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Isamu Okamoto
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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: 5
- 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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MS 25.02 - KRAS-Targeted Therapy or Angiogenesis: Still a Viable Target? (ID 7760)
14:50 - 15:10 | Presenting Author(s): Ravi Salgia | Author(s): I. Mambetsariev, I. Amanam, A. Nam
- Abstract
- Presentation
Abstract:
NSCLC is a heterogenous disease withvariable molecular mutations. Vi-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is one of the most common oncogenic drivers, especially in lung cancer, found in around 25-30% adenocarcinomas. The other molecular abnormalities related to RAS pathway are EGFR (10-23%), BRAF (2%), MET (2%), HER2 (1%) and NRAS (0.2%). Within KRAS, the most common mutations are G12C (40%), G12V (21%), G12D (17%), G12A (10%) and other (12%) G12 and G13 mutations [Dogan. Clinical Cancer Research 2012; 18: 6169-6177]. KRAS mutations are associated with poorer outcomes in NSCLC. Renaud et al, showed that KRAS mutant patients had worser outcomes compared to wild type cases[1]. KRAS may be a negative predictor of responsiveness to cytotoxic therapy based off of retrospective data. In addition, Renaud and colleagues have shown that KRAS mutations may be predictive of resistance to radiation therapy. Identifying ways to target these KRAS mutations may lead to benefit for patients in combination with other traditional means of treatment. Directly blocking RAS activity has remained difficult to attain, due to a variety of mechanisms and yet to demonstrate efficacy clinically. Therefore, much more focus has been spent on downstream targets of KRAS. Selumetinib an oral inhibitor of the mitogen-activated protein kinase kinase (MEK) 1/2 had promising phase II results in combination with docetaxel in comparison to docetaxel alone. Unfortunately, in the multicenter Phase III, SELECT-1 trial with 510 patients, PFS and OS were no different in the selumetinib and docetaxel arm versus docetaxel alone. This may be in part due to an increase in RAF-depedent MEK phosphorylation that may interfere with its efficacy. Combining inhibitors that target different components or parallel pathways have yielded success in other tumors like melanoma with combination MEK and BRAF inhibition. For KRAS mutant tumors, the PI3K-AKT- mTOR pathway has also been examined as it has been thought it can bypass resistance to MEK inhibition. The combination of MEK in addition to PI3K-aKT-mTOR has yet to yield any clinically impactful results. Inhibtion of the cysteine residue on KRAS G12C, which makes up more than 40% of KRAS mutants, has been shown to have some activity preclinically [2, 3] Our preliminary data shows that, KRAS is frequently associated with co-occuring mutations. The most common of these were TP53 (n=15, 25%), ATM (n=9, 15%), LRP1B (n=9, 15%), ARID1A (n=8, 13%), STK11 (n=8, 13%), ARID1B (n=7, 12%), TERT (n=7, 12%), EGFR (n=6, 10%), RBM10 (n=6, 10%), SPTA1 (n=6, 10%). We still are not clear on the role of co-mutations and their specific function as sensitizers or agents resistance. It was previously shown that KRAS plus TP-53 mutations had impaired response to docetaxel monotherapy. The addition of selumetinib provided substantial benefit in mice models [4]. Also, STK11 mutations in conjunction with KRAS mutant NSCLC has been shown to infer resistance to PD-1/PDL-1 blockade [5]. Lung cancer frequently exhibits upregulation of angiogenesis and has been reported to be associated with a negative prognostic factor. Over the past decade, novel insights into the role of angiogenesis in NSCLC tumor growth and progression have provided a rationale for the development of anti-angiogenic agents. The use of anti-angiogenic agents to treat NSCLC gained clinical interest in 2006, when the results of the Eastern Cooperative Oncology Group (ECOG) Trial 4599 were published in the New England Journal of Medicine and showed for the first-time improved overall survival(OS) and progression-free survival after the addition of bevacizumab (Avastin, Genentech), a humanized monoclonal antibody that inhibits the process of angiogenesis by binding to the vascular endothelial growth factor A (VEGF-A) protein, to treatment with carboplatin and paclitaxel in 878 patients who had recurrent or advanced NSCLC [6]. Since then, no other anti-angiogenic agent (such as sunitinib, sorafenib, etc.) has been able to demonstrate improved OS for patients with lung cancer. This may be in part because the mechanisms of actions for those drugs is completely different from bevacizumab; they work by inhibiting the internal tyrosine kinase domain of the VEGF receptor and are also not completely selective for the VEGF receptor and also hit other targets (such as PDGF, FGFR, etc.) [6]. This may play a role in the increased toxicity