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Pasi A Jänne
Moderator of
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OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 8
- Moderators:Adrian G. Sacher, Pasi A Jänne
- Coordinates: 10/18/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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OA 10.01 - Detection of EGFR mutations from plasma ctDNA in the osimertinib Phase III trial (AURA3): comparison of three plasma assays (ID 8984)
11:00 - 11:10 | Presenting Author(s): Myung-Ju Ahn | Author(s): Ji-Youn Han, C. Tsai, A. Delmonte, T. Hsia, J. Laskin, S. Kim, Y. He, T. Hida, M. Maemondo, T. Kato, S. Jenkins, A. Markovets, K.S. Thress, T. Mok
- Abstract
- Presentation
Background:
AURA3 (NCT02151981) showed osimertinib, a third-generation EGFR-TKI, significantly prolongs progression‑free survival and improves response rate vs platinum‑pemetrexed in patients with T790M-positive advanced NSCLC, whose tumors had progressed on first-line EGFR-TKI therapy. Using patient baseline samples, we report concordance between plasma circulating tumor DNA (ctDNA) and tissue for the detection of EGFR mutations (T790M, exon 19 deletions [Ex19Del], L858R) using three distinct plasma detection technologies.
Method:
Tumor tissue biopsy samples were taken following progression on first-line EGFR‑TKI treatment. Baseline central confirmation of EGFR mutation status was by cobas[®] EGFR Mutation Test (Roche Molecular Systems). Where possible, baseline blood samples for plasma ctDNA screening were collected from patients in the osimertinib treatment group and analyzed using allele specific (AS)‑PCR (cobas[®] EGFR Mutation Test v2), ddPCR (Biodesix) and next generation sequencing (NGS, Guardant Health).
Result:
Figure 1 ctDNA was undetectable (negative for all three EGFR mutations [T790M, Ex19Del, L858R]) in 51/228 (22%) patients by AS-PCR, 58/211 (27%) by ddPCR, and 54/230 (23%) by NGS. Robust correlations (Spearman’s Rank) were observed for EGFR mutant allelic fractions (AFs) between ddPCR and NGS assays: T790M R[2] 0.9129 (n=201), Ex19Del R[2] 0.9384 (n=201), L858R R[2] 0.8090 (n=200). Discordant results between ddPCR and NGS were observed in 24/201 (12%) samples for T790M, 17/201 (8%) Ex19Del and 11/200 (6%) L858R. All discordant samples had AFs ≤1% by both assays.
Conclusion:
Using cobas tissue test as a reference, sensitivity for the detection of plasma T790M appeared higher for ddPCR and NGS assays compared with AS-PCR. Robust correlations were observed between quantitative ddPCR and NGS assays for determination of AFs across all three mutations. About 25% of AURA3 patients did not appear to shed ctDNA, as evidenced by absence of all three EGFR mutations across the three platforms.
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OA 10.02 - Unique Genetic Profiles from Circulating Cell-Free DNA of Cerebrospinal Fluid in Leptomeningeal Metastases of EGFR Mutant NSCLC (ID 8258)
11:10 - 11:20 | Presenting Author(s): Benyuan Jiang | Author(s): Y. Li, Jin -Ji Yang, X. Yang, Qing Zhou, W. Zhong, X. Zhang, Yi-Long Wu
- Abstract
- Presentation
Background:
Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) with EGFR mutations. Resistance mechanisms of LM remained unclear due to limited access to leptomeningeal lesions.
Method:
Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing with 168 genes panel. Thirty patients diagnosed as LM and harboring EGFR mutation were enrolled in this cohort, and CSF cfDNA and plasma of two patients and CSF precipitates of another two patients were not available
Result:
Driver genes were detected in 100% (28/28) , 85.7% (24/28) and 75% (21/28) patients of CSF cfDNA, CSF precipitates and plasma, respectively; and 92.9% (26/28) patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA when compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were privately detected in CSF cfDNA, and CNVs in patients after TKI failure were more complicated when compared to those TKI naïve before LM. MET copy number gain identified in 44.0% (11/25) patients was the most frequent one, other CNVs included ERBB2, KRAS, ALK, MYC and FGFR1. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 67.9% (19/28) CSF cfDNA, which was much higher than that in plasma (2/28, 7.1%; p<0.001), and there was a trend towards higher rate of concomitant resistance mutations in patients with TP53 LOH than those without one (70.6% vs. 25%; p=0.036 ). EGFR T790M was identified in 28% (7/25) patients with progression to TKIs in CSF cfDNA.
