0%; p = .04). The 2-year relapse-free survival and distant recurrence rates did not differ significantly by genotype. The 2-year locoregional recurrence rate (LRR) was significantly lower in EGFR-mutant than in wild-type EGFR patients (17.8% versus 41.7%; p = .005). EGFR-mutant genotype was associated with a lower risk for LRR on multivariate analysis, but not OS, after adjusting for surgery and other potential confounders. CONCLUSION: We observed that EGFR-mutant patients with locally advanced NSCLC treated with RT had lower rates of LRR than wild-type EGFR patients, raising the hypothesis that EGFR mutations may confer sensitivity to RT and/or chemotherapy. The association between mutation status and OS after combined modality therapy was less robust. Our data may serve as a useful baseline estimate of outcomes by EGFR genotype for future prospective studies.

New Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for advanced non-small cell lung cancer: comparison with original RECIST and impact on assessment of tumor response to targeted therapy.

OBJECTIVE: The purpose of this article is to compare the recently published revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) to the original guidelines (RECIST 1.0) for advanced non-small cell lung cancer (NSCLC) after erlotinib therapy and to evaluate the impact of the new CT tumor measurement guideline on response assessment. MATERIALS AND METHODS: Forty-three chemotherapy-naive patients with advanced NSCLC treated with erlotinib in a single-arm phase 2 multicenter open-label clinical trial were retrospectively studied. CT tumor measurement records using RECIST 1.0 that were generated as part of the prospective clinical trial were reviewed. A second set of CT tumor measurements was generated from the records to meet RECIST 1.1 guidelines. The number of target lesions, best response, and time to progression were compared between RECIST 1.1 and RECIST 1.0. RESULTS: The number of target lesions according to RECIST 1.1 decreased in 22 patients (51%) and did not change in 21 patients (49%) compared with the number according to RECIST 1.0 (p < 0.0001, paired Student's t test). Almost perfect agreement was observed between best responses using RECIST 1.1 and RECIST 1.0 (weighted kappa = 0.905). Two patients with stable disease according to RECIST 1.0 had progressive disease according to RECIST 1.1 criteria because of new lesions found on PET/CT. There was no significant difference in time to progression between RECIST 1.1 and RECIST 1.0 (p = 1.000, sign test). CONCLUSION: RECIST 1.1 provided almost perfect agreement in response assessment after erlotinib therapy compared with RECIST 1.0. Assessment with PET/CT was a major factor that influenced the difference in best response assessment between RECIST 1.1 and RECIST 1.0.

Recurrent malignant peritoneal mesothelioma: radiological manifestations.

PURPOSE: To describe the CT imaging findings of recurrent malignant peritoneal mesothelioma in patients who underwent debulking surgery. MATERIALS AND METHODS: The history, clinical and laboratory data, and imaging studies of 13 patients with histologically proven diagnosis of Malignant Peritoneal Mesothelioma (MPM) and their recurrence following cytoreductive surgery were reviewed. CT studies were reviewed for presence of ascites, peritoneal, mesenteric and omental involvement, presence of solid abdominal viscera involvement, gastrointestinal involvement, presence and location of enlarged lymph nodes and extra abdominal sites of involvement. RESULTS: The most common finding at recurrence was ascites (n = 6). Peritoneal thickening was seen in five patients, infiltration of the peritoneum resembling omental caking was seen in one patient, and low density implants mimicking pseudomyxoma peritonei was seen in another patient. None of the peritoneal implants showed calcification. Three patients had large discrete soft tissue masses in the omentum and/or peritoneum. Multifocal serosal implants were seen in four patients; one had low grade small bowel obstruction which was managed conservatively. Three patients had evidence of intrathoracic disease seen as soft tissue pericardial mass and malignant pleural effusions. CONCLUSION: CT findings of recurrent MPM resemble primary MPM, metastatic or granulomatous diseases. Radiologist should be aware of its appearance and forms of recurrence which may be seen at extra abdominal sites.

Treatment of peritoneal mesothelioma in pediatric patients.