for these inhibitors and the subsequent lower OS. Since the recent positive data showing benefit of first-line carboplatin, pemetrexed, and pembrolizumab may lead to expedited FDA approval, the utility of anti-angiogenic drugs may enter a renaissance as a second-line therapeutic option. However, another consideration has to be made in the pursuit of improved anti-angiogenic drugs where the clinical and financial “value” for the patient are factored in clinical decision making. Though the VEGF/VEGFR pathway is seen as a crucial mediator of tumor survival and growth, the treatments currently available are overshadowed by excessive costs and several cost-effective analyses of bevacizumab have shown that the use of the drug can cost up to 350,000 per life-year gained [7]. References 1. Renaud, S., P.-E. Falcoz, M. Schaeffer, et al., Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases. Br J Cancer, 2015. 113(8): p. 1206-1215. 2. Ostrem, J.M., U. Peters, M.L. Sos, J.A. Wells, and K.M. Shokat, K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013. 503(7477): p. 548-51. 3. Patricelli, M.P., M.R. Janes, L.S. Li, et al., Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discov, 2016. 6(3): p. 316-29. 4. Chen, Z., K. Cheng, Z. Walton, et al., A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature, 2012. 483(7391): p. 613-617. 5. Skoulidis, F., M.D. Hellmann, M.M. Awad, et al., STK11/LKB1 co-mutations to predict for de novo resistance to PD-1/PD-L1 axis blockade in KRAS-mutant lung adenocarcinoma, 2017, American Society of Clinical Oncology. 6. Socinski, M.A., ANGIOGENESIS INHIBITION FOR THE TREATMENT OF NON–SMALL CELL LUNG CANCER. CLINICAL ADVANCES IN HEMATOLOGY AND ONCOLOGY, 2016. 14(5): p. 336-338. 7. Goulart, B. and S. Ramsey, A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer. Value Health, 2011. 14(6): p. 836-45.
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MS 25.03 - MET-Related Molecular Targets (ID 7761)
15:10 - 15:30 | Presenting Author(s): Alexander Drilon
- Abstract
- Presentation
Abstract:
MET activation in non-small cell lung cancers (NSCLCs) can occur via mechanisms including mutation and amplification. MET exon 14 splicing alterations and MET amplification are clinically actionable genomic alterations. Response to MET-directed targeted therapy has been reported for both subsets. In a phase 1 study of crizotinib for patients with MET exon 14-altered NSCLCs, the overall response rate (ORR) was 39% and the median progression-free survival was 8 months (Drilon et al, ASCO 2016). In the same phase 1 study, the ORR for crizotinib in patients with MET-amplified NSCLC was 17% and 50% for tumors with a FISH MET/CEP7 ratio of >2.2 to <5 and ≥5, respectively (Camidge et al, ASCO 2014). Furthermore, acquired MET amplification is associated with resistance to EGFR tyrosine kinase inhibition in EGFR-mutant lung cancers. Response to combined EGFR- and MET-directed therapy has been reported in patients with EGFR-mutant lung cancers with acquired resistance to prior EGFR tyrosine kinase inhibitor therapy. Prospective clinical trials of various MET inhibitors as single-agents or in combination with other therapies are ongoing. A number of different MET inhibitors have been tested in the clinic, including multikinase inhibitors with activity against MET such as crizotinib and cabozantinib, MET-selective inhibitors such as capmatinib, and MET antibodies such as onartuzumab and embituzumab. Newer agents such as MET antibody-drug conjugates are being explored. Data on acquired resistance to MET-directed targeted therapy has begun to emerge. The MET D1228N and D1228V kinase domain mutations have been identified as acquired mechanisms of resistance to MET tyrosine kinase inhibition (Heist et al, J Thoracic Oncol 2016; Bachall et al, Cancer Discov 2017)). The detection of MET mutation and amplification in the clinic is thus important, but is associated with specific challenges, and requires a comprehensive approach to testing. Notably, molecular profiling should not be restricted to the classic population of younger, never or former light cigarette smoker patients with advanced lung adenocarcinomas where other drivers such as sensitizing EGFR mutations and ALK or ROS1 rearrangements are enriched; MET exon 14 alterations, for example, are found in older patients with a more substantial prior smoking history, and in sarcomatoid carcinomas of the lung. The role of MET immunohistochemistry in selecting patients for MET-directed targeted therapy in the absence of comprehensive molecular profiling remains controversial, although the experience with this approach in prior prospective clinical trials has been disappointing. Advances have clearly been made in the development of MET-directed targeted therapy for subsets of patients with advanced NSCLCs that are hopefully moving the field closer to the regulatory approval of one or more these agents in the future.
