Suresh S Ramalingam

Emory University, Atlanta, Georgia, United States

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Publications (231)1700.23 Total impact

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    ABSTRACT: Background: The last 3 decades have witnessed limited therapeutic advances in small cell lung cancer (SCLC) management. This study evaluated real-world trends in the use of systemic therapies and the impact on patient outcomes in the United States. Methods: The Surveillance, Epidemiology, and End Results-Medicare database was used to find patients diagnosed with SCLC between 1985 and 2005. The 1985-1990 period served as the baseline for a temporal analysis conducted at 5-year intervals (1985-1990, 1991-1995, 1996-2000, and 2001-2005). Cox proportional models were used to estimate the effect of chemotherapy on survival. Results were validated with a propensity-matched analysis. Results: There were 47,351 eligible patients: 52% were male; the median age was 71 years; and 87% were white, 7% were black, and 1.4% were Asian. The proportion of patients treated with chemotherapy was low but increased over time (38%, 55%, 50%, and 53%; P < .001). Race, diagnosis period, age, stage, and location of residence significantly predicted chemotherapy use. Females (51%), Asians (53%), and rural residents (60%) were more likely to receive chemotherapy. The median overall survival with and without chemotherapy was 9.6 and 3.6 months, respectively. Linear trend analyses showed a modest reduction in the impact of chemotherapy on survival for patients treated with chemotherapy versus untreated patients (hazard ratios [HRs], 0.59, 0.61, 0.64, and 0.62; P < .001) but an overall trend of improved survival for treated (HRs, 1.0, 1.03, 1.00, and 0.96; P = .005) and untreated patients (HRs, 1.0, 0.99, 0.94, and 0.92; P < .001). There was no survival difference between patients treated with carboplatin and patients treated with cisplatin (HR, 0.99; confidence interval [CI], 0.81-1.19; P = .875). Additional therapy beyond platinum-based chemotherapy was associated with a survival benefit (HR, 0.78; CI, 0.75-0.81; P < .001). Conclusions: Chemotherapy use was associated with a survival benefit in Medicare patients with SCLC treated in a real-world setting. Cancer 2015. © 2015 American Cancer Society.
    Cancer 10/2015; DOI:10.1002/cncr.29674 · 4.89 Impact Factor
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    ABSTRACT: Objectives: Linifanib, a potent and selective inhibitor of the tyrosine kinase activity of vascular endothelial growth factor and platelet-derived growth factor receptors, has clinical activity in advanced non-small cell lung cancer (NSCLC) both as monotherapy in the relapsed setting or with carboplatin and paclitaxel in the first-line setting. Though benefit was observed in unselected patient populations, identification of predictive biomarkers is critical for further development of this novel agent. Materials and methods: Data from 4 randomized studies in relapsed NSCLC with linifanib (n=116) or other treatments (n=125) were examined in an exploratory analysis to identify a biomarker profile predictive of favorable survival. Results: A signature combining the established tumor markers carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) was predictive of a favorable outcome. This signature was associated with improved survival in patients receiving linifanib monotherapy (hazard ratio [HR]=0.51 vs signature negative; p=0.002), but not in those receiving other anti-cancer treatments (p=0.716). This signature was validated on baseline plasma samples from patients enrolled in a randomized trial of daily linifanib 7.5mg, linifanib 12.5mg, or placebo added to first-line carboplatin and paclitaxel chemotherapy for advanced, nonsquamous NSCLC. Only linifanib-treated signature-positive patients had significant improvement in progression-free survival (PFS). Median PFS with placebo was 5.2 months versus 10.2 months (HR=0.49, p=0.049) for those receiving linifanib 7.5mg, and 8.3 months (HR=0.38, p=0.029) for linifanib 12.5mg. Overall survival for signature-positive patients was 11.3 months with placebo, 12.5 months with linifanib 7.5mg (HR=1.02, p=0.758), and 17.4 months with linifanib 12.5mg (HR=0.54, p=0.137). Conclusion: This baseline plasma biomarker signature is associated with improved outcome in advanced NSCLC patients receiving linifanib. Utility of the biomarker signature in patient selection for linifanib therapy in NSCLC merits evaluation in larger, prospective trials that are powered to detect a survival benefit.
    Lung cancer (Amsterdam, Netherlands) 10/2015; DOI:10.1016/j.lungcan.2015.09.011 · 3.96 Impact Factor
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    Philip J. Webber · Chanhee Park · Min Qui · Suresh S. Ramalingam · Fadlo R. Khuri · Haian Fu · Yuhong Du ·
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    ABSTRACT: Discovery of effective drug combinations is a promising strategy to improve patient survival. This study explores the impact of heat shock protein 90 (Hsp90) inhibition in combination with focal adhesion kinase (FAK) inhibitor on the growth of non-small cell lung cancer cells (NSCLC cells). Our data show that 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), a well-studied Hsp90 inhibitor, synergized with FAK inhibitor, PF-573228, on the growth inhibition of NSCLC cells. This combination effect was confirmed using additional chemically distinct Hsp90 inhibitor, STA-9090, which is currently undergoing phase 3 clinical evaluation. Co-treatment of NSCLC cells with Hsp90 and FAK inhibitors significantly enhanced the inhibition on long-term colony formation compared to that with single agent. Inhibition of FAK exacerbated the G2 cell cycle arrest and annexin-V apoptotic staining induced by 17-AAG. Further mechanistic studies revealed that the combination of Hsp90 and FAK inhibitors reduced the activity of canonical proliferative and survival Akt-mTOR signaling, and increased pro-apoptotic caspase activation. Interestingly, FAK inhibition alone induced feedback activation of pro-survival Erk signaling, which was abrogated by co-treatment with Hsp90 inhibitors. Both Hsp90 and FAK inhibitors are undergoing clinical evaluation. Our studies suggest the tandem of Hsp90 and FAK inhibitors may provide an effective treatment option for NSCLC patients.
    09/2015; 2(9). DOI:10.18632/oncoscience.245
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    ABSTRACT: Purpose: The American College of Chest Physicians (ACCP) produced an evidence-based guideline on treatment of patients with small-cell lung cancer (SCLC). Because of the relevance of this guideline to American Society of Clinical Oncology (ASCO) membership, ASCO reviewed the guideline, applying a set of procedures and policies used to critically examine guidelines developed by other organizations. Methods: The ACCP guideline on the treatment of SCLC was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel updated the literature search, reviewed the content, and considered additional recommendations. Results: The ASCO Endorsement Panel determined that the recommendations from the ACCP guideline, published in 2013, are clear, thorough, and based on current scientific evidence. ASCO endorses the ACCP guideline on the treatment of SCLC, with the addition of qualifying statements. Recommendations: Surgery is indicated for selected stage I SCLC. Limited-stage disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle one or two of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. Extensive-stage disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in patients with limited-stage disease who achieve a complete or partial response to initial therapy and may do so in similarly responding patients with extensive-stage disease as well. Additional information is available at and
    Journal of Clinical Oncology 09/2015; DOI:10.1200/JCO.2015.63.7918 · 18.43 Impact Factor
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    ABSTRACT: Background: Recent data have suggested possible oncologic equivalence of sublobar resection with lobectomy for early stage NSCLC.Our aim was to evaluate and compare short and long term survival for these surgical approaches. Methods: This retrospective cohort study utilized the National Cancer Data Base. Patients undergoing lobectomy, segmentectomy,or wedge resection for preoperative clinical T1A N0 NSCLC from 2003-2011 were identified.Overall survival (OS) and 30-day mortality were analyzed using multivariable Cox proportional hazards models,logistic regression models,and propensity score matching.Further analysis of survival stratified by tumor size, facility type, number of lymph nodes examined, and surgical margins was performed. Results: A total of 13,606 patients were identified. After propensity score matching, 987 patients remained in each group. Both segmentectomy and wedge resection were associated with significantly worse OS when compared with lobectomy (HR 1.70 and 1.45, respectively, both p < 0.001), with no difference in 30 day mortality. Median OS for lobectomy, segmentectomy, and wedge resection were 100, 74, and 68 months, respectively (p < 0.001). Finally, sublobar resection was associated with increased likelihood of positive surgical margins, lower likelihood of having more than 3 lymph nodes examined, and significantly lower rates of nodal upstaging. Conclusion: In this large national-level, clinically diverse sample of clinical T1ANSCLC patients, wedge and segmental resectionswere shown to have significantly worse OS compared tolobectomy.Further patients undergoing sublobar resection were more likely to have inadequate lymphadenectomy and positive margins. Ongoingprospective study taking into account LN upstaging and margin status is still needed.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2015; 10(11). DOI:10.1097/JTO.0000000000000664 · 5.28 Impact Factor
  • Srihari Veeraraghavan · Suresh S Ramalingam · Fadlo R Khuri ·