Conclusion:
CSF cfDNA could reveal the unique genetic profiles of LM, and it should be the most representative medium of liquid biopsy for LM in NSCLC harboring EGFR mutations.
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OA 10.03 - Liquid Biopsy in the Lung Cancer Clinic: A Prospective Study of Plasma DNA next Generation Sequencing to Guide Matched Therapy (ID 8218)
11:20 - 11:30 | Presenting Author(s): Joshua K Sabari | Author(s): D. Stephens, A. Ni, A. Lee, Nick Pavlakis, S. Clarke, C.I. Diakos, M. Offin, S. Datta, N. Tandon, M. Duboff, J. Simpronio, A. Martinez, J. Isbell, Valerie W Rusch, D. Jones, Andreas Rimner, S. Henderson, C. Raymond, L. Lim, M. Li, Gregory J Riely, Charles M Rudin, Bob T. Li
- Abstract
- Presentation
Background:
Liquid biopsy for plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) is now commercially available and increasingly adopted in clinical practice with a paucity of evidence based guidance. We set out to prospectively determine the utility of plasma ctDNA NGS in the lung cancer clinic.
Method:
Patients (pts) with advanced NSCLC who were driver unknown or resistance mechanism unknown were eligible. Pts were enrolled prospectively at Memorial Sloan Kettering (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood was collected in Streck tubes (10-20mL) and sent to Resolution Bioscience (Bellevue, WA) for targeted NGS of extracted DNA using a bias corrected hybrid capture 21 gene assay in a CLIA laboratory with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1%. Clinical endpoints included detection of oncogenic drivers, turnaround time, comparison to tissue NGS when available, and ability to match pts to targeted therapy along with their treatment outcomes.
Result:
Seventy-six pts were prospectively accrued. Plasma NGS detected an oncogenic driver in 36% (27/76) of pts, of whom 14% (11/76) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insYVMA, BRAF L597Q and MET exon14. Of the 10 evaluable pts, 10 partial responses were observed. Mean turnaround time for plasma was 6 days (3-12) vs 21 days (16-30) for tissue (P <0.0001). Plasma ctDNA was detected in 60% (46/76) of pts; detection rate was 46% (16/35) if blood was drawn on active therapy and 73% (30/41) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.31, 95% CI 0.12 – 0.81; P=0.02). Of the 25 concurrent tissue NGS performed to date, there was a 96% plasma concordance with tissue and a 60% tissue concordance with plasma for driver mutations.
Conclusion:
In pts who were driver or resistance mechanism unknown, plasma NGS identified a variety of oncogenic drivers with significantly shorter turnaround time compared to tissue NGS, and matched patients onto targeted therapy with clinical benefit. Plasma ctDNA is best detected at diagnosis of metastatic disease or at progression. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide evidence to support the incorporation of plasma NGS into practice guidelines.
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OA 10.04 - Discussant - OA 10.01, OA 10.02, OA 10.03 (ID 10806)
11:30 - 11:45 | Presenting Author(s): R. Hui
- Abstract
- Presentation
Abstract not provided
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OA 10.05 - Non-Invasive Molecular Profiling in NSCLC by Targeted and Whole Exome Analysis of Plasma cfDNA (ID 10422)
11:45 - 11:55 | Presenting Author(s): Dana W.Y. Tsui | Author(s): M.L. Cheng, J.L. Yang, M. Shady, P. Ulz, E. Heitzer, N.D. Socci, V. Seshan, M. Offin, D. Stephens, A. Makhnin, N. Tandon, S. Datta, D.S. Selcuklu, K. Huberman, K. Vanness, E. Gedvilaite, A. Viale, Maria E Arcila, Marc Ladanyi, J.E. Chaft, Charles M Rudin, M.F. Berger, D.B. Solit, Bob T. Li
- Abstract
- Presentation
Background:
Molecular characterization of tumor can guide the choice of therapy for NSCLC patients. However, tumors are complicated by spatial heterogeneity and sometimes may not be of sufficient quality and quantity for analysis. NGS using plasma cell-free DNA (cfDNA) input may capture temporal and spatial heterogeneity, and enable genomic profiling in patients without adequate available tumor tissue. Targeted gene panels allow for robust detection of known oncogenic drivers, but may not be comprehensive enough to screen for novel biomarkers or mechanisms of acquired resistance. Whole exome sequencing (WES) allows for hypothesis-free biomarker discovery, but may be technically challenging in the setting of limited tumor-derived DNA content in plasma cfDNA. In this study, we aim to develop a workflow to guide the selection of samples for targeted and whole exome sequencing for noninvasive molecular profiling.