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MS 25.04 - FGFR-Related Novel Molecular Targets (ID 7762)
15:30 - 15:50 | Presenting Author(s): Kazuto Nishio
- Abstract
- Presentation
Abstract:
Aberrant activation of fibroblast growth factor (FGF) signaling due to up-regulation of FGF receptor gene (FGFR) expression, alternative splicing of FGFR transcripts, FGFR mutations or translocations, or increased availability of FGF has been found to contribute to prognosis in several types of tumors(1, 2). Our previous evidence suggest that these gene alterations increase the sensitivity to multi-kinase inhibitors (3, 4, 5). FGFR gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in preclinical and clinical studies for non-small cell lung cancer and other solid tumors (6,7,8). We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy. 1) Mizukami T, et al. Mol Carcinog. 2017;56(1):106-117. 2) Matsumoto K, et al. Br J Cancer. 2012;106(4):727-32. 3) Arao T, et al. Hepatology. 2013;57(4):1407-15. 4) Sakai K, et al. Oncotarget. 2015;6(25):21636-44. 5) Kaibori M, et al. Oncotarget. 2016; 7(31):49091-49098. 6) Kudo K, et al. Clin Cancer Res. 2011; 17(6):1373-81. 7) Okamoto I, et al. Mol Cancer Ther. 2010; 9(10):2825-33. 8) M. Takeda K. et al. Ann Oncol. 2016; 27(4): 748–750.
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MS 25.05 - Novel Fusions (ID 7763)
15:50 - 16:10 | Presenting Author(s): Robert C. Doebele
- Abstract
- Presentation
Abstract:
Chromosomal rearrangements or deletions can generate novel gene fusions that lead to the expression of chimeric proteins with oncogenic activity in lung and other cancers. The paradigm for gene fusions in lung cancer is the EML4-ALK gene fusion which is found in approximately 5% of lung adenocarcinomas.[1] Once identified, drug development for this target proceeded rapidly and crizotinib was the first approved tyrosine kinase inhibitor for patients with ALK+ non-small cell lung cancer based on its ability to generate substation objective response rates and prolonged progression free survival (NSCLC).[3,4 ]The development of CNS penetrant and/or next generation ROS1 inhibitors including lorlatinib, entrectinib and TPX-0005 is ongoing. RET gene fusions are also found in 1-2% of NSCLC, but the use of multiple different RET inhibitors have failed to reproduce the success of targeting ALK or ROS1 fusions.[5 ]The development of more selective RET inhibitors such as LOXO-292, BLU-667, and RXDX-105 are currently in clinical trials for RET+ lung and other cancers. NTRK1 fusions were recently identified in NSCLC and homologous NTRK2 and NTRK3 fusions are found in multiple tumor types.[6,7, ]Early clinical trials of larotrectinib showed an impressive objective response rate of 76% for 12 different tumor histologies harboring NTRK1/2/3 fusions and the CNS-penetrant entrectinib is similarly being evaluated in a basket trial. Other rare, novel fusions have recently been identified in NSCLC including EGFR fusions or MET fusions.[7] Early evidence suggests that these fusions may also respond to cognate TKIs. EGFR fusions break the paradigm of ALK and ROS1 fusions in which the 5’ end of ALK or ROS1 is replaced with the 5’ portion of another gene. EGFR fusions retain most of the EGFR gene, with the unrelated gene sequencing fusing at the 3’ end of EGFR. A related oncogenic EGFR mutation in which the kinase domain of EGFR is duplicated in tandem has also been described and appears responsive to EGFR TKIs.[7] Additional fusions involving the receptor tyrosine kinase (RTK) encoding genes AXL, PDGFRA, and ERBB4 fusions have been described, but little is known about the true incidence in lung cancer.