Journal of Thoracic Oncology:
Phase I Safety and Pharmacokinetic Study of the PI3K/mTOR Inhibitor SAR245409 (XL765) in Combination with Erlotinib in Patients with Advanced Solid Tumors
Jänne, Pasi A. MD, PhD*; Cohen, Roger B. MD†; Laird, A. Douglas PhD‡; Macé, Sandrine PharmD, PhD§; Engelman, Jeffrey A. MD‖; Ruiz-Soto, Rodrigo MD¶; Rockich, Kevin PhD#; Xu, Jianbo MS**; Shapiro, Geoffrey I. MD††; Martinez, Pablo MD‡‡; Felip, Enriqueta MD‡‡
*Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts; †Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; ‡Translational Medicine, Exelixis, Inc., South San Francisco, San Francisco, California; §Translational and Experimental Medicine, Sanofi, Vitry-sur-Seine, France; ‖Center for Thoracic Centers, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts; ¶Clinical Development Oncology, Sanofi, Cambridge, Massachusetts; #Pharmacokinetic Modeling and Simulation, Sanofi, Cambridge, Massachusetts; **Biostatistics and Programming, Sanofi, Cambridge, Massachusetts; ††Early Drug Development Center, Dana-Farber Cancer Institute, Boston, Massachusetts; ‡‡Department of Medical Oncology, Vall d’ebron University Hospital, Barcelona, Spain.
Disclosure: Dr. Cohen has received research funding from Exelixis, paid to the Fox Chase Cancer Center to support the conduct of the study. Pasi A. Jänne has received consulting fees from Sanofi Aventis, Roche, Genentech, Astra Zeneca, Pfizer, Boehringer Ingelheim, and Clovis Oncology and receives postmarketing royalties from Lab Corp for Dana-Farber Cancer Institute-owned IP on EGFR mutation testing. Roger B. Cohen has received an institutional grant from Exelixis Inc. A. Douglas Laird is an employee of Exelixis Inc. and holds stock/stock options in Exelixis Inc. Sandrine Macé and Kevin Rockich are employees of Sanofi. Jeffrey A. Engelman has received institutional grants from Sanofi Aventis, Astra Zeneca, GlaxoSmithKline, and Novartis; consulting fees or honorarium from Genentech, Roche, Chugai, Astra Zeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Cytomx, Ariad, Gerson Lehman Group, Madalon Consulting, Ensof, Intellikine, Morgan Stanley, Piramal, Janssen, Pathway Therapeutics, GlaxoSmithKline, Amgen, Quintiles, Endo, Agios, Aisling Capital, Guidepoint Global, F-star, Cell Signalling Technology, and Novartis; support for travel to meetings from Genentech, Roche, Chugai, and Astra Zeneca; payments for lectures from the Society for Translational Oncology; travel expenses from AACR, the European Association for Cancer Research, ESMO, NCRI, the Pezcoller Foundation, the Aspen Cancer Conference; the Forbeck Foundation, and the Cancer Education Consortium; is a co-founder of Gatekeeper; and holds stock/stock options with Agios and Gatekeeper. Rodrigo Ruiz-Soto is an employee of Sanofi and holds stock/stock options in Sanofi. Jianbo Xu receives consulting fees from Sanofi. The other authors declare no conflict of interest.
Presented, in part, at annual meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL, June 2010, and at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications, Boston, MA, November 15–19, 2009.
Address for correspondence: Pasi A. Jänne, MD, PhD, Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, 450 Brookline Avenue, HIM223, Boston, MA 02215. E-mail: Pasi_Janne@dfci.harvard.edu
Introduction: The primary objectives of this phase I study were to evaluate the safety and maximum tolerated dose (MTD) of SAR245409, a pan-class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin inhibitor, combined with erlotinib in patients with advanced solid tumors.
Methods: Forty-six patients with advanced solid tumors were enrolled. Patients with lung cancer (n = 37) had received an epidermal growth factor receptor (EGFR) inhibitor before study entry. SAR245409 30, 50, 70, or 90 mg once daily (QD) or 20 or 30 mg twice daily (BID) was administered, in combination with erlotinib 100 mg QD, in 28-day cycles. Dose escalation of SAR245409 followed a standard 3 + 3 design. Patients were evaluated for adverse events (AEs). Additional evaluations included pharmacokinetics, pharmacodynamic effects on PI3K and EGFR/mitogen-activated protein kinase signaling pathways in tumor and skin samples, and tumor response.