Method:
Plasma samples were collected from 20 NSCLC patients receiving a variety of treatment (chemotherapy, targeted therapy, or immunotherapy). Most patients (>70%) had stage III or IV disease at the time of plasma collection. CfDNA was extracted from 3 mL of plasma, and analyzed using low-pass shallow whole genome sequencing (sWGS) and MSK-IMPACT, a hybridization capture-based assay targeting over 400 cancer-related genes. Analysis of matched normal was performed for somatic variant calling.
Result:
Median cfDNA yield per plasma sample was 28ng (range 7 - 236ng). We applied z-score statistics to estimate the levels of tumor-derived mutant allele fractions in cfDNA based on sWGS data. We trained the algorithm using a separate cohort of cfDNA data from >100 patients with metastatic solid tumors to classify samples by mutant allele fraction (MAF) as either low (<5% MAF) or high (>5% MAF) tumor-derived DNA. In the subset of 10 patients with unknown drivers, two were estimated to have MAF >5% in cfDNA, and WES recapture was performed. MSK-IMPACT targeted sequencing identified actionable alterations in a subset of patients who did not have sufficient materials for tissue profiling. WES in cases with high tumor-derived DNA content by sWGS identified alterations in genes outside of the MSK-IMPACT panel.
Conclusion:
Molecular profiling using cfDNA is feasible in lung cancer and may identify actionable alterations to inform treatment decisions in patients without sufficient tissue for molecular characterization. The application of sWGS to estimate the levels of tumor-derived mutant allele fractions in plasma cfDNA samples may help guide selection of the optimal downstream sequencing strategy.
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OA 10.06 - Longitudinal Mutation Monitoring in Plasma by Deep Sequencing as a Potential Predictor of Disease Progression in NSCLC (ID 9595)
11:55 - 12:05 | Presenting Author(s): John Jiang | Author(s): H. Adams, M. Lange, S. Siemann, M. Feldkamp, S. Schulze, S. Froehler, S. Yaung, L. Yao, A. Balasubramanyam, N. Tikoo, H..J. Achenbach, R. Krügel, J.F. Palma, André Rosenthal
- Abstract
- Presentation
Background:
Circulating tumor DNA (ctDNA) sequencing and analysis has the potential to transform clinical management of patients with advanced NSCLC. Non-invasive sampling of blood draws at different time points during treatment could potentially be used for routine monitoring of disease progression and detection of therapy resistant mutations by using next generation sequencing (NGS).
Method:
448 longitudinal plasma samples (mean 6.3 per subject) collected from 71 subjects with advanced NSCLC during 1[st] line treatment were analyzed by NGS. Of these 71 subjects, 47 also had matched baseline tumor tissue samples. The AVENIO ctDNA Surveillance kit and AVENIO FFPET Analysis kit (RUO, Roche, Pleasanton, CA, USA) were used for sequencing analysis. The Surveillance kit contains 17 cancer driver genes and additional 180 frequently mutated genes mainly selected for NSCLC and colorectal cancer. This kit is capable of detecting four mutation classes: SNVs, fusions, CNVs and InDels. CT images were reviewed centrally using RECIST v1.1.