[8,9] The fusions described thus far all involve genes that encode RTKs, but additional gene fusions have also been identified in lung cancer including BRAF fusions.[7,9 ]BRAF fusions replace the 5’ region of BRAF, including the Ras-binding domain (RBD), with sequences from another gene. Anecdotal evidence suggest that these alterations may be responsive to MEK inhibition. Analogous splice alteration which remove a region including the RBD have also been described in cancer and are oncogenic. Finally, gene fusions involving NRG1, which encodes the HER3/4 ligand neuregulin-1, have been described, mostly in invasive mucinous adenocarcinomas of the lung.[9,10 ]Several challenges exist to the development of targeted therapies for these novel fusions. Even in the era of next-generation sequencing tests these alterations may go undetected due to limited testing of genes to those with approved therapies (ALK, ROS1, EGFR, and BRAF) and not all assays are designed to detect all of these alterations. Furthermore, the rarity of some of these alterations may make clinical trials for these novel fusions less appealing, although amalgamating some of these alterations with analogous mutations, e.g., MET gene fusions with MET exon 14 splice alterations or MET gene amplification, may allow for a more rapid path to approval. References 1. Chia PL, Mitchell P, Dobrovic A, et al: Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin Epidemiol 6:423-32, 2014 2. Camidge DR, Bang YJ, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. The lancet oncology 13:1011-9, 2012 3. Davies KD, Le AT, Theodoro MF, et al: Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 18:4570-9, 2012 4. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963-71, 2014 5. Gautschi O, Milia J, Filleron T, et al: Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry. J Clin Oncol 35:1403-1410, 2017 6. Vaishnavi A, Capelletti M, Le AT, et al: Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nature medicine 19:1469-72, 2013 7. Stransky N, Cerami E, Schalm S, et al: The landscape of kinase fusions in cancer. Nat Commun 5:4846, 2014 8. Seo JS, Ju YS, Lee WC, et al: The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22:2109-19, 2012 9. Nakaoku T, Tsuta K, Ichikawa H, et al: Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res 20:3087-93, 2014 10. Fernandez-Cuesta L, Plenker D, Osada H, et al: CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4:415-22, 2014
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Author of
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.02 - Osimertinib vs SoC EGFR-TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC (FLAURA): Plasma ctDNA Analysis (ID 8978)
15:55 - 16:05 | Author(s): Isamu Okamoto
- Abstract
- Presentation
Background:
FLAURA (NCT02296125) is a Phase III, double-blind, randomized study assessing efficacy and safety of osimertinib vs standard of care (SoC) EGFR-TKI as first-line treatment for patients with EGFRm advanced NSCLC. Concordance between tissue and plasma testing for EGFRm (Ex19del/L858R), and progression-free survival (PFS) by baseline plasma EGFRm status were evaluated.
Method:
Eligible patients: ≥18 years (Japan ≥20 years); Ex19del/L858R mutation-positive lung adenocarcinoma; no prior systemic anti-cancer/EGFR-TKI therapy for advanced NSCLC. Randomization: 1:1 to osimertinib 80 mg once daily (qd) orally (po) or SoC (gefitinib 250 mg or erlotinib 150 mg, qd po). At baseline, patients provided tumor tissue samples for central analysis of EGFRm status (cobas EGFR Mutation Test) and blood samples for retrospective analysis of EGFRm status by plasma ctDNA (cobas EGFR Mutation Test v2). PFS by baseline plasma EGFRm status was assessed. Comparison of EGFRm status between baseline tumor tissue and evaluable ctDNA samples was an exploratory endpoint.