    Cancer 09/2015; 121 Suppl 17(S17):3055-7. DOI:10.1002/cncr.29601 · 4.89 Impact Factor
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    ABSTRACT: BACKGROUND Stereotactic body radiation therapy (SBRT) has demonstrated high rates of local control with low morbidity and has now emerged as the standard of care for medically inoperable, early stage non–small cell lung cancer (NSCLC). However, the impact of lung SBRT on survival in the elderly population is less clear given competing comorbid conditions. An analysis of the National Cancer Data Base (NCDB) was undertaken to determine whether definitive SBRT improves survival relative to observation alone patients ages 70 years and older.METHODS The NCDB, a retrospective national database that captures approximately 70% of all patients treated for cancer, was queried for patients aged 70 years or older with early stage (T1-T3N0M0) NSCLC from 2003 to 2006. Overall survival was compared between patients who received stereotactic body radiotherapy alone and those who received no treatment. An extended Cox proportional hazards model was applied to estimate the treatment effect of SBRT.RESULTSIn total, 3147 patients met the selection criteria for this analysis. SBRT was delivered to 258 patients (8.2%), and 2889 patients (91.8%) received no treatment. There was no significant difference in the distribution of Charlson/Deyo comorbidity index scores between the 2 groups (P = .076). Multivariable analysis revealed improved overall survival with SBRT compared with observation for the entire cohort (hazard ratio, 0.64; P < .001).CONCLUSIONSSBRT is associated with improved survival in elderly patients with early stage NSCLC who have concurrent comorbid conditions compared with observation alone. The current data support the use of SBRT for the treatment of elderly patients with early stage NSCLC who have limiting comorbid conditions. Cancer 2015. © 2015 American Cancer Society.
    Cancer 09/2015; DOI:10.1002/cncr.29640 · 4.89 Impact Factor
  • Suresh S. Ramalingam · Fadlo R. Khuri ·

