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V. Papadimitrakopoulou
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ED 07 - How to Treat Advanced Squamous Carcinoma of the Lung (ID 7)
- Event: WCLC 2015
- Type: Education Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:B.C. Cho, P. Lara Jr.
- Coordinates: 9/08/2015, 14:15 - 15:45, Four Seasons Ballroom F1+F2
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ED07.03 - Lung Master Protocol in Squamous Cell Lung Cancer (Lung-MAP, S1400) (ID 1800)
15:00 - 15:20 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Abstract:
In recent years, our understanding of non-small cell lung cancer (NSCLC) has evolved from thinking of this malignancy as a single disease, or a small number of histologic subtypes, to now a multitude of genomically-defined subsets, both in adenocarcinoma and squamous lung cancer. In development of new targeted therapies against these abnormalities, so-called Master Protocols offer a number of advantages over traditional single study designs for drug-biomarker approval, including a common infrastructure, homogeneous patient populations with consistent eligibility across multiple independent sub-studies, and the ability to screen large numbers of patients in rapid fashion. Thus, the Lung-MAP project was designed to facilitate approval of targeted therapy-predictive biomarker combinations in squamous lung cancer, a recognized area of unmet need. Lung-MAP is constructed as a unique public-private partnership engaging the National Cancer Institute (NCI) and its Thoracic Malignancies Steering Committee (TMSC), the Foundation of the NIH (FNIH), the pharmaceutical industry and advocacy groups such as Friends of Cancer Research (FOCR), along with an advisory role by the Federal Drug Administration (FDA). The design is multiple simultaneously running Phase II/III trials, each capable of independently opening and/or closing without affecting the other sub-studies, in which patients eligible for 2[nd] line therapy for lung SCC have their cancers genomically screened through a next generation sequencing (NGS) platform (Foundation Medicine). Patients are then randomized into one of several sub-studies, each comparing an experimental targeted therapy with standard of care therapy, based on identification of candidate predictive biomarkers associated with each sub-study. At launch, drug targets under study consisted of “match sub-studies” for PI3K, FGFR, CDK 4/6 and HGF, and a non-match sub-study testing PD-L1-directed therapy, as described below. Rapid turn-around time of NGS screening results, within 2 weeks, allows real time assignment into the appropriate sub-study. For those patients with cancers that do not “match” into a biomarker-driven sub-study, there is a ‘non-match” sub-study, in which a predictive biomarker is not yet of sufficient validation to utilize it in a drug-biomarker registration strategy. Due to changes in the therapeutic landscape since the launch of Lung-MAP, a number of amendments and modifications have been implemented, which will be discussed during this presentation.
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MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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MINI02.14 - Discussant for MINI02.11, MINI02.12, MINI02.13 (ID 3469)
12:00 - 12:10 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Abstract not provided
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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.10 - Rociletinib in NSCLC Patients with Negative Central Testing for T790M in TIGER-X (ID 951)
17:40 - 17:45 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. New insights into mutEGFR NSCLC suggest clonal heterogeneity – activating EGFR mutations are truncal (present in all tumor clones) and T790M is a dominant branch mutation with variable clonal frequency between patients and over time. The extent of this clonal heterogeneity may relate to rociletinib efficacy. Here we present preliminary findings to evaluate this hypothesis from an ongoing Phase 1/2 clinical trial.
Methods:
TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with metastatic or unresectable locally advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). Screening included mandatory tumor biopsy and T790M testing. For Phase 1, patients could be T790M negative, positive or unknown. For Phase 2, T790M negative patients (by validated central testing) could have a contemporaneous local T790M+ result.
Results:
As of March 2015, 36 patients were enrolled in TIGER-X who were T790M central negative by cobas® or Qiagen therascreen® and evaluable for efficacy. Sensitivity analysis indicated that the 2 assay platforms were comparable for T790M detection. 69% (25/36) were T790M negative centrally but positive locally; 4/36 (11%) were negative by both central and local testing; and 7/36 (19%) were centrally negative with no local result. Median number of previous TKIs was 1 and median number of previous therapies was 2; 81% (29/36) were treated with a TKI as their most recent prior therapy. In central negative/local+ patients the ORR was 40% (10/25). In central negative/local negative patients the ORR was 25% (1/4). The most common treatment emergent adverse events in this subset (all grades) were fatigue, diarrhea, nausea and hyperglycemia.
