Showing papers by "David R. Gandara published in 2017"
Aix-Marseille University1, Genentech2, Samsung Medical Center3, Seconda Università degli Studi di Napoli4, Wayne State University5, Pontifícia Universidade Católica do Rio Grande do Sul6, University of California, Los Angeles7, European Institute of Oncology8, Istanbul University9, Seoul National University Bundang Hospital10, University of California, Davis11
TL;DR: Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations, and overall survival improvement was similar in patients with squamous non-squamous lung cancer.
3,496 citations
TL;DR: This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.
Abstract: A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.
381 citations
Centre Hospitalier Universitaire de Toulouse1, Ohio State University2, University of Colorado Denver3, Institut Gustave Roussy4, Harvard University5, Yonsei University6, University of Texas MD Anderson Cancer Center7, Netherlands Cancer Institute8, Stanford University9, The Chinese University of Hong Kong10, National Taiwan University11, University of California, Irvine12, University of Paris13, University of California, Davis14, Cleveland Clinic15, Kantonsspital St. Gallen16, The Royal Marsden NHS Foundation Trust17, University of Basel18, Heidelberg University19, University of Rennes20, Memorial Sloan Kettering Cancer Center21
TL;DR: The results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to the authors' knowledge, on outcomes of RET-directed therapy thus far, are presented.
Abstract: Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.
263 citations
Stanford University1, Harvard University2, Montefiore Medical Center3, Albert Einstein Medical Center4, University of California, Davis5, State University of New York Upstate Medical University6, Roswell Park Cancer Institute7, Princess Margaret Cancer Centre8, Rutgers University9, Northwestern University10, University of Wisconsin-Madison11, University of Alberta12, University of Pennsylvania13, Thomas Jefferson University14, Vanderbilt University Medical Center15, Emory University16, University of Texas Southwestern Medical Center17
TL;DR: A phase III study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC provides modest survival benefit and has 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0·025-level test.
Abstract: Summary Background Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC. Methods We did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6–12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m 2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m 2 on days 1 and 8), docetaxel (75 mg/m 2 on day 1), gemcitabine (1200 mg/m 2 on days 1 and 8), or pemetrexed (500 mg/m 2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805. Findings Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9–68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82–1·19; p=0·90). Grade 3–5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3–5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment. Interpretation Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC. Funding National Cancer Institute of the National Institutes of Health.
118 citations
Eli Lilly and Company1, University of California, Davis2, University of Colorado Boulder3, Rush University Medical Center4, Carolinas Healthcare System5, University of Pennsylvania6, Cedars-Sinai Medical Center7, University of Turin8, Complutense University of Madrid9, University of Lyon10, Emory University11, Sarah Cannon Research Institute12, Stanford University13
TL;DR: Evaluating recently approved treatment options, and the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC, and proposing a treatment algorithm incorporating these agents for this challenging-to-treat disease are reviewed.
104 citations
City of Hope National Medical Center1, University of Texas MD Anderson Cancer Center2, Washington University in St. Louis3, University of Southern California4, Cornell University5, Pennsylvania State University6, Yeshiva University7, University of Chicago8, University of California, Davis9, Mayo Clinic10, University of Pittsburgh11, National Institutes of Health12, Leidos13
TL;DR: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC and higher baseline PAR was associated with clinical benefit.
Abstract: Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome.Experimental Design: Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome.Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit.Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066-76. ©2017 AACR.
85 citations
TL;DR: This research presents a novel and scalable approach to Oncology Biomarker Development that addresses the challenge of integrating cell reprograming and “ ‘spatially aggregating’ signals” into the immune system through a probabilistic approach.
72 citations
TL;DR: Insight is provided into the biochemical and molecular biological reprogramming that may accompanies early stage lung tumorigenesis and potential therapeutic targets are highlighted.