    Cancer 09/2015; 121(S17):3058-3060. DOI:10.1002/cncr.29569 · 4.89 Impact Factor
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    ABSTRACT: The SQUIRE trial demonstrated that adding necitumumab to chemotherapy for patients with metastatic squamous cell lung cancer (mSqCLC) increased median overall survival by 1.6 months (hazard ratio, 0.84). However, the costs and value associated with this intervention remains unclear. Value-based pricing links the price of a drug to the benefit that it provides and is a novel method to establish prices for new treatments. To evaluate the range of drug costs for which adding necitumumab to chemotherapy could be considered cost-effective. We developed a Markov model using data from multiple sources, including the SQUIRE trial, which compared standard chemotherapy with and without necitumumab as first-line treatment of mSqCLC, to evaluate the costs and patient life expectancies associated with each regimen. In the analysis, patients were modeled to receive gemcitabine and cisplatin for 6 cycles or gemcitabine, cisplatin, and necitumumab for 6 cycles followed by maintenance necitumumab. Our model's clinical inputs were the survival estimates and frequency of adverse events (AEs) described in the SQUIRE trial. Log-logistic models were fitted to the survival distributions in the SQUIRE trial. The cost inputs included drug costs, based on the Medicare average sale prices, and costs for drug administration and management of AEs, based on Medicare reimbursement rates (all in 2014 US dollars). We evaluated incremental cost-effectiveness ratios (ICERs) for the use of necitumumab across a range of values for its cost. Model robustness was assessed by probabilistic sensitivity analyses, based on 10 000 Monte Carlo simulations, sampling values from the distributions of all model parameters. In the base case analysis, the addition of necitumumab to the treatment regimen produced an incremental survival benefit of 0.15 life-years and 0.11 quality-adjusted life-years (QALYs). The probabilistic sensitivity analyses established that when necitumumab cost less than $563 and less than $1309 per cycle, there was 90% confidence that the ICER for adding necitumumab would be less than $100 000 per QALY and less than $200 000 per QALY, respectively. These findings provide a value-based range for the cost of necitumumab from $563 to $1309 per cycle. This study provides a framework for establishing value-based pricing for new oncology drugs entering the US marketplace.
    08/2015; DOI:10.1001/jamaoncol.2015.3316