Results: The MTDs of SAR245409, in combination with erlotinib 100 mg QD, were 70 mg QD and 20 mg BID. The most frequently reported treatment-related AEs (any grade) were diarrhea (35%), rash (35%), and nausea (28%). No treatment-related AE occurred at grade 3/4 in more than one patient (2.2%). No major pharmacokinetic interaction between SAR245409 and erlotinib was noted. Suppression of PI3K and EGFR/mitogen-activated protein kinase signaling pathway biomarkers was observed in skin and tumor samples. Stable disease was the best overall response reported, occurring in 12 of 32 (37.5%) evaluable patients.
Conclusion: MTDs of SAR245409 and erlotinib were below the single-agent doses of either agent, despite the lack of major pharmacokinetic interaction.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays an important role in essential cellular functions, including growth, cell survival, and metabolism.1,2 Aberrant PI3K signaling is implicated in tumor cell invasion, migration, and dissemination.3 Molecular alterations that dysregulate the PI3K signaling pathway, such as deletion or downregulation of phosphatase and tensin homolog (PTEN) or somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), occur frequently in multiple tumor types, including breast, colon, and endometrial cancers and glioblastoma.4,5 Hyperactivation of the PI3K signaling pathway is associated with resistance to anticancer therapies, including resistance of epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors (TKIs) and mediated by mechanisms such as insulin-like growth factor 1 receptor activation and increased MET signaling.6–8 In a preclinical study, exogenous activation of PI3K signaling was sufficient to render EGFR inhibitor–sensitive EGFR mutant cells resistant to gefitinib.9 Furthermore, another study found that an acquired PIK3CA mutation was present in samples from one of 37 patients with erlotinib-resistant EGFR-mutant NSCLC.10 Consistent with these observations, PI3K pathway inhibition has been shown to sensitize cancer cells to various agents, including EGFR inhibitors.8,11–16
SAR245409 (XL765) is a pan-class I PI3K/mammalian target of rapamycin (mTOR) inhibitor with specific adenosine triphosphate (ATP)-competitive reversible binding to the catalytic domains of PI3K and mTOR.17–19 Preclinical studies showed that SAR245409 inhibited PI3K/mTOR signaling, significantly slowing tumor growth or shrinking tumors in multiple models; these antitumor effects correlated with inhibition of tumor cell proliferation and angiogenesis and induction of apoptosis.17
Prompted by these findings, we performed a phase I study (TED11442/XL765-003) investigating treatment with SAR245409 combined with erlotinib in patients with advanced solid tumors, including patients with lung cancer previously treated with EGFR TKIs.
PATIENTS AND METHODS
Patients aged 18 years or older with Eastern Cooperative Oncology Group performance status 1 or less, acceptable organ function, and a histologically or cytologically confirmed solid tumor that was metastatic or unresectable and was no longer responding to therapies or for which no standard treatment exists were eligible. Patients with lung cancer must have received an EGFR inhibitor before study entry. Patients who were intolerant to erlotinib or who had received previous treatment with a PI3K inhibitor were not eligible. For any previous treatment, the last dose must have been administered at least 3 weeks before the first dose of SAR245409.
Study Design and Treatment
This was a phase I, open-label, nonrandomized study. Dose escalation of SAR245409 followed a standard 3 + 3 design. Doses administered to different patient cohorts in 28-day cycles were 30, 50, 70, or 90 mg once daily (QD) and 20 or 30 mg twice daily (BID). SAR245409 was taken concomitantly with erlotinib 100 mg QD after a 2-week run-in period during which single-agent erlotinib was administered. A starting dose of 100 mg of erlotinib was chosen because of the potential overlap in adverse events (AEs) with SAR245409. Primary study objectives were to evaluate the safety and maximum tolerated dose (MTD) of SAR245409 when combined with erlotinib. Secondary objectives were to evaluate the pharmacokinetics (PK) and preliminary efficacy of the treatment regimen. Pharmacodynamic effects were evaluated as exploratory objectives. The total patient number was not predetermined and depended on the number of dose cohorts and patients required to establish an MTD. The study was registered at ClinicalTrials.gov (NCT00777699). Approval was obtained from ethics committees of participating institutions and regulatory authorities. All patients provided informed consent. The study followed the Declaration of Helsinki and Good Clinical Practice guidelines.