Result:
Globally, 556 patients were randomized: osimertinib, n=279; SoC, n=277. Good concordance was observed between central laboratory tissue and plasma testing for EGFRm in the screened population (see table). In plasma EGFRm-positive patients (n=359), osimertinib (n=183) reduced the risk of progression or death by 56% vs SoC (n=176), hazard ratio (HR) 0.44 (95% CI 0.34, 0.57). This was consistent with the overall PFS result observed with osimertinib vs SoC in the full analysis set (FAS; tumor tissue EGFRm-positive by local/central testing), HR 0.46 (95% CI 0.37, 0.57); p<0.0001 and in plasma EGFRm-negative patients (n=124: osimertinib, n=60; SoC, n=64), HR 0.48 (95% CI 0.28, 0.80).Figure 1
Conclusion:
In the subgroup of plasma EGFRm-positive patients, clinical benefit of osimertinib was superior to SoC, consistent with the overall FLAURA FAS. These results, and good concordance between tissue and plasma testing for EGFRm, support the utility of plasma EGFRm testing for selecting patients eligible for first-line osimertinib treatment.
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-004 - Alectinib for Patients with ALK Rearrangement–Positive Non–Small Cell Lung Cancer and a Poor Performance Status (ID 8115)
09:30 - 09:30 | Author(s): Isamu Okamoto
- Abstract
Background:
Alectinib is a potent and highly selective inhibitor of the tyrosine kinase ALK and has shown marked efficacy and safety in patients with ALK rearrangement–positive non–small cell lung cancer (NSCLC) and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS.
Method:
Eligible patients with advanced ALK rearrangement–positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement. Plasma concentrations of alectinib were measured by liquid chromatography-mass spectrometry (LC-MS/MS).
Result:
Between September 2014 and December 2015, 18 patients were enrolled in this phase II study (Lung Oncology Group in Kyushu 1401). Twelve, five, and one patients had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The median follow-up time for all patients was 9.8 months (range, 5.6 to 18.0 months) at the time of the primary analysis. The ORR was 72.2% (90% confidence interval [CI], 52.9–85.8%), and the disease control rate was 77.8% (90% CI, 58.7–89.6%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of ≥3 (58.8% and 100%, respectively, P = 0.114). The PS improvement rate was 83.3% (90% CI, 64.8–93.1%, P < 0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression-free survival (PFS) was 10.1 months (95% CI, 7.1 to17.8 months), with no difference between the patients with a PS of 2 and those with a PS of ≥3 (median PFS, 10.1 and 17.8 months, respectively, P = 0.24). Toxicity was mild, with the frequency of adverse events of grade ≥3 being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary. The trough concentration of alectinib in plasma was 235 ± 65 ng/mL (mean ± SD), which is slightly lower than that previously reported in patients with a good PS, supporting the tolerability of alectinib administration in those with a poor PS.
Conclusion:
Alectinib is a treatment option for patients with ALK rearrangement–positive NSCLC and a poor PS. Updated data and that for overall survival will be available at presentation.
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-014 - Association of Preoperative Serum CRP with PD-L1 Expression in NSCLC: A Comprehensive Analysis of Systemic Inflammatory Markers (ID 8909)
09:30 - 09:30 | Author(s): Isamu Okamoto
- Abstract
Background:
Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio.
Method:
We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression.
Result:
Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P=0.0336, 0.0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P=0.0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P<0.0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P<0.0001).
Conclusion:
Our results indicate that among all systemic inflammatory markers examined, serum CRP level could be a helpful biomarker for PD-L1 expression that is easily determined and available worldwide.
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P1.08 - Locally Advanced NSCLC (ID 694)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.08-006 - Phase I/II Study of Carboplatin, nab-paclitaxel, and Concurrent Radiation Therapy for Patients with Locally Advanced NSCLC. (ID 8356)
09:30 - 09:30 | Author(s): Isamu Okamoto
- Abstract
Background:
A regimen of weekly paclitaxel plus carboplatin (CBDCA) with concurrent thoracic radiotherapy is recognized as standard for patients with unresectable stage III lung cancer. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a cremophor-free formulation of paclitaxel to increase solubility and intratumor drug delivery and is effective for patients with advanced NSCLC. The purpose of this study is to determine recommended dose and investigate the efficacy and safety profile of a regimen of nab-PTX plus CBDCA with concurrent thoracic radiotherapy for patients with unresectable non-small cell lung cancer (NSCLC).
