José Baselga

Memorial Sloan-Kettering Cancer Center, New York City, New York, United States

Are you José Baselga?

Claim your profile

Publications (246)3387.42 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Transforming growth factor-beta (TGF-β) signaling plays an important role in the fetal development of cardiovascular organs and in the repair mechanisms of the heart. Hence, inhibitors of the TGF-β signaling pathway require a careful identification of a safe therapeutic window and a comprehensive monitoring of the cardiovascular system. Seventy-nine cancer patients (67 glioma and 12 solid tumor) enrolled in a first-in-human dose study and received the TGF-β inhibitor LY2157299 monohydrate (LY2157299) as monotherapy (n = 53) or in combination with lomustine (n = 26). All patients were monitored using 2D echocardiography/color and Spectral Doppler (2D Echo with Doppler) every 2 months, monthly electrocardiograms, thorax computer tomography scans every 6 months, and monthly serum brain natriuretic peptide (BNP), troponin I, cystatin C, high-sensitivity C-reactive protein (hs-CRP). Administration of LY2157299 was not associated with medically relevant cardiovascular toxicities, including patients treated ≥6 months (n = 13). There were no increases of troponin I, BNP, or hs-CRP or reduction in cystatin C levels, which may have been considered as signs of cardiovascular injury. Blood pressure was generally stable during treatment. Imaging with echocardiography/Doppler showed an increase in mitral and tricuspid valve regurgitation by two grades of severity in only one patient with no concurrent clinical symptoms of cardiovascular injury. Overall, this comprehensive cardiovascular monitoring for the TGF-β inhibitor LY2157299 did not detect medically relevant cardiac toxicity and hence supports the evaluation of LY2157299 in future clinical trials.
    Cardiovascular toxicology. 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Expression of p95HER2 has been associated with resistance to trastuzumab (T)-based therapy in metastatic breast cancer patients. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in breast cancer patients. Experimental Design: We measured p95HER2 and HER2 by VeraTag® and HERmark®, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathological complete response (pCR) and progression-free survival (PFS) following lapatinib (L), T, or the combination of both agents (L+T). Results: A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) where quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)-positive subset of patients. High HER2 expression was associated with increased pCR rate upon L+T irrespective of the HR status. In order to examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with L, T or L+T, we fit to the PFS data in Cox models containing log2(p95HER2) or log2(HER2). Both variables correlated with longer PFS. Conclusions: Increasing HER2 protein expression correlated with increased benefit of adding L to T. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to L, T and, more significantly, L+T. Copyright © 2014, American Association for Cancer Research.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Transforming growth factor-beta (TGF-β) signaling plays a key role in tumor progression, including malignant glioma. Small molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGF-β signaling and reduce tumor progression in preclinical models. To use LY2157299 in the treatment of malignancies, we investigated its properties in a First-in-Human Dose (FHD) study in cancer patients. Experimental Design: Sixty five patients (58 with glioma) with measurable and progressive malignancies were enrolled. Oral LY2157299 was given as a split dose morning and evening on an intermittent schedule of 14 days on and 14 days off (=28-day cycle). LY2157299 monotherapy was studied in dose escalation (Part A) first and then evaluated in combination with standard doses of lomustine (Part B). Safety was assessed using Common Terminology Criteria for Adverse Events version 3.0, echocardiography/Doppler imaging, serum troponin I and brain natriuretic peptide (BNP) levels. Anti-tumor activity was assessed by RECIST and Macdonald criteria. Results: In Part A, 16.6% (5/30) and in Part B, 7.7% (2/26) of evaluable patients with glioma had either a complete (CR) or a partial response (PR). In both parts 15 patients with glioma had stable disease (SD), 5 of whom had SD ≥6 cycles of treatment. Therefore, clinical benefit (=CR+PR+SD ≥6 cycles) was observed in 12/56 patients with glioma (21.4%). LY2157299 was safe with no cardiac adverse events. Conclusions: Based on the safety, PK and antitumor activity in glioma patients, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation. Copyright © 2014, American Association for Cancer Research.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 11/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110β blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.
    Nature 11/2014; · 38.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906mm(3), 95% confidence interval = 1274 to 538 mm(3); trastuzumab+doxorubicin: 259mm(3), 95% confidence interval = 387 to 131 mm(3); P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells.
    JNCI Journal of the National Cancer Institute 11/2014; 106(11). · 14.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To explore the prognostic and/or predictive value of human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers in the phase III CLEOPATRA study of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer.
    Cancer Research 10/2014; · 8.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD) have a high frequency of BRAFV600E mutations and respond to RAF inhibitors. However, detection of mutations in tissue biopsies is particularly challenging in histiocytoses due to low tumor content and stromal contamination. We applied a droplet-digitial PCR assay for quantitative detection of the BRAFV600E mutation in plasma and urine cell-free (cf)DNA and performed a prospective, blinded study in 30 ECD/LCH patients. There was 100% concordance between tissue and urinary cfDNA genotype in treatment naïve samples. cfDNA analysis facilitated identification of previously undescribed KRASG12S mutant ECD and dynamically tracked disease burden in patients treated with a variety of therapies. These results indicate that cfDNA BRAFV600E mutational analysis in plasma and urine provides a convenient and reliable method of detecting mutational status and can serve as a non-invasive biomarker to monitor response to therapy in LCH and ECD.
    Cancer Discovery 10/2014; · 15.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: mTOR inhibition activates compensatory IGFR signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental design: In vitro and in vivo models, and a phase I study where advanced cancer patients received ridaforolimus (10-40 mg/day QD×5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg QOW) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main DLTs of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 breast cancer patients); 10/23 breast cancer patients and 6/11 ER+/high proliferative breast cancer patients showed antitumor activity. Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high proliferative breast cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 10/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two).
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: To document the rate and outcome of trastuzumab-associated cardiac dysfunction in patients following 1 or 2 years of adjuvant therapy.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear.
    Molecular cancer. 06/2014; 13(1):141.