Conclusion:
These preliminary findings suggest that patients who test negative for T790M using a sensitive tissue test may still benefit from treatment with rociletinib. In part, this clinical activity may be driven by T790M tumor heterogeneity, demonstrated by the discordant T790M results described. In addition, inhibition of IGF-1R/IR by the previously reported (Soria 2014) rociletinib metabolite M502 may also be driving some of the activity observed. This possible explanation is important, since the response rates reported herein are higher than described for other T790M inhibitors in T790M-negative patients. Furthermore, TKI re-treatment effect is unlikely to be a major driver of these results, since the majority of patients came on study directly after progression on another EGFR TKI. To further explore these findings, the open-label TIGER-2 (NCT02147990) and the randomized Phase 3 TIGER-3 (NCT02322281) studies include T790M negative patients.
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.03 - Dose Optimization of Rociletinib for EGFR Mutated NSCLC (ID 967)
16:55 - 17:00 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible mutant selective tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. A maximum tolerated dose was not identified in Phase 1 with 1000 mg BID the highest dose studied. Here we assess the efficacy and safety of the three doses of rociletinib (500 mg BID, 625 mg BID and 750 mg BID) selected for Phase 2 study.
Methods:
TIGER-X (NCT01526928) is a Phase 1/2 open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutant NSCLC progressing after ≥1 EGFR tyrosine kinase inhibitor (TKI). Efficacy is assessed using RECIST. Safety is evaluated using standard adverse event (AE) reporting.
Results:
As of April 2015, a total of 231 central T790M positive patients were evaluable for efficacy and 343 for safety (any T790M). All patients were enrolled in the USA (85%), Europe (9%) and Australia (6%). Baseline characteristics were similar in each dose group. The median number of prior therapies was 2. 85% had EGFR TKI as their most recent prior therapy and 10% had a history of diabetes/hyperglycemia. Immature ORRs are 53% (500 mg BID), 52% (625 mg BID) and 43% (750 mg BID), with disease control rates of 89% (500 mg BID), 87% (625 mg BID) and 82% (750 mg BID). The most common ≥grade 3 treatment-related AE was hyperglycemia [16% (500 mg BID), 25% (625 mg BID) and 35% (750 mg BID)] which was managed with oral hypoglycemic agents. Only one patient discontinued the study for hyperglycemia. Grade 3 QTc prolongation was uncommon, occurring in 2% (500 mg BID), 7% (625 mg BID) and 10% (750 mg BID) of patients, and demonstrated a relationship to dose. There were no clinically relevant cutaneous toxicities with 7 cases of grade 1 rash and 4 cases of grade 1 stomatitis (no dose relationship) and no paronychia.
Conclusion:
All 3 Phase 2 doses of rociletinib are active and well tolerated in a Western patient population with advanced NSCLC. The lack of cutaneous toxicities confirms the selectivity of rociletinib for mutant forms of EGFR and is an important contributor to QOL and maintaining dose intensity (Lacouture et al. 2011). Overall, the adverse event frequency appears to be related to dose, but antitumor activity does not, thus the risk/benefit profile may be optimal at the lowest dose studied.
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MINI16.04 - Activity of Rociletinib in EGFR Mutant NSCLC Patients with a History of CNS Involvement (ID 965)
17:00 - 17:05 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) with activity against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). An overall response rate of 67% has previously been reported in this trial for T790M positive patients treated with the 500 and 625 mg BID doses (Soria 2014). Here we provide preliminary data on the activity of rociletinib in the subgroup of patients with a history of CNS disease.
Methods:
Patients with a history of CNS disease were permitted if asymptomatic and stable, as defined by steroid requirements. The primary activity endpoint was RECIST overall response rate. However, patients who developed progressive disease (PD) while on study treatment were allowed to continue therapy with rociletinib if deemed clinically beneficial by the investigator.