Method:
Patients with unresectable stage IIIA or IIIB NSCLC, good performance status, age between 20 and 74 years, and adequate organ function, a relative volume of normal lung receiving a dose of ≥ 20 Gy (V20) ≤35% were eligible. In a phase I study (standard 3+3 design), weekly nab-PTX plus CBDCA was administered intraveneously for six weeks. Doses of each drug were planned as follows: level 1, 40/2; level 2, 50/2 (nab-PTX [mg/m[2]] / CBDCA [area under the plasma concentration time curve (AUC) mg/ml/min]). Concurrent thoracic radiotherapy was administered in 2 Gy fractions to a total dose of 60 Gy. Dose-limiting toxicity (DLT) was observed during concurrent chemotherapy and thoracic radiation and up to 28 days following the end of radiotherapy. After the evaluation of DLT, patients received an additional two cycles of consolidation chemotherapy that consisted of 3-week cycles of nab-PTX (100 mg/m[2] on Days 1, 8 and 15) plus CBDCA (AUC 6 mg/ml/min on Day 1). In a phase II study, we planned to enroll 50 patients treated with recommended dose.
Result:
In a Phase I study, 11 patients were enrolled and received treatment per protocol, with 9 evaluable for efficacy and toxicity. At nab-PTX dose level 1 (40mg/m[2]), none of 3 patients experienced DLT. At nab-PTX dose level 2 (50mg/m[2]), 1 of 6 patients experienced DLT: grade 3 leukopenia requiring a second consecutive skip in the administration of weekly nab-PTX plus CBDCA. The recommended doses (RDs) for the phase II study were nab-paclitaxel 50 mg/m[2] and CBDCA (AUC=2). From October 2015 to November 2016, a total of 52 patients were entered in the phase II portion ( median age, 66 years; age range, 48–74 years; male/female 44/8) .
Conclusion:
Concurrent chemoradiotherapy with nab-PTX 50 mg/m[2] and CBDCA AUC 2 was the recommended dose. We will report the latest efficacy and safety profile of the present therapy. Trial registration: UMIN000012719.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-045 - Updated Results of Phase II, Liquid Biopsy Study in EGFR Mutated NSCLC Patients Treated with Afatinib (WJOG 8114LTR) (ID 9715)
09:30 - 09:30 | Author(s): Isamu Okamoto
- Abstract
Background:
Liquid biopsy has been approved as an optional method to detect clinically relevant EGFR mutations in NSCLC. WJOG8114LTR is a prospective, multi-institutional study of liquid biopsy in EGFR mutated NSCLC patients. Previously, we reported that complete molecular response at 4 weeks could be an early surrogate marker of durable efficacy. Here, we report updated results.
Method:
Chemotherapy naïve, advanced NSCLC patients with EGFR-sensitizing mutation received afatinib monotherapy (40 mg/body) until progressive disease (PD) or unacceptable toxicity. Plasma DNA was obtained from patients at baseline, weeks 2, 4, 8, 12, 24, 48, and at PD. Three types of clinically relevant EGFR mutations (exon 19 deletion, exon 20 T790M and exon 21 L858R) will be analyzed using plasma DNA with multiplexed, pico-droplet digital PCR assay (RainDrop® system, RainDance Technologies, Billerica, MA). Complete molecular response (CMR) was defined as mutant allele event/frequency of exon 19 deletion or exon 21 L858R below the cutoff for the positivity by digital PCR in plasma. This study was registered at UMIN (ID: 000015847).
Result:
Fifty-seven patients were registered in the study. Efficacy of afatinib was comparable to previous reports (overall response rate: 78.6%, and median progression-free survival (mPFS): 14.2 months). At baseline, 62.5% of patients (35/56) were positive for EGFR mutation in plasma. Among those, CMR rate at 2, 4, 8, 12, 24 weeks was 60.6%, 87.5%, 93.8%, 87.1%, and 83.3%, respectively. About 40% of patients who achieved CMR at any time point maintain CMR at 48 weeks and had durable progression-free survival (more than 400 days). At the time of analysis, 17 patients experienced disease progression, and 14 plasma samples were collected. Of those, 8 (57.1%) were positive for mutation in plasma. In five patients, plasma progression was observed prior to radiological progression. Exon 20 T790M was detected in five patients (detection rate: 62.5%).
Conclusion:
Among EGFR mutated NSCLC patients, liquid biopsy was a useful method to predict durable efficacy and progression. Applicability of liquid biopsy should be explored in further study.