  • Cancer Research 08/2015; 75(15 Supplement):1317-1317. DOI:10.1158/1538-7445.AM2015-1317 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):2922-2922. DOI:10.1158/1538-7445.AM2015-2922 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):CT303-CT303. DOI:10.1158/1538-7445.AM2015-CT303 · 9.33 Impact Factor
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    ABSTRACT: In preclinical studies, the efficacy of the combination of antiangiogenic agents with chemotherapy seems to be dependent on the specific cytotoxic agent. We conducted a systematic review of the efficacy of bevacizumab in combination with taxane or non-taxane containing regimens for untreated, nonsquamous non-small-cell lung cancer patients. An extensive search of published clinical trials was conducted from electronic databases (MEDLINE, EMBASE, and Cochrane) and meeting proceedings using relevant search criteria. Phase 2 and randomized trials reporting on the efficacy of bevacizumab combined with taxane or non-taxane regimens were selected. A systematic analysis of extracted data was performed using Comprehensive Meta-Analysis (Version 2.2) software. Clinical outcome in patients treated with taxane versus non-taxane regimen was compared using point estimates for weighted values of median overall survival, progression-free survival, and response rate. Twenty-nine studies reported between 2005 and 2015 were eligible. A total of 5890 patients (2767 and 3123 in the taxane and non-taxane groups, respectively) were included. The taxane and non-taxane groups were comparable in patient characteristics: median age, 62.8 versus 61.2 years; males, 57% versus 58%; adenocarcinomas, 83% versus 83%; stage IV, 87% versus 82%; performance status 0/1- 45/55% versus 41/59%, respectively. The weighted median overall survival was 14.4 versus 13.7 months (p = 0.5); progression-free survival was 6.93 versus 6.99 months (p = 0.61); response rate was 41% versus 39% (p = 0.65) for taxane and non-taxane groups. The outcomes between taxane and non-taxane regimens when given in combination with bevacizumab for patients with nonsquamous non-small-cell lung cancer are comparable.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2015; 10(8):1142-7. DOI:10.1097/JTO.0000000000000572 · 5.28 Impact Factor
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    ABSTRACT: We previously reported that progression-free survival (PFS) may be a candidate surrogate end point for overall survival (OS) in first-line extensive-stage small-cell lung cancer (ES-SCLC) using data from three randomized trials (Foster, Cancer 2011). In this validation study (N0424-Alliance), we assessed the patient-level and trial-level surrogacy of PFS using data from seven new first-line phase II/III ES-SCLC trials and across all 10 trials as well (seven new, three previous). Individual patient data were utilized across the seven new trials (2259 patients) and all 10 trials (2855 patients). Patient-level surrogacy (Kendall's τ) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed through association of the log hazard ratios on OS and PFS across trials, including weighted (by trial size) least squares regression (WLS R) of Cox model effects and correlation of the copula effects (copula R). The minimum effect on the surrogate (MES) needed to detect a nonzero treatment effect on OS was also calculated. The median OS and PFS across all 10 trials were 9.8 and 5.9 months, respectively. PFS showed strong surrogacy within the 7 new trials (copula R = 0.90 [standard error = 0.27], WLS R = 0.83 [95% confidence interval: 0.43, 0.95]; MES = 0.67, and Kendall's τ = 0.58) and across all 10 trials (copula R = 0.81 [standard errors = 0.25], WLS R = 0.77 [95% confidence interval: 0.47-0.91], MES = 0.70, and Kendall's τ = 0.57). PFS demonstrated strong surrogacy for OS in first-line ES-SCLC based on this external validation study of individual patient data. PFS is a good alternative end point to OS and should be considered when resource constraints (time or patient) might make it useful or desirable in place of OS. Additional analyses are needed to assess its appropriateness for targeted agents in this disease setting.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 07/2015; 10(7):1099-106. DOI:10.1097/JTO.0000000000000548 · 5.28 Impact Factor
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    ABSTRACT: We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.
    Cell 06/2015; 161(7):1681 - 1696. DOI:10.1016/j.cell.2015.05.044 · 32.24 Impact Factor
  • Conor E. Steuer · Suresh S. Ramalingam ·
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    ABSTRACT: The development of individualized therapies has become the focus of current oncology research. Precision medicine has demonstrated great potential for bringing safe and effective drugs to those patients stricken with cancer, and is becoming a reality as more oncogenic drivers of malignancy are discovered. The discovery of Epidermal Growth Factor Receptor (EGFR) mutations as a driving mutation in non-small cell lung cancer (NSCLC) and the subsequent success of the tyrosine kinase inhibitors (TKI) have led the way for NSCLC to be at the forefront of biomarker-based drug development. However, this direction was not always so clear, and this article describes the lessons learned in targeted therapy development from EGFR in NSCLC. Copyright © 2015. Published by Elsevier Ltd.