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report detailed safety analyses by geographic region from the phase III study CLEOPATRA with pertuzumab, trastuzumab, and docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer.PATIENTS AND METHODS: Patients received pertuzumab/placebo at 840 mg in cycle 1 and 420 mg in subsequent cycles, and trastuzumab at 8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles; docetaxel was initiated at 75 mg/m(2). All study drugs were given intravenously, 3 times weekly.RESULTS: Docetaxel dose reductions below 75 mg/m(2) were more common in patients from Asia (47.0%) than other regions (13.4%); docetaxel dose escalations to 100 mg/m(2) were less frequent in Asia (2.4%) than other regions (18.7%). Rates of edema (26.1% and 5.4% for Asia and other regions, respectively), myalgia (42.3%, 14.7%), nail disorder (39.9%, 15.1%), febrile neutropenia (18.6%, 7.1%), upper respiratory tract infection (25.7%, 10.2%), decreased appetite (47.0%, 19.1%), and rash (44.3%, 22.0%) were at least twice as high in Asia as in other regions. Adverse events did not result in a reduction in the median number of study treatment cycles administered in patients from Asia. Efficacy analyses per region showed hazard ratios similar to those of the whole intention-to-treat (ITT) population for progression-free survival (ITT: 0.63; Asia: 0.68; other regions: 0.61) and overall survival (ITT: 0.66; Asia: 0.64; other regions: 0.66).CONCLUSION: Despite a higher proportion of docetaxel dose reductions in patients from Asia, survival benefits were comparable between regions. The benefit-risk profile of pertuzumab, trastuzumab, and docetaxel supports this regimen as the first-line therapy for patients with HER2-positive metastatic breast cancer from all geographic regions.
    The Oncologist 05/2014; · 4.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Agents targeting the insulin-like growth factor receptor type 1 (IGF1R) have shown antitumor activity. Based on the evidence for interaction between the IGF-1 and TRAIL pathways, we hypothesized that the combination of ganitumab (monoclonal antibody to IGF1R) with the pro-apoptotic death receptor 5 agonist, conatumumab, might increase antitumor response. Ganitumab and conatumumab were tested in combination in a Colo-205 xenograft model. Part 1 of the clinical study was a phase Ib program of three doses of conatumumab (1, 3, 15 mg/kg) in combination with 18 mg/kg ganitumab to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. Part 2 was conducted in six cohorts with advanced non-small cell lung cancer (squamous or non-squamous histology), colorectal cancer, sarcoma, pancreatic cancer, or ovarian cancer, treated at the recommended doses of the combination. The combination was significantly more active in the Colo-205 xenograft model than either single agent alone (p < 0.0015). In part 1 of the clinical study, no dose-limiting toxicities were observed and the MTD of conatumumab was 15 mg/kg in combination with 18 mg/kg ganitumab. In part 2, 78 patients were treated and there were no objective responses but 28 patients (36 %) had stable disease (median 46 days, range 0-261). The combination was well-tolerated with no new toxicities. In conclusion, the combination of ganitumab and conatumumab was well-tolerated but had no objective responses in the population tested. The successful future application of this combination of antitumor mechanisms may rely on the identification of predictive biomarkers.
    Targeted Oncology 05/2014; · 3.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy. We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495. Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5·4 years (IQR 3·1-6·8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0·64 (95% CI 0·44-0·93; two-sided log-rank p=0·016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0·29 (95% CI 0·11-0·78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group). These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease. F Hoffmann-La Roche.
    The Lancet Oncology 03/2014; · 25.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases. Patients and Methods: Patients with p-Met-positive tumors enrolled in 3 dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed. No dose-limiting toxicities occurred in the 19 patients enrolled (n=6, 2 mg/kg; n=7, 10 mg/kg; n=6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n=15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (-53%), p-ERK (-43%), p-Akt (-2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4 to 10 days). Best overall response was stable disease (SD) in 28% of patients, including 1 pancreatic cancer patient with SD >1 year. Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase 2 dose of 20 mg/kg once per 14-day cycle.
    Clinical Cancer Research 03/2014; · 7.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This phase I, first-in-human study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409, an inhibitor of pan-Class I PI3K and mTOR, administered orally once or twice daily in patients with advanced solid tumors. Eighty-three patients received SAR245409. Doses ranged from 15-120 mg twice daily, and 70-100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events (AEs) and response. Assessments included PK, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related AEs were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%) and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 AEs were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96-7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin and tumor samples. Best response was stable disease (SD) in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with SD were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant SD.
    Clinical Cancer Research 02/2014; · 7.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response-ypT0 ypN0, ypT0/is ypN0, and ypT0/is-for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70). Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. US Food and Drug Administration.
    The Lancet 02/2014; · 39.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This phase 1 trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog (Hh) signaling, in patients with advanced solid tumors. Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma (MB) and basal cell carcinoma (BCC), at doses ranging from 100 to 3000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose PK run-in period. Dose-escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, PK, and biomarkers in skin and tumor biopsies were assessed. The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear PK at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with MB and BCC were associated with evidence of Hh pathway activation. Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed MB, which is strongly associated with activated Hh pathway, as determined by gene expression.
    Clinical Cancer Research 02/2014; · 7.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy. In the dose-escalation portion of this Phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of Grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended Phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, seven (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways. In this patient population, the combination of buparlisib and trastuzumab was well tolerated and preliminary signs of clinical activity were observed. The Phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D.
    Clinical Cancer Research 01/2014; · 7.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The effects of selective PI3K and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of RTKs, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild type RAS and of RAF/MEK/ERK signaling. Inhibition of RAS-ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death and in murine models of HER2+ cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regressions. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.
    Cancer Discovery 01/2014; · 15.93 Impact Factor