Safety was evaluated using standard clinical and laboratory assessments and through monitoring of AEs (NCI CTCAE version 3.0)20 and Eastern Cooperative Oncology Group performance status. All AEs occurring during treatment or within 30 days of last treatment dose were recorded. Dose-limiting toxicity (DLT) was defined as the occurrence of a specified event during cycle 1 that warranted a dose reduction or, that in the opinion of the Cohort Review Committee, was of potential clinical significance such that further dose escalation would expose patients to unacceptable risk (including gastrointestinal AEs, hyperglycemia, hematologic AEs, and liver enzyme elevations; a full definition is provided in Supplemental Digital Content 1, Supplementary Methods, http://links.lww.com/JTO/A521).
Plasma concentrations of SAR245409 and erlotinib were assayed using liquid chromatography tandem mass spectrometry. The following PK parameters were determined: Cmax (maximum plasma concentration observed), tmax (time to reach Cmax), AUC0–12 or AUC0–24 (area under the plasma concentration versus time curve from 0 to 12 or 0 to 24 hours postdose), and t1/2z (terminal half-life associated with the terminal slope). Further details are provided in Supplemental Digital Content 1, Supplementary Methods (http://links.lww.com/JTO/A521).
Pharmacodynamic and Molecular Profiling Evaluations
Pharmacodynamic evaluations were conducted to determine the level of PI3K and EGFR pathway inhibition and included the phosphorylation state of signaling proteins (AKT, 4E-binding protein 1 [4EBP1], EGFR, and extracellular signal-regulated kinase [ERK] 1/2) in skin and tumor tissue. Molecular profiling evaluations were performed to investigate the molecular basis of acquired resistance to EGFR TKIs and included the assessment of mutations and/or copy number variation within genes of interest (including EGFR, PIK3CA, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS], MET, liver kinase B1 [LKB1], and various other PI3K pathway components/modulators). Tissue sampling was optional during the dose escalation phase. Noninvasive samples were collected from some subjects, but due to technical challenges with these sample types, they were not analyzed. Full details of the pharmacodynamic methods are provided in Supplemental Digital Content 1, Supplementary Methods (http://links.lww.com/JTO/A521).
Tumor response was assessed using Response Evaluation Criteria In Solid Tumors v1.0.21 Patients were evaluated every 8 weeks during SAR245409 treatment until disease progression or discontinuation. Partial response or complete response had to be confirmed 4 weeks after initial achievement. For stable disease (SD), criteria had to be met for 6 weeks. Disease progression was defined per Response Evaluation Criteria In Solid Tumors or by clinical deterioration.
Between October 2008 and March 2011, 46 patients were enrolled: 33 in the QD group and 13 in the BID group (Table 1). All patients had received a prior anticancer treatment; 26 (56.5%) patients had received more than two prior anticancer regimens, and 50% (n = 23) had received both anticancer drugs and radiation. All patients with lung cancer (n = 37, 80.4%) had received a prior EGFR inhibitor, of which 25 had received erlotinib as part of their last treatment regimen before study entry. Four patients (all QD group) discontinued during the erlotinib run-in period and did not receive SAR245409. The median duration (range) of treatment with SAR245409 and erlotinib was 56 (0–346) and 70 (9–360) days, respectively. All patients discontinued study treatment; the most common reasons were disease progression (34 patients; 73.9%), AEs (4 patients; 8.7%), and withdrawal of consent (4 patients; 8.7%), and proportions were similar between treatment groups defined by dosing levels/schedules.
DLT and MTD
Four patients experienced DLTs (2 of 5 patients in the 90 mg QD group and 2 of 6 patients in the 30 mg BID group). These included grade 2 photophobia (90 mg QD) in a patient with a prior dose interruption for photophobia, grade 3 stomatitis (90 mg QD), grade 3 generalized rash (30 mg BID), and grade 4 cerebrovascular accident (30 mg BID), which occurred 3 days after treatment had been discontinued following the discovery of brain metastases. MTDs were determined to be SAR245409 70 mg QD plus erlotinib 100 mg QD and SAR245409 20 mg BID plus erlotinib 100 mg QD. An expansion cohort was planned (per protocol) but not initiated because of both apparent lack of efficacy and because the MTDs in both cohorts were below the recommended phase II dose of SAR245409 (90 mg QD or 50 mg BID) and below the registered dose of erlotinib (150 mg QD, which was not tested).