Peritoneal mesothelioma is a rare and often aggressive malignancy, mostly affecting asbestos exposed adults. We present four pediatric peritoneal cases treated with a cisplatin-based doublet regimen, the standard of care in the systemic therapy of adult mesothelioma. Treatment was well tolerated, and three of these patients have achieved long-term survival. The fathers of three of the patients worked in the construction industry and may have been the source of indirect asbestos exposure.

Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, lead to significant tumor regressions in 10% to 15% of non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, 30% to 40% of NSCLC patients, majority of whom are EGFR wild-type, develop stable disease following EGFR tyrosine kinase inhibitor therapy. EGFR-directed antibodies (cetuximab) are effective treatments for head and neck squamous cell carcinomas, which seldom contain EGFR mutations. The determinant(s) of efficacy of EGFR-targeted therapies in EGFR wild-type cancers is not well defined. EXPERIMENTAL DESIGN: We examined the relationship of EGFR ligands, EGF, transforming growth factor-alpha,and amphiregulin and the efficacy of gefitinib and cetuximab in EGFR wild-type NSCLC (n=10) and head and neck squamous cell carcinoma (n=4) cell lines. We compared amphiregulin expression using immunohistochemistry in EGFR wild-type NSCLC patients (n=24) that developed either stable or progressive disease following erlotinib or gefitinib treatment. RESULTS: Cell lines which produced >or=20 pmol/L amphiregulin, as detected by an ELISA, were significantly more likely to be growth inhibited by both gefitinib and cetuximab than those that produced minimal or no amphiregulin. In these cell lines, both cetuximab and gefitinib led to cell cycle arrest at the G(1)-S boundary and was associated with preferential inhibition of extracellular signal-regulated kinase 1/2 but not Akt signaling. Amphiregulin expression was significantly higher in NSCLC patients that developed stable disease compared with those that developed disease progression following gefitinib or erlotinib treatment. CONCLUSIONS: Amphiregulin expression may help select EGFR wild-type patients who are likely to develop stable disease from EGFR-targeted therapies.

Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib.

PURPOSE: Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib; however, resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y and L747S) are rare. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated patients resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. EXPERIMENTAL DESIGN: Retrospective review of 18 EGFR mutated (exon 19 deletions, L858R, and L861Q) patients that were given gefitinib and subsequently erlotinib. Seven patients had tumor resampling after TKI therapy and were analyzed for secondary EGFR mutations and MET amplification. RESULTS: Most patients (14 of 18) responded to gefitinib with median progression-free survival of 11 months (95% confidence interval, 4-16). After gefitinib resistance (de novo or acquired), 78% (14 of 18) of these patients displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). Six of 7 resampled patients acquired the T790M mutation, and 0 of 3 had MET amplification. Only 1 gefitinib-resistant patient with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib. CONCLUSIONS: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.

Current options for systemic therapy in mesothelioma.

Systemic therapy options for patients with mesothelioma remain limited. Although many conventional chemotherapeutic agents have shown modest activity in this disease, only the combination of cisplatin plus pemetrexed has demonstrated an improvement in clinical outcomes in a phase III trial when compared with single modality therapies. Clinical investigations of the use of targeted therapies in mesothelioma are ongoing, as investigators attempt to inhibit critical pathways in this disease. This article surveys the current clinical landscape of systemic therapies in mesothelioma and explores the impact of both conventional and targeted agents.

Rationale for a phase I trial of erlotinib and the mammalian target of rapamycin inhibitor everolimus (RAD001) for patients with relapsed non small cell lung cancer.