Publication Stats

23k Citations
3,387.42 Total Impact Points

Institutions

  • 1994–2014
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Medicine
      • • Division of Molecular Pharmacology & Chemistry
      New York City, New York, United States
  • 2013
    • Weill Cornell Medical College
      New York City, New York, United States
    • The Washington Institute
      Washington, Washington, D.C., United States
    • Duke University Medical Center
      Durham, North Carolina, United States
    • Unicancer
      Lutetia Parisorum, Île-de-France, France
    • IEO - Istituto Europeo di Oncologia
      Milano, Lombardy, Italy
  • 2012–2013
    • Université Libre de Bruxelles
      • Bordet Institute
      Brussels, BRU, Belgium
    • University of Valencia
      Valenza, Valencia, Spain
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
  • 2011–2013
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
    • Sarah Cannon Research Institute
      Nashville, Tennessee, United States
    • Hospital Universitario Virgen del Rocío
      Hispalis, Andalusia, Spain
  • 2010–2013
    • University of Barcelona
      • Department of Statistics
      Barcelona, Catalonia, Spain
    • Novartis Institutes for BioMedical Research
      Cambridge, Massachusetts, United States
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      Milano, Lombardy, Italy
  • 2005–2013
    • Autonomous University of Barcelona
      • Department of Biochemistry and Molecular Biology
      Cerdanyola del Vallès, Catalonia, Spain
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
  • 2002–2013
    • Vall d’Hebron Institute of Oncology
      Barcino, Catalonia, Spain
    • The Portland Hospital
      Londinium, England, United Kingdom
  • 2011–2012
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2010–2012
    • Broad Institute of MIT and Harvard
      • Cancer Program
      Cambridge, Massachusetts, United States
  • 2002–2012
    • Vanderbilt University
      • • Vanderbilt-Ingram Cancer Center (VICC)
      • • Department of Medicine
      Nashville, MI, United States
  • 1997–2012
    • University Hospital Vall d'Hebron
      • Department of Medical Oncology
      Barcelona, Catalonia, Spain
  • 2009
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
  • 2008
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
    • University of Leeds
      Leeds, England, United Kingdom
    • University of Antwerp
      Antwerpen, Flanders, Belgium
  • 2007
    • Universitair Ziekenhuis Antwerpen
      Antwerpen, Flanders, Belgium
  • 2006
    • VHIR Vall d’Hebron Research Institute
      Barcino, Catalonia, Spain
  • 2003–2006
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy
    • Kinki University
      • Department of Internal Medicine
      Ōsaka, Ōsaka, Japan
  • 2004
    • University Hospital Essen
      Essen, North Rhine-Westphalia, Germany