Abstract: Lung cancer is the leading cause of cancer mortality in the United States with non-small cell lung cancer (NSCLC) adenocarcinoma being the most common histological type. Early perturbations in cellular metabolism are a hallmark of cancer, but the extent of these changes in early stage lung adenocarcinoma remains largely unknown. In the current study, an integrated metabolomics and proteomics approach was utilized to characterize the biochemical and molecular alterations between malignant and matched control tissue from 27 subjects diagnosed with early stage lung adenocarcinoma. Differential analysis identified 71 metabolites and 1102 proteins that delineated tumor from control tissue. Integrated results indicated four major metabolic changes in early stage adenocarcinoma: (1) increased glycosylation and glutaminolysis; (2) elevated Nrf2 activation; (3) increase in nicotinic and nicotinamide salvaging pathways; and (4) elevated polyamine biosynthesis linked to differential regulation of the SAM/nicotinamide methyl-donor pathway. Genomic data from publicly available databases were included to strengthen proteomic findings. Our findings provide insight into the biochemical and molecular biological reprogramming that may accompanies early stage lung tumorigenesis and highlight potential therapeutic targets.
64 citations
University of Western Australia1, National University of Singapore2, St. Vincent's Health System3, Medical University of South Carolina4, University of Colorado Denver5, University of Liverpool6, University of Groningen7, Rush University Medical Center8, University of Basel9, University of Pittsburgh10, University of Barcelona11, Yale University12, Imperial College London13, Keio University14, New York University15, Stanford University16, Emory University17, VU University Amsterdam18, Peter MacCallum Cancer Centre19, Seoul National University20, Sarah Cannon Research Institute21, National Taiwan University22, Harvard University23, Sungkyunkwan University24, University of Chicago25, Vanderbilt University26, University of Lausanne27, Manchester Academic Health Science Centre28, Memorial Sloan Kettering Cancer Center29, University of Texas MD Anderson Cancer Center30, Netherlands Cancer Institute31, Johns Hopkins University32, University of Toronto33, University of Turin34, University of California, Davis35, Anschutz Medical Campus36
TL;DR: Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC and mesothelioma.
41 citations
39 citations
TL;DR: Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS‐mutated NSCLC and meeting prespecified criteria was observed.
TL;DR: In these models, INC‐280 treatment was sufficient to restore erlotinib‐induced inhibition of MET, GAB1, AKT, and ERK in the presence of HGF, and provide a preclinical rationale for an ongoing phase 1 clinical trial of erlot inib plus INC‐ 280 in EGFR‐mutated NSCLC.
TL;DR: The results suggest that trametinib and 4‐MU are promising therapeutic agents in MPM and that further study of the combination is warranted.
TL;DR: Onartuzumab did not confer any clinical benefit in the intent‐to‐treat population or in the MET immunohistochemistry‐positive population, and the development of onartzumab for squamous cell NSCLC will not be pursued further.
TL;DR: The current situation in the management of lung cancer in Latin America is reviewed, hoping that this initiative will help physicians, patient associations, industry, governments, and other stakeholders better face this epidemic in the near future.
TL;DR: This data indicates that CIT can have a positive impact on OS that exceeds response rate or PFS effects, termed post progression prolongation of survival (PPPS), and this effect can also affect survival in animals with normal immune status.
Abstract: 9001Background: Cancer immunotherapy (CIT) can have a positive impact on OS that exceeds response rate or PFS effects, termed post progression prolongation of survival (PPPS). This effect can also ...
TL;DR: Cediranib combined with cisplatin‐pemetrexed has a reasonable toxicity profile and preliminary promising efficacy and the maximum tolerated dose of cedirAnib was established as 20 mg in a dose deescalation scheme.
TL;DR: No evidence for the activity of dovitinib in patients who had recently progressed on anti-VEGF therapy and toxicities were significant.
Abstract: Background Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-vascular endothelial growth factor (VEGF) therapy. We tested dovitinib, an inhibitor of both FGF and VEGF receptors, in patients progressing on anti-VEGF treatment. Methods Patients with measurable advanced colorectal or non-small cell lung cancer with progression despite anti-VEGF treatment within 56 days, good performance status and adequate organ function were eligible. A research tumor biopsy was followed by treatment with dovitinib 500 mg on a 5-day on /2-day off schedule for 28-day cycles. The primary endpoint of tumor response was evaluated every 2 cycles. Secondary endpoints included toxicity and 8-week disease control rate. Intratumor mRNA expression of angiogenic mediators was analyzed using a next generation sequencing based expression array. Results Ten patients treated previously with bevacizumab or ziv-aflibercept enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable patients. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All patients experienced at least one grade ≥3 treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA. Conclusions We found no evidence for the activity of dovitinib in patients who had recently progressed on anti-VEGF therapy and toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway.