The most frequently reported AEs (any grade), regardless of causality, were diarrhea (28 patients; 60.9%), rash (21 patients; 45.7%), nausea (20 patients; 43.5%), and vomiting (15 patients; 32.6%) (Table, Supplemental Digital Content 2, http://links.lww.com/JTO/A522; AEs occurring in ≥10% of patients). Except for rash, which was more common with SAR245409 30 mg QD than with other dosing regimens, there were no dose-related trends. Twenty patients (43.5%) experienced a grade 3/4 AE; the most frequently reported, regardless of causality, were dyspnea (5 patients; 10.9%) and vomiting (4 patients; 8.7%). Although grade 3/4 AEs were more common with BID versus QD treatment, there were no notable dose-related trends in AEs. AEs considered related or possibly related to treatment occurred in 41 patients (89.1%; Table 2); no consistent dose-related trends were observed. Four patients experienced a treatment-related serious AE: grade 3 DRESS (drug reaction [or rash] with eosinophilia and systemic symptoms) syndrome (70 mg QD; n = 1), which led to treatment discontinuation; grade 2 photophobia (DLT; 90 mg QD; n = 1) and grade 2 nausea and vomiting (20 mg BID; n = 1), which led to dose interruption; and grade 4 cerebrovascular accident (DLT; 30 mg BID; n = 1). Four patients (8.7%) had an AE that led to discontinuation of study treatment. In addition, one patient discontinued during the erlotinib run-in period because of AEs. Two patients had treatment-related AEs, leading to study drug discontinuation during treatment with SAR245409 and erlotinib (the patient with grade 3 DRESS and the patient with grade 2 increases in aspartate aminotransferase and alanine aminotransferase).
With QD treatment, SAR245409 exposure on day 22 increased over the three-fold dose range (30–90 mg) in a greater than dose-proportional manner (mean Cmax and AUC0–24 increased by 5.54- and 4.66-fold, respectively) (Table 3). With BID dosing, the increased exposure on day 22 to SAR245409 20 to 30 mg was dose proportional (Cmax and AUC0–12 increased by 1.46- and 1.30-fold, respectively). After SAR245409 administration (30–90 mg QD and 20–30 mg BID) with erlotinib (100 mg), SAR245409 was absorbed with a median tmax ranging from 1.6 to 2.0 hours, and mean t1/2 for the QD group ranged from 4.30 to 8.03 hours (t1/2 was not calculated for the BID group). In different SAR245409 dose cohorts, the median tmax for erlotinib ranged from 1.5 to 6.8 hours (Table 3). After 36 days of erlotinib dosing (day −14 to 22), mean accumulation ratios for Cmax and AUC0–24 ranged from 1.29 to 3.76 and 1.86 to 4.09, respectively. No major PK interaction between SAR245409 and erlotinib was noted (Figure, Supplemental Digital Content 3, http://links.lww.com/JTO/A524; erlotinib plasma concentration–time profiles).
Serial normal skin biopsies from three patients showed good antigen preservation and were suitable for analysis by immunofluorescence. Of the three patients, two had lung adenocarcinoma and one had lung squamous cell carcinoma; SAR245409 doses administered were 30, 50, and 50 mg QD, respectively. Suppression of PI3K and EGFR/mitogen-activated protein kinase (MAPK) pathway biomarkers increased over time (pAKTT308: 40%–73%; p4EBP1T70: 43%–67%; pEGFRY1045: 31%–62%; and pERKT202/Y204: 37%–75%) (Table 4, Fig. 1, and see Supplemental Figure 2, Supplemental Digital Content 4, http://links.lww.com/JTO/A523; reduction of PI3K and EGFR/MAPK pathway signaling in serial skin samples). The maximum inhibition in skin tissue for any PI3K or EGFR/MAPK biomarker plateaued at approximately 60%–75%.