Result:
Somatic, disease-associated mutations were detected with allele frequency (AF) of >5% in 94% of baseline tumor samples (44/47), and in 100% of plasma samples with AF in ctDNA ranging from ≥0.5% to ≤30%. The most commonly mutated genes in tumors were TP53 (22/47 subjects), KRAS (14/47), BRAF (7/47), STK11 (5/47), and ERBB2 (5/47). Tracking the AF’s of key tumor mutations by the Surveillance panel in the paired longitudinal plasma samples allowed the monitoring of treatment response at the molecular level. We identified a number of subjects in which the AF of cfDNA mutations increased three to four months before clinical evidence of progression of disease detected by CT scans that were centrally reviewed according to RECIST v1.1. Cases were also observed where the AF’s of key mutations decreased in 1[st] line chemotherapy to nearly zero which correlated with clinical partial response and stable disease. . Additionally, first post treatment plasma samples collected during first line treatment showed a difference of 96 days in median survival times of ctDNA- vs ctDNA+ groups (logrank p value =0.0371).
Conclusion:
ctDNA testing with molecular bar coded duplex sequencing and digital background error suppression of a large 197 gene panel offers high sensitivity for tumor variant detection. The study demonstrated that the presence of tumor variants detected in blood at the beginning and end of 1[st] line treatment is a risk factor for early disease progression. Longitudinal mutation monitoring has the potential to predict disease progression earlier than regular CT imaging.
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- Abstract
- Presentation
Background:
The detection of driver gene mutation based on tumor tissue can instruct target therapy and conduct molecular monitoring after drug-resistance in advanced NSCLC, but many patients have no access to this kind of test because of inadequate tumor tissue or inability to tolerate the invasive test. Some studies have explored the value of EGFR mutation test in body fluids such as plasma，urine and sputum from NSCLC patients. But the sensitivity based on individual liquid specimen is poor compared with gold standard---tissue. We detect multi-genes in multi-liquid samples in parallel to investigate the Consistency and complementarity of genetic profile in different liquid samples and it’s correlation with efficacy of the real world therapy in advanced NSCLC.
Method:
The patients newly diagnosed with NSCLC and first-generation EGFR-TKI acquired drug-resistance were enrolled into our research (NCT:02778854) prospectively, the pre-treatment samples including tumor tissue, plasma, urine and sputum were collected. We conducted capture-based NGS (next generation sequencing) on all of these samples from 50 patients with a ctDNA panel covering significant exons and introns from 400 human genes including EGFR, KRAS, ALK, ROS1, c-MET and other important genes in the tumor related singling pathways such as PI3K-AKT-mTOR, JAK-STAT, Notch, Wnt and so on. Patients recruited in our experiment have been given unique treatment such as targeted treatment or chemotherapy according to the clinical examination. The final molecular diagnostic results of all clinical liquid or tissue specimen are supposed to be correlated with clinical response data.
Result:
（Applied for Late-Breaking Abstract） This section is not applicable now because the sequencing and complex data analysis is in progress. Therefore, we will submit the final results as late-breaking abstract.
Conclusion:
Section not applicable. We expect to figure out the molecular diagnostic value of different body fluid compared with tumor tissue. we are able to analyze for correlation of the genomic profile derived from liquid samples and respective tissue results and clinical response of each patient.
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OA 10.08 - Discussant - OA 10.05, OA 10.06, OA 10.07 (ID 10807)
12:15 - 12:30 | Presenting Author(s): Naoko Aragane
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.02 - STK11/LKB1 Loss of Function Genomic Alterations Predict Primary Resistance to PD-1/PD-L1 Axis Blockade in KRAS-Mutant NSCLC (ID 10367)
15:50 - 15:55 | Author(s): Pasi A Jänne
- Abstract
- Presentation
Background:
The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).
Method:
The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).
Result:
188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.
Conclusion:
Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.08 - Clinical Implications of ALK Resistance Mutations: Institutional Experience and Launch of Remote Participation Study (ID 7931)
16:30 - 16:35 | Author(s): Pasi A Jänne
- Abstract
- Presentation
Background:
ALK resistance mutations are detected in 30-50% of the patients with ALK-positive non-small cell lung cancer (NSCLC) and resistance to ALK tyrosine kinase inhibitors (TKIs). Preliminary data suggests that TKI-resistant patients benefit from further ALK inhibition based on the specific resistant mutations, but clinical data are limited.
Method:
Patients with ALK-positive NSCLC were identified from our institutional database with IRB approval. Tumor specimens from patients with TKI-resistance were analyzed using next-generation sequencing (NGS). We aimed to study the relationship between specific ALK-resistant mutations, patient characteristics and clinical outcomes.