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P2.15 - SCLC/Neuroendocrine Tumors (ID 716)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.15-004 - Underrepresentation of Elderly Patients with ED-SCLC as Clinical Trial Candidates (JCOG1201/TORG1528) (ID 8837)
09:30 - 09:30 | Author(s): Isamu Okamoto
- Abstract
Background:
Since December 2013, we initiated a phase II/III trial [Japan Clinical Oncology Group (JCOG) 1201/Thoracic Oncology Research Group (TORG) 1528: UMIN000012605] for elderly patients with extensive-disease small-cell lung cancer (ED-SCLC). Aim of the study is to demonstrate that a carboplatin plus irinotecan regimen is superior to carboplatin plus etoposide in elderly patients with ED-SCLC. However, the patient accrual rate did not satisfactorily match our expectations a year from the time of initiation of our study. To define factors related to low accrual, we searched institutional records and analyzed.
Method:
We collected data of elderly patients with ED-SCLC from each institution and investigated the total number of elderly patients with ED-SCLC, number of patients eligible/ineligible for the study, numbers of patients registered for the study, and the reasons for non-registration of even eligible patients. Doctor-reported questionnaires concerning elderly (≥71 years old) ED-SCLC patients diagnosed in their institutions were sent to chief or coordinate doctors at each institution in December 2014.
Result:
We received a response from 32 (84%) of 38 institutions. Approximately 260 patients were diagnosed as elderly patients with ED-SCLC in the last year. Only 100 patients (38%) were eligible for the JCOG 1201/TORG1528 trial. Reasons for ineligibility primarily included poor performance status (PS) (25%), low organ functions (25%), interstitial pneumonitis (19%) and double cancer (18%). Only 23 patients among the 100 eligible candidates accrued to the study. The primary reasons for non-accrual were delayed approval from the Institutional Review Board (IRB) of the individual institution (24%), physician preferences (23%), patient refusal (18%), and registration for other trials (12%).
Conclusion:
Our data demonstrated that 62% of ED-SCLC patients were ineligible for the protocol due to frailty with the most frequent reason being comorbidities such as poor PS and low organ functions. However, inactive institutions need to increase their efforts to register a greater number of eligible patients in addition to obtaining quicker IRB approval of protocol. Based on responses to questionnaires sent out as part of our investigation, in January 2016, the protocol was revised in terms of eligibility criteria to enhance patient accrual. Eligibility criteria for participation of elderly patients with ED-SCLC need to be formulated prudently so that patients are benefitted in routine clinical practice.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-075 - Afatinib Dose Adjustment: Effect on Safety, Efficacy and Patient-Reported Outcomes in the LUX-Lung 3/6 Trials in EGFRm+ NSCLC (ID 9365)
09:30 - 09:30 | Author(s): Isamu Okamoto
- Abstract
Background:
Afatinib 40mg/day is approved globally for first-line treatment of EGFR mutation-positive (EGFRm+) NSCLC. Afatinib is available in several tablet strengths (20/30/40/50mg), and tolerability-guided dose adjustment schemes are well established. Here, we evaluate the impact of afatinib dose reduction on safety (AEs), pharmacokinetics, PFS and patient-reported outcomes (PROs) in the Phase III LUX-Lung (LL) 3 and 6 trials.