BACKGROUND AND RATIONALE: Only 10% of patients with relapsed non-small cell lung cancer (NSCLC) treated with chemotherapy or erlotinib have a partial response to treatment, and nearly all eventually recur and die from their NSCLC. Agents that can block other pathways in addition to the epidermal growth factor receptor signals may improve the therapeutic efficacy of erlotinib. Everolimus (RAD001) is an inhibitor of the mammalian target of rapamycin, which is downstream of initial epidermal growth factor receptor signaling. A trial combining erlotinib with everolimus has been undertaken for patients with relapsed NSCLC. MATERIALS AND METHODS: Subjects with previously treated NSCLC are treated with increasing doses of daily erlotinib and everolimus given either daily or once weekly. The study's objectives in phase I are to assess the feasibility of combining daily erlotinib and either daily or weekly everolimus, to assess toxicity, and to determine the appropriate dose for subsequent trials. RESULTS: The protocol calls for patients to be treated with escalating daily or weekly everolimus in combination with erlotinib given at doses of 100 mg daily to escalate to 150 mg daily. The dose escalation with both daily and weekly everolimus and erlotinib is ongoing. CONCLUSIONS: Everolimus has an appropriate rationale for therapeutic use in combination with erlotinib for patients with NSCLC. This manuscript will review the preclinical rationale for undertaking a study of erlotinib combined with everolimus for patients with relapsed NSCLC.

Implementation to Optimization: A Tailored, Data-Driven Approach to Improve Provider Efficiency and Confidence in Use of the Electronic Medical Record.

PURPOSE: Nine months after the implementation of a new electronic medical record (EMR) system at a single institution, physicians (MDs), nurse practitioners (NPs), and physician assistants (PAs) expressed frustration with its use. We aimed to test if an individually tailored training approach reduced time spent with the EMR and increased confidence. MATERIALS AND METHODS: Two hours of training were conducted in a one-on-one manner with a trainer. Content was individualized according to the following: provider survey, EMR utilization profile, and shadowing in clinic. Surveys assessed confidence before training and immediately after training. Changes in time spent in various EMR activities before training and after training were compared. RESULTS: Three trainers delivered one-on-one training to 133 MDs, 42 NPs, and 10 PAs who specialized in medical oncology. Participants reported an increase in confidence across all activities, and almost all providers (98%) who responded to our survey agreed that the training enhanced their efficiency. A non-statistically significant trend toward reduction in the overall time in the system was observed. Time in system was reduced primarily in activities such as documentation and ordering of laboratory tests, imaging, medications, and chemotherapy. CONCLUSION: A personalized and data-driven training approach was highly regarded by providers. EMR usage reports provided extensive data to identify and prioritize training content and were valuable to measure the impact of training on provider time in system. With the growth of EMR implementation and the reported relationship of EMR use to burnout, continuous and personalized training after EMR implementation is effective to reduce the time in system and increase confidence.

Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: Results From the CA209-003 Study.

Purpose In two phase III studies, nivolumab, a programmed death-1 (PD-1) inhibitor antibody, improved overall survival (OS) versus docetaxel in pretreated advanced non-small-cell lung cancer (NSCLC). We report 5-year follow-up results from an early phase I study of nivolumab in this patient population and describe characteristics of 5-year survivors. Patients and Methods Patients with pretreated, advanced NSCLC received nivolumab 1, 3, or 10 mg/kg every 2 weeks in 8-week cycles for up to 96 weeks. OS from the time of first dose was estimated by the Kaplan-Meier method. Results The estimated 5-year OS rate was 16% for all treated patients (N = 129); 5-year OS rates were similar for squamous (16%) and nonsquamous (15%) NSCLC. Of 16 5-year survivors, most (88%) were known current or former smokers. Of 10 5-year survivors with quantifiable PD-1 ligand 1 expression, 70% had ≥ 1% PD-1 ligand 1 expression at baseline. Twelve 5-year survivors (75%) achieved a partial response to nivolumab per Response Evaluation Criteria in Solid Tumors, version 1.0, and two each (12%) had stable disease and progressive disease as best response. Nine 5-year survivors (56%) completed the maximum 96 weeks of nivolumab; four (25%) discontinued owing to adverse events and three (19%) owing to disease progression. As of a November 2016 database lock, 12 5-year survivors (75%) received no subsequent therapy and were without evidence of progressive disease at last follow-up. Conclusions Nivolumab treatment resulted in long-term OS and durable responses in a proportion of patients with pretreated advanced NSCLC. Long-term survivors had diverse baseline and on-treatment characteristics.