Result:
Among 82 ALK-positive NSCLC patients, we identified 29 cases with advanced disease, TKI resistance, and specimens available for NGS. Twenty-two specimens from 19 patients were adequate for genomic analyses. Patients received a median of 4 lines of treatment for advanced disease including a median of 2 ALK TKIs, with a median overall survival (OS) of 3.3 years. In 9 of 22 specimens, crizotinib was the only TKI received. Ten specimens (45.5%) showed an ALK resistance mutation: one G1128A, one L1152R, four I1171N/T, two F1174V and two G1202R. ALK-resistance mutations were more common with EML4-ALK variant 3 (4/5) than variant 1 (1/5). Three cases with sequential biopsies showed features of tumor evolution, such as a compound mutation (I1171N + C1156Y) or a mutational change (L1152R to G1128A). One case initially had an EGFR L858R mutation, then acquired an ALK rearrangement, then acquired a G1202R mutation. OS was longer in 8 patients with secondary ALK mutation (5.5y) compared to 11 patients without (1.8 y). Using these learnings from an institutional cohort of ALK resistant patients, we designed and are launching a prospective study to characterize ALK TKI resistance, which uses remote-participation and plasma NGS to enroll patients from across the US. Patients with systemic progression while on a next-generation ALK TKI submit blood to a central lab for analysis and banking. Plasma NGS results are returned to the patient and their provider, and including expected TKI sensitivities for any identified ALK-resistance mutations. Through monitoring outcomes, this study can assess if molecularly-guided therapy for ALK TKI-resistance is feasible and effective.
Conclusion:
ALK resistance mutations arise in a large portion of patients and are associated with longer survival. The SPACEW-ALK study (Study of Plasma next-generation sequencing for remote Assessment, Characterization, Evaluation of patients With ALK drug resistance) uses plasma NGS and remote consent to assess ALK resistance and the feasibility of precision resistance therapy for these patients.
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MA 07.12 - Short-Term Culture of Patient Derived Tumor Organoids Identify Neratinib/Trastuzumab as an Effective Combination in HER2 Mutant Lung Cancer (ID 10119)
17:00 - 17:05 | Author(s): Pasi A Jänne
- Abstract
- Presentation
Background:
There are currently no effective targeted therapies for HER2 mutant lung cancer. Both neratinib alone or in combination with temsirolimus both have low response rates. One challenge is the lack of patient derived HER2 mutant cell line models and a platform in which to identify the most effective therapeutic strategy. Patient derived xenografts (PDXs) are emerging as an alternative tool to screen for drug efficacy, but can take months to generate and are impractical for screening of large sets of drug combinations. Here we report on a novel 3D microfluidic platform that allows for evaluating ex vivo responses to targeted therapies or targeted therapy combinations from patient derived tumor spheroids (xDOTS).
Method:
We generated xDOTS from DFCI 359, a PDX derived from a HER2 mutant (InsYVMA) NSCLC patient under an IRB approved protocol. Tumor organoids (<100 μm and >40μm) were treated with: HER2 covalent inhibitors (neratinib, afatinib); an EGFR inhibitor (gefitinib), and combinations of HER2 inhibitors and other compounds (neratinib/trastuzumab or neratinib/temsirolimus) at known peak plasma concentrations for 3 days in our 3D microfluidic cell culture device. Live/death quantification was performed by dual labeling de-convolution fluorescence microscopy using acridine orange for live and propidium iodide for dead cells. Cell type characterization was performed by immunofluorescence. The most effective combination was used to treat the DFCI 359 PDX and a HER2 InsYVMA genetically engineered mouse model (GEMM).
Result:
Both neratinib alone and afatinib alone, but not gefitinib, induced high degree of cell death in the DFCI 359 xDOTS. The combinations of neratinib/trastuzumab, and neratinib/temsirolimus enhanced the therapeutic benefit compared to neratinib alone, with the former combination being more effective than the latter. Using fluorescence microscopy we demonstrate that the effects are specific to the tumor cells, rather than the stromal component. We then went on to confirm these findings in a concomitant in-vivo efficacy experiment using the DFCI 359 PDX and the HER2 InsYVMA GEMM. In both in vivo models, the neratinib/trastuzumab combination led to significant tumor regressions and was superior to either single agents or the neratinib/temsirolimus combination.