Results:
As of 16 March 2015, a total of 401 patients received therapeutic dose levels of rociletinib (500, 625 and 750 mg BID) including 170 (42%) patients with a history of CNS metastases. Based on this interim analysis, the RECIST overall response rate among these patients with a history of CNS disease is 41%. To date, 42 patients with a history of CNS disease have continued therapy with rociletinib post-progression. Of those who continued for at least 14 days the average treatment duration beyond PD was 89 days (range: 14 - 336 days). Twenty-two of the 42 patients with a history of CNS disease with PD also received brain radiation and continued rociletinib treatment for an average of 120 days (range: 22 – 336 days) after PD. Rociletinib is held on radiation days only. Progression-free survival data for these subgroups is not yet mature. The three most common adverse events in the patient population with a history of CNS disease are similar to those found in the general TIGER-X patient population: hyperglycemia, diarrhea and nausea.
Conclusion:
In patients with a history of CNS disease, a factor associated with poor prognosis, rociletinib is active with a RECIST response rate of 41%. Local CNS radiation has been administered safely with rociletinib held on radiation days and continued afterwards. Prolonged use of rociletinib post CNS radiation suggests ongoing systemic benefit is still experienced by these patients. The role of rociletinib in NSCLC patients with CNS involvement is being further explored in the ongoing TIGER clinical development program.
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MTE 02 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (Ticketed Session) (ID 54)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Advocacy
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 07:00 - 08:00, 105
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MTE02.01 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (ID 1979)
07:00 - 07:30 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Abstract:
The traditional obstacles to approval of oncologic therapeutic agents, especially targeted therapies that address a rare-biomarker defined group of patients are the long processes from initial drug discovery to clinical implementation, the difficulties in recruitment for these clinical trials and high number of screen failures and the overall low rate of enrollment in clinical trials. The Lung Master Protocol (Lung-MAP, S1400) is a precedent-setting clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer of the lung (SCCA). There are few new effective therapeutic options for patients with advanced lung SCCA. Immunotherapies, including nivolumab, have already shown clear benefit for patients with SCCA in 2015 leading to approval by the FDA which has been an unprecedented step forward for the treatment of patients, however we are still lacking predictive markers for these therapies that are reliably selecting patients more likely to benefit. Lung-MAP (S1400) is aiming to identify biomarker-drug pairs that will lead to successful therapeutic outcomes and registration of new agents. It is a registration-intent master protocol that includes a screening component and clinical trial component; the clinical trial component includes multiple sub-studies which independently evaluate investigational therapies. The clinical trial component is designed to be modular such that new sub-studies can be added either as other sub-studies close or as new biomarker-drug pairs are identified for testing in this patient population. Lung-MAP is utlilizing a broad NGS screening platform capitalizing on the expanding application of genomic sequencing in oncology that has through the Cancer Genome Atlas and other sequencing initiatives revealed targetable genetic aberrations including gene mutations, rearrangements, amplifications, and deletions, and creating an immense opportunity to implement personalized therapy with a high potential to improve patients outcomes. Immunotherapy has been integrated in the design of Lung-MAP from its launch in June of 2014. The original study design and structure is shown in the figure. Figure 1 The modular design of the study has allowed for the flexibility to adapt to the approval of nivolumab and the hault in further development of AMG102 (rilotumumab) with discontinuation of the corresponding sub-study by implementing timely modifications which include the following:1)Eligibility has changed from exclusively second line therapy to second-or more line therapy 2)Pre-screening, while patient receive first line therapy has been added to boost accrual 3)the unmatched arm has been changed to a single (not randomized) arm study with the anti-PD-L1 agent MEDI-4736. Theses changes are reflected in the figure. Each independently conducted and analyzed sub-study specifies investigator-assessed progression-free survival (IA-PFS) and overall survival (OS) as the co-primary endpoints for the phase 3 primary objectives. The primary objectives for the phase 3 are to determine if there is a statistically significant difference in OS and to determine if there is both a clinically meaningful and statistically significant difference in IA-PFS. The conduct of Lung-MAP relies on close collaboration (a public-private partnership) among the NCI and NCTN (spearheaded by SWOG), the pharmaceutical industry, the Foundation for the NIH (FNIH), Friends of Cancer Research, advocates, and FDA. This Master Protocol will improve genomic screening of SCC patients for clinical trial entry, and improve time lines for drug-biomarker testing, allowing for inclusion of the maximum numbers of otherwise eligible patients. The clinical trial continues to be updated following science and alterations in the therapeutic landscape, with adaptations in design and incorporation of new agents against matched targets and the implementation of novel immunotherapy approaches for the unmatched arm. Figure 2
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ORAL 13 - Immunotherapy Biomarkers (ID 104)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Kim, D. Grunenwald
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL13.07 - EMT Is Associated with an Inflammatory Tumor Microenvironment with Elevation of Immune Checkpoints and Suppressive Cytokines in Lung Cancer (ID 2134)
17:50 - 18:01 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Background:
Promising results in the treatment of NSCLC have been seen with immunomodulatory agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1). However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune checkpoint blockade is critical to successful clinical translation of these agents. Epithelial-mesenchymal transition (EMT) is a key process driving metastasis and drug resistance. Previously we have developed a robust EMT gene signature, highlighting differential patterns of drug responsiveness for epithelial and mesenchymal tumor cells.