In one patient with NSCLC adenocarcinoma who had prestudy and on-study tumor biopsies available, phosphoprotein biomarkers decreased substantially by cycle 1 day 21, including biomarkers of the PI3K (pAKTT308 by 57%, p4EBP1T70 by 60%) and MAPK (pERKT202/Y204 by 61%) pathways (see Supplemental Figure 3, Supplemental Digital Content 5, http://links.lww.com/JTO/A537; reduction of PI3K and EGFR/MAPK pathway signaling in paired tumor biopsies from a patient with NSCLC adenocarcinoma). Furthermore, cellular proliferation was reduced by 36%, and apoptosis was increased by 1.6-fold. There was a reduction in both pEGFRY1045 and total EGFR, making interpretation of effects on EGFR difficult. In this patient, a greater pharmacodynamic effect was seen in tumor tissue compared with normal tissue (pAKTT308, p4EBP1T70, and pERKT202/Y204 were reduced by 37%–43% in skin). This patient died as a result of disease progression within 30 days of last dose of study treatment (duration of treatment was 42 days).
In the patient with lung squamous cell carcinoma who had prestudy and on-study tumor biopsies available, pAKTT308 and pERKT202/Y204 were reduced at cycle 1 day 18 by 67% and 62%, respectively, and apoptosis was increased (by 2.6-fold). In contrast, treatment had only a modest effect on p4EBP1T70, with no effect on pEGFRY1173 and no evident inhibition of proliferation (Table 4). This patient died as a result of disease progression within 30 days of last dose of study treatment (duration of treatment was 59 days).
Molecular Profiling Analyses
Of the 39 patients who received SAR245409 and provided samples for molecular profiling, 31 had NSCLC. Full details of samples with identified mutations are described in Supplemental Digital Content 6 (http://links.lww.com/JTO/A525), Molecular Profiling Analyses. Briefly, molecular alterations were identified in PI3K pathway components; gene copy number analyses showed a two- to six-fold amplification of PIK3CA in three of eight samples tested (including 1 NSCLC patient whose tumor also harbored an activating EGFR mutation), and PTEN alterations were identified in four samples, including two with NSCLC. One NSCLC tumor showed a lower than expected level of PTEN expression (H-score = 36) as assessed by immunohistochemistry. Overall, samples from six patients, including three with NSCLC, showed molecular alterations in the PI3K/AKT pathway.
Mutations in EGFR were identified in 15 of 27 (55.6%) samples from NSCLC patients (none in other tumor types), including 11 samples with known activating mutations (such as L858R and in-frame deletions in exon 19). Mutations or deletions/insertions with unknown function were found in three samples. A known mutation associated with de novo or acquired resistance to erlotinib (D761Y) was identified in one NSCLC patient, along with other EGFR mutations of unknown function. A two- to seven-fold amplification of EGFR was identified in four of eight samples tested (including two NSCLC patients, both of whom also had activating EGFR mutations).
Mutations in KRAS were identified in two NSCLC samples, revealing molecular alterations in the MAPK pathway. Mutations in NRAS, TP53, or LKB1 were identified in three of 39 patients (1 mutation per patient, all NSCLC except for NRAS mutation). None of the four tested NSCLC samples exhibited MET copy number variation.
Of the 32 patients with measurable disease who were assessed for efficacy at baseline and on study, SD was the best overall response reported and occurred in 12 patients (37.5%), including 11 patients with NSCLC. Of note, one patient with an EGFR mutation had a long duration of treatment (360 days), which corresponded to a long duration of SD (11.8 months). The 10 patients with NSCLC who had SD and provided samples for molecular analysis included six patients with molecular alterations in the EGFR or MAPK pathways; none had alterations in the PI3K pathway (Fig. 2). The patient with NSCLC with concomitant PI3KCA amplification and EGFR-activating mutation did not have SD.
Despite the clinical efficacy of EGFR kinase inhibitors in patients with EGFR-mutant NSCLC, all patients ultimately develop acquired drug resistance. Molecular and biochemical analyses from drug-resistant cancers reveal diverse mechanisms of resistance, usually leading to reactivation of EGFR and/or downstream signaling pathways.9,10 One such pathway is the PI3K/AKT signaling pathway.
In the current study, we evaluated the feasibility of whether a pan-PI3K/mTOR inhibitor (SAR245409) could be combined clinically with erlotinib and whether this combination could lead to reversal of clinical drug resistance in patients with EGFR-mutant, erlotinib-resistant NSCLC. Unfortunately, despite two different schedules, the MTDs of SAR245409 and erlotinib in combination were below the single-agent doses for both agents (SAR245409-recommended phase II dose 90 mg QD or 50 mg BID and erlotinib-registered dose 150 mg QD), despite no major PK interactions between SAR245409 and erlotinib. In addition, this combination had limited efficacy at the tolerated dose combination. A prior study combining a specific mTOR inhibitor, everolimus, with EGFR inhibitors also demonstrated no objective responses in patients who had developed acquired resistance to EGFR inhibitors.22
Twenty-five patients with lung cancer had received an erlotinib-based regimen as their last treatment before study entry. Two of these patients discontinued during the erlotinib run-in period, and 23 patients went on to receive SAR245409 plus erlotinib. Of these, six (26%) patients received SAR245409 plus erlotinib for more than 90 days, with documented SD at their first disease evaluation. Although this could represent potential clinical activity of the combination, the lack of objective tumor responses or a control arm prevents making definitive conclusions.