Conclusion:
Our findings demonstrate the ability to use a 3-D in vivo microfluidic system to identify combination therapies for HER2 mutant NSCLC. Based on our studies, neratinib/trastuzumab is a promising combination for a clinical trial for HER2 mutant lung cancer.
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MS 25 - Novel Molecular Targets (KRAS/MET/Novel Fusions): Druggable or Not? (ID 547)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:Rafael Rosell, Isamu Okamoto
- Coordinates: 10/18/2017, 14:30 - 16:15, Main Hall
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MS 25.01 - Discovery of Novel Molecular Targets (ID 7759)
14:30 - 14:50 | Presenting Author(s): Pasi A Jänne
- Abstract
Abstract not provided
Information from this presentation has been removed upon request of the author.
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.02 - Osimertinib Resistance Mediated by Loss of EGFR T790M Is Associated with Early Resistance and Competing Resistance Mechanisms (ID 9000)
11:10 - 11:20 | Author(s): Pasi A Jänne
- Abstract
- Presentation
Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in EGFR-mutant NSCLC with resistance to prior TKI. Improved understanding of the clinical and molecular characteristics of acquired resistance to osimertinib is needed.
Method:
We initially studied resistance biopsies and plasma specimens from an institutional cohort of 119 patients treated with osimertinib for T790M-positive NSCLC with resistance to prior TKI. For validation, we studied plasma from 157 patients treated with osimertinib on the AURA trial (NCT01802632).
Result:
45 of 119 patients underwent a resistance biopsy and 33 had resistance tumor genotyping available. 11 patients maintained T790M at resistance: 7 acquired EGFR C797S, 1 had a PIK3CA mutation. 22 patients had loss of T790M at resistance: 14 harbored a competing resistance mechanism, including histologic transformation to SCLC, MET amplification, mutations in BRAF, PIK3CA, or KRAS, or fusions in RET or FGFR. Median time to treatment failure (TTF) on osimertinib was 3 months in patients with loss of T790M and 15 months in patients with maintained T790M. In the validation cohort, 110 of 157 patients had detectable tumor DNA in plasma and were eligible for analysis. 58 patients (53%) maintained T790M at resistance; 24 (22%) also acquired a C797S mutation. 52 patients (47%) had loss of T790M at resistance and no C797S. Median TTF was shorter in patients with loss of T790M than in those with maintained T790M at resistance (5.7 vs 12.5 months). 50 patients had both pre- and post-osimertinib plasma genotyping. Studying the relative allelic fraction (AF) of T790M compared to driver EGFR mutation, patients with T790M loss had only slightly lower relative T790M AF pretreatment (29% vs. 38% median, p = 0.06). The ability of plasma response to predict subsequent resistance was studied in 19 patients from the initial cohort with baseline and follow-up plasma genotyping after 1-3 weeks on osimertinib. Studying the difference between the relative change in plasma levels of T790M and the EGFR driver, patients with T790M loss at time of resistance consistently had a greater T790M response than driver response (median difference 16%), suggesting incomplete suppression of the driver due to competing resistance mechanisms.
Conclusion:
In patients with acquired resistance to osimertinib, repeat testing for T790M could offer key insights into disease biology. Patients with early resistance on osimertinib are at risk of T790M loss with emergence of a complex variety of competing resistance mechanisms, and represent intuitive candidates for combination approaches such as combined EGFR & MET inhibition.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-055 - Spectrum of Early Progression in Advanced NSCLC Patients Treated with PD-1 Inhibitors: Identifying Markers for Poor Outcome (ID 8275)
09:30 - 09:30 | Author(s): Pasi A Jänne
- Abstract
Background:
While marked responses have been observed in patients with non-small-cell lung cancer (NSCLC) treated with PD-1 pathway inhibitors, anecdotal evidence indicates that rapid progression with dramatic tumor burden increase early in the course of therapy may be noted in a few patients. The study characterized the spectrum of early progression of advanced NSCLC treated with PD-1 inhibitors, and investigated quantitative imaging markers for poorer outcome.