    Molecular Aspects of Medicine 05/2015; 45. DOI:10.1016/j.mam.2015.05.004 · 10.24 Impact Factor
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    ABSTRACT: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced NSCLC and to identify patient populations most likely to benefit from the combination. Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75mg/m(2) on Day 1) was administered alone or with ganetespib (150mg/m(2) on Days 1 and 15) every 3 weeks. The primary endpoints were progression-free survival (PFS) in 2 subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). Out of 385 patients enrolled, 381 were treated. Early in the trial increased hemoptysis and lack of efficacy were observed in non-adenocarcinoma patients (n=71), therefore only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm vs. 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N=114, adjusted HR=0.77, P=0.1134) or mKRAS (N=89, adjusted HR=1.11, P=0.3384) subgroups. In the ITT adenocarcinoma population there was a trend in favor of the combination, with PFS (N=253, adjusted HR=0.82, P=0.0784) and overall survival (OS) (adjusted HR=0.84, P=0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N=177): PFS (adjusted HR=0.74, P=0.0417); OS (adjusted HR=0.69, P=0.0191). Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary endpoints were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the Phase 3 study. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 05/2015; 26(8). DOI:10.1093/annonc/mdv220 · 7.04 Impact Factor
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    ABSTRACT: The BH4 domain of Bcl2 is required for its antiapoptotic function, thus constituting a promising anticancer target. We identified a small-molecule Bcl2-BH4 domain antagonist, BDA-366, that binds BH4 with high affinity and selectivity. BDA-366-Bcl2 binding induces conformational change in Bcl2 that abrogates its antiapoptotic function, converting it from a survival molecule to a cell death inducer. BDA-366 suppresses growth of lung cancer xenografts derived from cell lines and patient without significant normal tissue toxicity at effective doses. mTOR inhibition upregulates Bcl2 in lung cancer cells and tumor tissues from clinical trial patients. Combined BDA-366 and RAD001 treatment exhibits strong synergy against lung cancer in vivo. Development of this Bcl2-BH4 antagonist may provide a strategy to improve lung cancer outcome. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 05/2015; 27(6). DOI:10.1016/j.ccell.2015.04.010 · 23.52 Impact Factor
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    ABSTRACT: Veliparib (V) potentiated therapeutic efficacy of cisplatin (C) and etoposide (E) in preclinical models of SCLC. We conducted this phase 1 study to establish the safety of the combination in human subjects. The study employed the 3+3 dose escalation design to establish the safety and recommended phase 2 dose (RP2D) of V when combined with fixed doses of C (75mg/m(2) on day 1) and E (100mg/m(2) on days 1-3) in a 21-day cycle. The starting dose of V was 60mg (bid days 1-7) with plan to escalate to 100mg (days 1-7) or de-escalate to 40mg (days 1-7) depending on the dose limiting toxicity (DLT) experience during cycle 1. Patients with treatment-naïve, extensive stage SCLC were included. The study enrolled 9 patients: M/F (4/5); median age (60); White/African American (8/1). V was tolerated at the 60mg (DLT in 0 of 3 patients) and 100mg dose (DLT in 1 of 6 patients; grade 5 cardiac failure). Veliparib at 100mg in combination with standard doses of C and E was established as the RP2D. Grades 3-5 adverse events irrespective of attribution during cycle 1 included: dehydration (1), diarrhea (1), fatigue (1), febrile neutropenia (1), heart failure (1), leukopenia (6), lymphopenia (1), nausea (2), neutropenia (8), respiratory failure (1), and thrombocytopenia (2). Investigator-assessed efficacy outcome in 7 evaluable patients were stable disease in 2/7 (28.6%), partial response in 4/7 (57.1%), and complete response in 1/7 (14.3%) patients. This study demonstrated the safety of combining veliparib with cisplatin and etoposide in previously untreated SCLC patients. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Lung cancer (Amsterdam, Netherlands) 05/2015; 89(1). DOI:10.1016/j.lungcan.2015.04.015 · 3.96 Impact Factor
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    ABSTRACT: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; number, NCT01802632.).
    New England Journal of Medicine 04/2015; 372(18):1689-99. DOI:10.1056/NEJMoa1411817 · 55.87 Impact Factor

Publication Stats

3k Citations
1,700.23 Total Impact Points


  • 2008-2015
    • Emory University
      • • Department of Hematology and Medical Oncology
      • • Winship Cancer Institute
      Atlanta, Georgia, United States
  • 2014
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 2012
    • University of Miami Miller School of Medicine
      Miami, Florida, United States
  • 2004-2011
    • University of Pittsburgh
      • • Department of Medicine
      • • Department of Pharmacology and Chemical Biology
      • • Division of Medical Toxicology
      Pittsburgh, Pennsylvania, United States
  • 2010
    • Penn State Hershey Medical Center and Penn State College of Medicine
      Hershey, Pennsylvania, United States
  • 2007-2008
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States