The on-study skin and tumor biopsies provide some insight into the lack of clinical efficacy of this therapeutic combination. In the limited number of paired specimens, the maximum inhibition of PI3K, EGFR, and MAPK (ERK 1/2) signaling pathways was between 37% and 75% (Table 4). It is not known what degree of inhibition of these pathways in tumors is necessary to obtain a clinical response. In BRAF-mutant melanoma, inhibition of pERK1/2 by more than 80% in tumors of patients treated with vemurafenib was closely correlated with clinical response.23 Thus, alternative dosing strategies with SAR245409, such as intermittent dosing at higher doses, may be necessary to achieve plasma levels sufficient to inhibit PI3K signaling to a greater extent than achievable in the current daily dosing study.
The authors thank participating patients and their families as well as Art DeCillis (VP Medical Affairs and Clinical Research, Exelixis) and the clinical research team at Exelixis who initiated this trial. In addition, the authors thank Bin Wu (Sanofi), Linh Nguyen, Frauke Bentzien, Belinda Cancilla, and Valentina Vysotskaia (Exelixis) for their contributions to PK, pharmacodynamic, and molecular profiling analyses and Coumaran Egile (Sanofi) for his contribution to this work. This study was funded by Sanofi. Editorial assistance in the form of medical writing services was provided by Melissa Purves and Simone Blagg of MediTech Media, funded by Sanofi.
1. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–1657
2. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–619
3. Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res. 2009;102:19–65
4. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627–644
5. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28:1075–1083
6. Cortot AB, Repellin CE, Shimamura T, et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res. 2013;73:834–843
7. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–1043
8. Donev IS, Wang W, Yamada T, et al. Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer. Clin Cancer Res. 2011;17:2260–2269
9. Engelman JA, Mukohara T, Zejnullahu K, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116:2695–2706
10. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26
11. Chakrabarty A, Rexer BN, Wang SE, Cook RS, Engelman JA, Arteaga CL. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene. 2010;29:5193–5203
12. Faber AC, Li D, Song Y, et al. Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci U S A. 2009;106:19503–19508
13. Klein S, Levitzki A. Targeting the EGFR and the PKB pathway in cancer. Curr Opin Cell Biol. 2009;21:185–193
14. Priulla M, Calastretti A, Bruno P, et al. Preferential chemosensitization of PTEN-mutated prostate cells by silencing the Akt kinase. Prostate. 2007;67:782–789
15. Santiskulvong C, Konecny GE, Fekete M, et al. Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma. Clin Cancer Res. 2011;17:2373–2384
16. Li B, Gao S, Wei F, Bellail AC, Hao C, Liu T. Simultaneous targeting of EGFR and mTOR inhibits the growth of colorectal carcinoma cells. Oncol Rep. 2012;28:15–20
17. Laird AD. XL765 targets tumor growth, survival, and angiogenesis in preclinical models by dual inhibition of PI3K and mTOR [Abstract]. 2007;241 San Francisco, CA In Proceedings of the Molecular Targets and Cancer Therapeutics Conference : October 22–26,
18. Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway—beyond rapalogs. Oncotarget. 2010;1:530–543
19. Markman B, Atzori F, Pérez-García J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol. 2010;21:683–691
20. U.S. Department of Health and Human Services, National Cancer Institute & National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. 2006
21. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216
22. Riely GJ, Kris MG, Zhao B, et al. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res. 2007;13:5150–5155
23. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467:596–599
PI3K/mammalian target of rapamycin inhibitor; Epidermal growth factor receptor inhibitor; Pharmacokinetics; Pharmacodynamics; Advanced solid tumors
Supplemental Digital Content
Copyright © 2014 by the European Lung Cancer Conference and the International Association for the Study of Lung Cancer.
Highlight selected keywords in the article text.