Method:
The study included 134 patients (53 men, 81 women; median age: 66) with advanced NSCLC treated with commercially prescribed single-agent nivolumab or pembrolizumab, who had follow-up CT scans at 8 +/- 2 weeks of therapy. Tumor burden measurements were performed using RECIST1.1 on baseline and 8-week scans to characterize the spectrum of early progression during PD-1 therapy. Tumor burden changes at 8 weeks were studied for association with overall survival (OS), which was measured from the 8-week scan date.
Result:
The tumor burden changes at 8 weeks comparing to baseline ranged from -72.7% to +138.7% (median: +4.3%; the 90[th] percentile: +50.07%). OS of 15 patients with ≥50% increase of tumor burden at 8 weeks was significantly shorter compared to 119 patients with <50% increase at 8 weeks (median OS: 4.5 months [95%CI: 1.3-4.9] vs. 12.7 months [95%CI: 8.5-14.7]; log-rank p=0.0003). Among 42 patients who experienced tumor burden increase ≥20% (RECIST progression threshold) at 8 weeks, 15 patients with ≥50% increase had shorter OS than 27 patients with ≥20% but <50% increase (median OS: 4.5 months [95%CI: 1.3-4.9] vs. 6.8 months [95%CI: 5.4-20.1]; log-rank p=0.08), indicating that ≥50% increase threshold may identify a distinct group of early progressors with poorer prognosis. Never smokers were more likely to experience ≥50% increase at 8 weeks than former or current smokers (Fisher p=0.03).
Conclusion:
Tumor burden increase of ≥50% at 8 weeks of therapy was associated with significantly shorter OS in advanced NSCLC patients treated with commercial PD-1 inhibitors, indicating that it can serve as an imaging marker to identify a distinct subset of patients with poorer outcome of PD-1 inhibitor therapy, and may thus help guide treatment decisions.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-066 - Wild-Type KRAS Mediates Growth Inhibition and Resistance to MEK Inhibitors through Dimerization with Mutant KRAS in Lung Adenocarcinoma (ID 8807)
09:30 - 09:30 | Author(s): Pasi A Jänne
- Abstract
Background:
Mutations in KRAS are the most frequent RAS alterations in human cancers and the prevalent driver event in lung adenocarcinoma (LUAD). There are no effective targeted therapies for KRAS-driven LUAD and chemotherapy remains the standard of care. Small-molecule inhibitors of the MAPK pathway, one of the prominent downstream KRAS mediators, show minimal clinical activity either as single agents or in combination with chemotherapy. Recently, wild-type KRAS (KRAS[WT]) was shown to enhance tumor fitness in KRAS mutant AML and CRC cell lines while concomitantly increasing sensitivity to MEK inhibition. We hypothesized that dimerization between KRAS proteins could be a key regulator for lung adenocarcinoma biology and determinant of treatment response.
Method:
To study the role of wild-type KRAS in the context of KRAS-driven cancer cells, we used genetically inducible models of KRAS loss of heterozigosity (LOH). We developed an isogenic KRAS[MUT] inducible system that lacks endogenous HRas/NRas but harbors conditional CRE[ERT2]-controlled KRas[lox] alleles. Furthermore, we reconstituted KRAS[WT] and dimerization-deficient KRAS[D154Q] in KRAS-driven murine and human LUAD cell lines lacking the wild-type KRAS allele and evaluated the in vitro and in vivo impact on tumor progression and response to MEK inhibition.
Result:
KRAS[WT] decreased in vitro and in vivo fitness of human and murine KRAS mutant LUAD tumor cells. However, this phenotype was reverted upon MEK inhibition, with KRAS LOH cells being more sensitive than KRAS[WT ]expressing cells. Interestingly, both effects were dependent on wild-type/mutant KRAS dimerization and not observed with the dimerization-deficient KRAS[D154Q]. We provide a mechanistic model of the ambivalent function of KRAS[WT], linking its tumor suppressor function with increased MEK inhibitor resistance through dimerization with mutant KRAS.