Methods:
We conducted an integrated analysis of gene expression profiling from three independent large datasets, including The Cancer Genome Atlas (TCGA) of lung and two large datasets from MD Anderson Cancer Center, Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (named PROSPECT) and the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (named BATTLE-1). Comprehensive analysis of mRNA gene expression, reverse phase protein array (RPPA), immunohistochemistry, in vivo mouse models and correlation with clinical data were performed.
Results:
EMT is highly associated with an inflammatory tumor microenvironment in lung adenocarcinoma, independent of tumor mutational burden. We found immune activation co-existent with elevation of immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, BTLA and CTLA-4, along with increases in tumor infiltration by CD4+Foxp3+ regulatory T cells in lung adenocarcinomas that displayed an EMT phenotype. Similarly, IL-6 and indoleamine 2, 3-dioxygenase (IDO) were elevated in these tumors. We demonstrate that in murine models of lung adenocarcinoma, many of these changes are recapitulated by modulation of the miR-200/ZEB1 axis, a known regulator of EMT. Furthermore, B7-H3 is found to negatively correlate with overall survival and recurrence free survival, indicating a potential new therapeutic target in lung adenocarcinoma in the future.
Conclusion:
EMT, commonly related to cancer metastasis and drug resistance, is highly associated with an inflammatory tumor microenvironment with elevation of multiple targetable immune checkpoints and that is regulated at least in part by the miR-200/ZEB1 axis. These findings suggest that EMT may have potential utility as a biomarker selecting patients more likely to benefit from immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly a broad range of other cancers.
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ORAL 21 - Biology - Moving Beyond the Oncogene to Oncogene-Modifying Genes (ID 118)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:A. Katz, M.S. Tsao
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 4a-4f
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ORAL21.02 - Landscape and Functional Significance of KRAS Co-Mutations in Lung Adenocarcinoma (LUAC) (ID 3224)
10:56 - 11:07 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Background:
The biological heterogeneity of KRAS-mutant LUAC represents a major impediment to the successful implementation of targeted therapeutic strategies for this clinically challenging group of lung cancer patients. Through integrative, multi-platform analysis of large scale omics data we recently identified three major subsets of KRAS-mutant LUAC defined on the basis of co-occurring genomic alterations in STK11/LKB1 (KL subgroup), TP53 (KP) and CDKN2A/B (KC), the latter coupled with low expression of the TTF1 transcription factor. We further demonstrated subset-specific molecular dependencies, patterns of immune system engagement and therapeutic vulnerabilities. Here, we extend these findings through comprehensive analysis of a wide panel of KRAS co-mutations and assess the impact of key co-mutations on facets of the malignant phenotype including flux through the MAPK and PI3K/AKT pathways and heterotypic interactions with the host immune system.