Method:
Treatment-naïve patients with stage IIIB/IV EGFRm+ NSCLC in LL3/6 received either 40mg/day afatinib or chemotherapy. In case of any treatment-related grade ≥3 AEs or selected prolonged grade 2 AEs, afatinib dose was reduced by 10mg decrements (minimum dose 20mg/day). In this post-hoc analysis of all afatinib-treated patients in LL3/6 (n=229/n=239), we compared incidence and severity of common AEs before and after dose reduction, afatinib plasma concentrations in patients who reduced to 30mg versus those remaining on 40mg, and PFS in patients with/without dose reductions in the first 6 months of treatment. PROs were measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and the EQ-5D™ health status self-assessment questionnaire, and pooled data from both trials were assessed before/after dose reduction; these included scores on the EORTC Global Health/Quality of Life scale (GH/QoL; 0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
Dose reductions occurred in 122/229 (53.3%) patients in LL3 and 67/239 (28.0%) in LL6; >80% of dose reductions occurred in the first 6 months of treatment. Dose reductions decreased the incidence of treatment-related AEs (grade ≥3 AEs before/after dose reduction: LL3, 73%/20%; LL6, 81%/12%), and were more likely among patients who had higher afatinib plasma concentrations prior to subsequent dose reduction (Day 22). On Day 43, geometric mean afatinib plasma concentrations were comparable between patients who had dose reduced (n=59; 23.3ng/mL) and patients who remained on 40mg (n=284; 22.8ng/mL). Median PFS was comparable between patients with or without dose reductions in the first 6 months (LL3: 11.3 versus 11.0 months; HR [95% CI] 1.25 [0.91–1.72]; p=0.175; LL6: 12.3 versus 11.0 months; 1.00 [0.69–1.46]; p=0.982). There were no clinically meaningful changes in PROs following afatinib dose reduction: GH (40/30mg: 59.1/66.9; n=136); PF (79.4/83.0; n=136); EQ VAS (70.1/75.1; n=135); EQ UK utility (0.70/0.78; n=135).
Conclusion:
Tolerability-guided dose adjustments effectively reduced afatinib-related AEs without negatively affecting therapeutic efficacy and PROs.
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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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P3.04-002 - A Randomized Phase II Study of Carboplatin plus Nab-Paclitaxel with or Without Nintedanib for NSCLC with IPF (J-SONIC): Trial in Progress (ID 9627)
09:30 - 09:30 | Author(s): Isamu Okamoto
- Abstract
Background:
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by worsening dyspnea and progressive loss of lung function. Acute exacerbation of IPF is associated with high morbidity and mortality. Several studies have provided evidence of an association between lung cancer and IPF, with a prevalence of lung cancer in IPF patients ranging from 9.8% to 38%. Although the efficacy of nintedanib for IPF has been demonstrated, it has remained unknown whether this agent also reduces the risk of chemotherapy-induced acute exacerbation of IPF. Patients with interstitial pneumonia have been excluded from most prospective clinical trials for NSCLC because of the risk of acute exacerbation, with only two prospective single-arm phase II studies having been reported. In addition, it has been difficult to perform a randomized prospective clinical trial for patients with advanced NSCLC and IPF because of their rarity. The optimal chemotherapy regimen for advanced NSCLC with IPF has thus remained unclear.
Method:
Chemotherapy-naïve patients with advanced NSCLC associated with IPF (enrollment target of n = 170) are randomized at a 1:1 ratio to receive four cycles of carboplatin (AUC 6 on day 1) plus nab-paclitaxel (100 mg/m[2] on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg b.i.d., daily), to be followed in arm B by single-agent administration of nintedanib (150 mg b.i.d., daily). The primary end point of the study is time to acute exacerbation of IPF.Figure 1
Result:
Section not applicable
Conclusion:
J-SONIC is the first randomized controlled study for treatment of NSCLC associated with IPF. The goal of the study is to demonstrate that nintedanib in combination with carboplatin plus nab-paclitaxel prolongs time to acute exacerbation of IPF compared with carboplatin plus nab-paclitaxel alone. Study enrollment began in May 2017 and is to continue for 3 years.
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P3.04-004 - Treatment Rationale and Study Design for the TAKUMI Trial (ID 9691)
09:30 - 09:30 | Author(s): Isamu Okamoto
- Abstract
Background:
50%-60% of patients after the first-generation EGFR-TKI, gefitinib and erlotinib showed acquired resistance of T790M mutation and osimertinib is a standard regimen for this population. However, the median PFS by osimertinib alone is 8-10M and a better strategy is needed. One promising option is a combination of osimertinib and chemotherapy, and previous trials have suggested the promising efficacy by the combined treatment of EGFR-TKI with pemetrexed. We here present the treatment rationale and study design of TAKUMI trial, a multicenter randomized phase Ⅱ study of of osimertinib (Tagrisso) alone versus osimertinib plus carboplatin/pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed with previous epidermal growth factor receptor tyrosine kinase inhibitor therapy and whose tumours harbour a T790M mutatIon within the epidermal growth factor receptor gene.
Method:
Figure 1schema of this study
Result:
Section not applicable
Conclusion:
Section not applicable