TL;DR: S1400D is a phase II biomarker-driven therapeutic sub-study evaluating the FGFR inhibiting substance in patients with SqNSCLC who have previously been treated with FGFR antagonists.
Abstract: 9055Background: LungMAP is a National Clinical Trials Network umbrella trial for previously-treated SqNSCLC. S1400D is a phase II biomarker-driven therapeutic sub-study evaluating the FGFR inhibito...
TL;DR: Taselisib (GDC-0032), a potent, small molecule inhibitor of Class 1 PI3K with beta isoform sparing selectivity, has been shown to be a potent inhibitor in preclinical models of PIK3CA-mutant tumors.
Abstract: 9054Background: Lung-MAP (S1400) is a National Clinical Trials Network “umbrella” trial for previously-treated SqNSCLC. Sub-study S1400B included patients (pts) with tumors harboring PI3K mutations.Taselisib (GDC-0032), a potent, small molecule inhibitor of Class 1 PI3K with beta isoform sparing selectivity, has been shown to be a potent inhibitor in preclinical models of PIK3CA-mutant tumors. Methods: Eligibility stipulated progressive SqNSCLC after primary platinum-based therapy and presence of a PIK3CA mutation as determined by Foundation Medicine (FMI+) NGS. . The primary analysis population was a subgroup of the total PIK3CA mutation group (GNE+) with alterations limited to substitutions: E542K, E545A, E545G, E545K, E545Q, H1047L, H1047R, H1047Y. Primary endpoint was response rate (RR) in GNE+ pts. The initial protocol randomized PIK3 mt (+) pts to taselisib 4 mg po daily or docetaxel, but was amended to single arm phase II trial of taselisib with interim analysis based on first 20 eligible GNE+ pts ...
TL;DR: In patients with SCLC, age less than 50 years was an independent predictor of improved CSS, and these results have potential clinical applications.
Fox Chase Cancer Center1, Fred Hutchinson Cancer Research Center2, Loyola University Chicago3, Kaiser Permanente4, Mercy Medical Center (Baltimore, Maryland)5, University of Pittsburgh6, Washington University in St. Louis7, University of Texas MD Anderson Cancer Center8, University of California, Davis9, Yale University10
TL;DR: S1400 is a master platform trial designed to assess targeted therapies in SCC and evaluated the response rate (RR) to P, a CDK 4/6 inhibitor, in pts with cell cycle gene abnorm...
Abstract: 9056Background: S1400 is a master platform trial designed to assess targeted therapies in SCC. Study C evaluated the response rate (RR) to P, a CDK 4/6 inhibitor, in pts with cell cycle gene abnorm...
TL;DR: The therapeutic landscape in advanced non-small-cell lung cancer (NSCLC) is rapidly changing and this rapid evolution and resultant increasing complexity in the therapeutic decision-making process for the practicing oncologist is described.
TL;DR: This data indicates that EGFR exon 20 insertions, the 3rd most common EGFR activating mutation, are generally unresponsive to 1st and 2nd generation EGFR-TKIs, and the potential of osimertinib remains to be fully assessed in patients (pts) with Ex20Ins NSCLC.
Abstract: 9030Background: EGFR exon 20 insertions (Ex20Ins), the 3rd most common EGFR activating mutation, are generally unresponsive to 1st and 2nd generation EGFR-TKIs. Development of EGFR-TKIs that effectively target NSCLC with Ex20Ins mutations represents a major unmet need. Osimertinib is an EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M, but the potential of osimertinib remains to be fully assessed in patients (pts) with Ex20Ins NSCLC. Methods: CRISPR engineered Ex20Ins cell line xenografts representing the two most common Ex20Ins (D770_N771InsSVD and V769_D770InsASV) and pt derived xenograft (PDX) of 3 EGFR Ex20Ins (V769_D770InsASV, M766_A767insASV, H773_V774insNPH) were used for in vivo experiments. Xenografts were treated by oral gavage with vehicle, erlotinib (50 mg/kg/day) or afatinib (20 mg/kg/day), osimertinib metabolite AZ5104 (50 mg/kg/day) and osimertinib (25 mg/kg/day) and assessed for tumor growth inhibition (TGI). Immunoblotting was performed for EGFR and relevant sign...