Methods:
Our datasets consisted of 431 tumors from TCGA (122 KRAS-mutant), 41 additional chemo-naive KRAS-mutant LUACs (PROSPECT dataset) and 36 platinum-refractory KRAS-mutant LUACs from the BATTLE-2 clinical trial. Significant KRAS co-mutations were identified on the basis of a P value threshold of ≤0.05 (Fisher’s exact test) coupled with a baseline prevalence of ≥3%. RNASeq data were downloaded directly from the TCGA site. Expression profiling of PROSPECT tumors was performed using the Illumina Human WG-6 v3 BeadChip Array whereas BATTLE-2 tumors were profiled using the GeneChipâHuman Gene 1.0 ST Array from Affymetrix. Generation of MAPK and PI3K proteomic scores, based on Reverse Phase Protein Array (RPPA) data, has been previously reported.
Results:
Our analysis identified somatic mutations in 31 genes as significantly co-mutated with KRAS in LUAC samples. Among them, co-mutations in STK11/LKB1 (P=0.00011) and ATM (P=0.0004) predominated. Somatic mutations in ERBB4 (P=0.0059), encoding a member of the ErbB family of receptor tyrosine kinases and MAP3K4 (P=0.0017) were also enriched in KRAS-mutant LUAC. We assessed the impact of KRAS co-mutations on the amplitude and directionality of signaling downstream of mutant KRAS using the proteomic “MAPK score“ and “PI3K score” as surrogates of effector pathway activation. Interestingly, co-mutations in ERBB4 were associated with significantly suppressed flux through the MAPK pathway (P=0.0024, t-test). Somatic mutations in other genes, including CAMSAP2, were associated with suppressed signaling through both the MAPK (P=0.00876, t-test) and PI3K-AKT (P=0.0032, t-test) cascades. Finally, within KRAS-mutant tumors, co-mutations in NLRC5, a master transcriptional regulator of MHC Class I molecules were associated with reduced mRNA expression of several of its classical target genes. In addition, low mRNA expression of NLRC5 correlated strongly with reduced expression of key components of the antigen presentation pathway across multiple independent datasets of chemotherapy naïve and platinum refractory KRAS-mutant tumors and cell lines. Thus, in addition to cell autonomous effects, co-mutations can also impinge on the reciprocal relationship between malignant cells and their immune microenvironment.
Conclusion:
Our work identifies a compendium of KRAS co-mutations that impact classical and emerging cancer hallmarks, including evasion of the host immune response. Systematic interrogation of the functional impact of prevalent KRAS co-mutations is essential for the development of personalized treatment approaches for this heterogeneous group of tumors.
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ORAL 42 - Drug Resistance (ID 160)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:R.C. Doebele, J.V. DeGregori
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 4a-4f
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ORAL42.04 - Rictor Alterations Elicit Mechanisms of Survival Advantage and Resistance to Targeted Therapy in Non-Small Cell Lung Cancer (NCSLC) (ID 2991)
19:02 - 19:13 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Background:
Rictor (RPTOR independent companion of MTOR, complex 2) is a highly conserved protein and is a critical component for assembly and functionality of the mTORC2 complex. Alterations of the PI3K/mTOR/AKT pathway are hallmark of many cancer types, underscoring the potential important role of Rictor. The goal of our current study was to characterize the functional consequences of genomic alterations of Rictor in advanced refractory NSCLC. Our preliminary data suggest that Rictor alterations have the potential to, not only signal canonically (via activation of AKT), but also provide cancer cells with alternate, more advantageous oncogenic signaling via non-canonical mechanisms.
Methods:
We correlated genomic data (DNA next generation sequencing (NGS), Foundation Medicine, Inc) gene expression profiling, and clinical outcome in the context of the ongoing BATTLE-2 clinical trial of targeted therapies in chemo-refractory NSCLC(198 cases). We further (1) surveyed early stage NSCLC cases(230 cases) in The Cancer Genome Atlas (TCGA) database to perform two-way hierarchical clustering comparing gene expression profiling in amplified vs diploid cases; (2) utilized a single-nucleotide polymorphism array to select Rictor amplified and diploid NSCLC cell lines; (3) assessed Rictor protein and RNA expression by Western blot and qRT-PCR, respectively; (4) performed Rictor knockdown (siRNA), and (5) performed drug sensitivity to targeted therapies by MTS assay.