Conclusion:
• KRAS[WT] affects cellular fitness in KRAS-driven LUAD • KRAS[WT] impairs response to MEK inhibitors in KRAS-driven LUAD • KRAS[WT] inhibitory effect is dependent on dimerization with mutant KRAS • Impaired wild-type/mutant KRAS dimerization restores sensitivity to MEK inhibitors in vivo
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-012 - Phase 1 Study of the AXL Inhibitor DS-1205c in Combination with Osimertinib in Subjects with Metastatic or Unresectable EGFR-Mutant NSCLC (ID 10172)
09:30 - 09:30 | Presenting Author(s): Pasi A Jänne
- Abstract
Background:
In patients with metastatic EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), resistance to EGFR tyrosine kinase inhibition arises from the T790M EGFR mutation in over half of cases; up-regulation of “bypass track” activity in non-EGFR signaling pathways is observed in other cases. Up-regulation of expression of the AXL tyrosine kinase has been observed in EGFRm NSCLC patients experiencing disease progression on erlotinib, and xenograft studies have explored the role of AXL inhibition in combination with EGFR TKI treatment in overcoming such resistance. DS-1205c is a novel, orally administered, specific small molecule inhibitor of AXL.
Method:
Trial Design: This is a multicenter, open-label, Phase 1 study of DS-1205c in combination with osimertinib in metastatic or unresectable EGFR-mutant NSCLC subjects experiencing disease progression during treatment with erlotinib, gefitinib, or afatinib, and without T790M resistance mutation. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, or afatinib, have at least one measurable lesion per RECIST v1.1, do not have spinal cord compression or clinically active brain metastases, and do not have any factors that increase the risk of QTc prolongation. This study includes two parts: Dose Escalation and Dose Expansion. In Dose Escalation, subjects receive DS-1205c during a run-in period, followed by continuous combination treatment with DS-1205c and osimertinib. Escalation of DS-1205c dosing between subjects is determined from dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model (BLRM) following the escalation with overdose control (EWOC) principle. In Dose Expansion, subjects receive DS-1205c at the recommended dose for expansion determined in Dose Escalation, in combination with osimertinib. Primary objectives are to determine the safety, tolerability, and recommended dose for expansion of DS-1205c in combination with osimertinib. Secondary objectives are to assess the pharmacokinetic parameters of DS-1205a (free form of DS-1205c), osimertinib, and osimertinib active metabolites, and to assess antitumor activity (RECIST v1.1).Clinicaltrials.gov identifier: NCT03255083
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.04-013 - Phase 1 Study of the Anti-HER3 Antibody Drug Conjugate U3-1402 in Metastatic or Unresectable EGFR-Mutant NSCLC (ID 10206)
09:30 - 09:30 | Presenting Author(s): Pasi A Jänne
- Abstract
Background:
While the treatment of EGFR-mutant NSCLC has significantly improved with the use of EGFR tyrosine kinase inhibitors, there remain limited treatment options for many patients who develop resistance to these agents. The HER3/ERBB3 oncogene is overexpressed in many cancers, including NSCLC, and higher expression is correlated with poorer outcomes. U3-1402 is a novel antibody-drug conjugate (ADC) comprised of a recombinant fully human anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan. After U3-1402 binds to HER3 on the tumor cell surface, it is internalized and leads to apoptosis via inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody ratio of ~8:1.
Method:
Trial Design: This is a multicenter, open-label Phase 1 study of U3-1402 in metastatic or unresectable non-squamous NSCLC subjects harboring EGFR-activating mutation who (a) are T790M mutation-negative after disease progression during treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while on osimertinib. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib, have at least one measurable lesion per RECIST v1.1, have adequate bone marrow and organ function, do not have LVEF < 45% by either ECHO or MUGA scan, do not have mean QTc prolongation to > 470 ms for females and >450 ms for males, and do not have spinal cord compression or clinically active brain metastases. This study includes two parts: Dose Escalation and Dose Expansion. In Dose Escalation, subjects receive U3-1402 via intravenous infusion in 21-day cycles. In Dose Escalation, escalation of U3-1402 dosing between subjects is based on dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model (BLRM) following the escalation with overdose control (EWOC) principle. In Dose Expansion, subjects receive U3-1402 at the recommended dose for expansion determined in Dose Escalation. Primary objective is to determine the safety, tolerability, and recommended dose for expansion of U3-1402. Secondary objectives are to assess the pharmacokinetic parameters of U3-1402, total anti-HER3 antibody, and MAAA-1181a (drug payload), and to assess antitumor activity of U3-1402 (RECIST v1.1).Clinicaltrials.gov identifier: NCT03260491
Result:
Section not applicable
Conclusion:
Section not applicable