Results:
In the Battle-2 cases, we identified 15% of Rictor alterations (9% gene amplifications, 6.6% mutations, non-concomitant). Among the mutations, 1 was mapped to an N-terminal phosphorylation site, while all others are of unknown significance to date. Rictor alterations were significantly associated with lack of 8-week disease control in the AKTi+MEKi therapeutic arm. In the TCGA we found: (1) 10% Rictor amplifications and 3% mutations; (2) significant correlation between amplification and elevated Rictor gene expression; (3) a putative functional gene expression signature associated with Rictor amplification. In diploid cell lines we found concordance between AKT phosphorylation and activation of other downstream mTORC2 targets (i.e. SGK1 and PKCα), but in Rictor amplified cell lines we witnessed a discordant activation of these pathways. Furthermore, following Rictor knockdown in our amplified cell lines, a significant reduction of colony formation, migratory, and invasive potential was seen in a pathway-differential manner. Thus, suggesting that Rictor amplifications may provide survival advantage in select cancer cells by tipping the signaling balance toward a non-canonical oncogenic pathway (AKT-independent[I1] ).Also in a differential pathway manner, Rictor gene amplification and overexpression contributed to resistance to a number of targeted therapies
Conclusion:
Rictor alterations may constitute a potential novel mechanism of targeted therapy resistance via the activation of non-canonical signaling pathways. These alterations could define new molecular NSCLC subtypes with distinct biology that expose unique avenues for therapeutic implication. Ongoing studies are exploring therapeutic vulnerabilities, non-canonical signaling and Rictor mutations.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-079 - Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone as First-Line Therapy for NSCLC (ID 2993)
09:30 - 09:30 | Author(s): V. Papadimitrakopoulou
- Abstract
Background:
Platinum doublet chemotherapy with or without bevacizumab is the standard first-line therapy for patients with advanced NSCLC without EGFR sensitizing mutations or ALK rearrangement. Pembrolizumab (MK-3475), a humanized monoclonal antibody against PD-1 designed to block the interaction of PD-1 with its ligands PD-L1 and PD-L2, has shown efficacy and a manageable toxicity profile in patients with NSCLC treated at doses ranging from 2 mg/kg every 3 weeks to 10 mg/kg every 2 weeks. In 45 patients with treatment-naive advanced NSCLC treated in KEYNOTE-001, single-agent pembrolizumab has demonstrated a response rate of 26%.
Methods:
KEYNOTE-021 (ClinicalTrials.gov, NCT02039674) is an international, open-label, multi-arm, phase 1/2 trial of pembrolizumab for advanced NSCLC. After establishing the safety and tolerability of pembrolizumab plus carboplatin and pemetrexed in phase 1, a randomized phase 2 cohort comparing the efficacy of pembrolizumab plus carboplatin and pemetrexed with that of carboplatin and pemetrexed has been initiated. Key eligibility criteria for this cohort are previously untreated stage IIIB/IV nonsquamous NSCLC, no sensitizing EGFR mutation or ALK rearrangement, and ECOG PS 0-1. Patients will be randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg Q3W plus carboplatin and pemetrexed at standard doses or carboplatin and pemetrexed alone. Randomization will be stratified by PD-L1 expression determined by immunohistochemistry at a central laboratory (positive [membranous expression in ≥1% of tumor cells] vs negative). Pembrolizumab will be given for 24 months or until progression, intolerable toxicity, or investigator decision. Pembrolizumab may be continued beyond radiographic progression in eligible patients. Carboplatin and pemetrexed will be given for 4 cycles followed by maintenance pemetrexed, alone or with pembrolizumab. Patients allocated to the chemotherapy-alone arm who experience progression may cross over to the pembrolizumab arm of the study. AEs will be monitored throughout treatment and for 30 days thereafter. Response will be assessed every 6 weeks for the first 18 weeks, then every 9 weeks in year 1 and every 12 weeks in year 2. Survival follow-up will occur every 3 months after discontinuation of study treatment. Primary end point is progression-free survival (RECIST v1.1, central review); secondary end points include overall survival, objective response rate, and correlation of PD-L1 expression with antitumor activity. This cohort is currently enrolling patients.
Results:
Not applicable.
Conclusion:
Not applicable.
