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Nobuyuki Yamamoto
Moderator of
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 12
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.01 - A Phase Ib Study of the Combination of Afatinib and Ruxolitinib in EGFR Mutant NSCLC Progressed on EGFR-TKI: An Updated Analysis (ID 9021)
11:00 - 12:30 | Presenting Author(s): Ji Soo Park | Author(s): M.H. Hong, Byoung Chul Cho, Hye Ryun Kim
- Abstract
- Presentation
Background:
T790M mutation of EGFR exon 20 is observed in approximately 50% of the non-small cell lung cancer (NSCLC) patients progressed on EGFR tyrosine kinase inhibitors (TKIs). Based on a preclinical study demonstrating that pharmacologic JAK1 inhibition increased the anti-tumor activity of afatinib in T790M-positive NSCLC cell lines, we conducted a phase Ib study to evaluate the safety and efficacy of the combination of afatinib and ruxolitinib, a selective JAK inhibitor, in NSCLC patients who had progressed on EGFR-TKIs.
Method:
We used the classical 3+3 design for dose-escalation cohort (DAC). Patients with histologically diagnosed, EGFR mutant stage IV NSCLC and documented disease progression on EGFR-TKIs were considered eligible. Afatinib was administered alone once daily from day 1 through day 8 (run-in period), then ruxolitinib was orally administered twice daily concomitantly with afatinib until progression. The primary endpoint was to determine RP2D and DLT. If DLT was not observed in 9 patients at the cohort of the highest level, we planned to decide RP2D and enroll 6 additional patients in the dose-expansion cohort (DEC).
Result:
As of June 14, 2017, 21 patients (12 with exon19 deletion, 9 with exon21 L858R) were enrolled in DAC, 8 of which had T790M mutations. All patients were previously treated with erlotinib (n=6) or gefitinib (n=15), and previously received a median of 2 (range, 1-4) lines of chemotherapy. Because no DLT was observed in the 9 patients at the highest dose level (afatinib 50 mg once daily plus ruxolitinib 25 mg twice daily), 6 patients with T790M mutation were enrolled in the DEC. Frequent AEs included paronychia (G1 in 11 cases, G2 in 2 cases), diarrhea (G1 in 14 cases, G2 in 2 cases, and G3 in 2 cases), acneiform rash (G1 in 13 cases), and oral mucositis (G1 in 7 cases, G2 in 3 cases). SAEs were reported in 6 patients, which were not related to the investigational products. Partial responses were observed in 7 patients (25.9%) with disease control rate (CR+PR+SD) of 96.3%. Median PFS was 5.7 months (95% CI, 4.2-7.2) and 3 patients remain on study.
Conclusion:
The combination of afatinib with ruxolitinib was well tolerated with clinical benefit of disease control in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).
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MA 12.02 - Phase I/II Study of S49076, a MET/AXL/FGFR Inhibitor, Combined with Gefitinib in NSCLC Patients Progressing on EGFR TKI (ID 7974)
11:00 - 12:30 | Presenting Author(s): Gee-Chen Chang | Author(s): G. Curigliano, Wan-Teck Lim, S. Viteri, F. Ciardiello, T. Hida, Chia-Chi Lin, H. Murakami, Makoto Nishio, Luis Paz-Ares, F. Cantero, C. Gabarroca, E. Gandossi, N. Kamsu-Kom, S. Pennaforte, M.-. Secouard-Faure, Keunchil Park
- Abstract
- Presentation
Background:
S49076 is a potent ATP-competitive TKI that targets MET, AXL and FGFR1/2/3 at clinically relevant doses. Preclinical data showed that combination of S49076 with 1[st] generation EGFR-TKI can overcome acquired resistance to EGFR inhibition in a NSCLC EGFR-mutated MET-amplified cell model. Here we report interim phase I data from NSCLC patients treated with S49076 in combination with gefitinib to overcome acquired non-EGFR-T790M-mediated resistance to EGFR TKI (1[st]/2[nd] generation).
Method:
This is a phase I dose-finding study of S49076 combination with a standard dose of gefitinib using a modified Bayesian Continual Reassessment Method with S49076 doses of 500 and 600mg. Both agents are administered orally once daily. The primary objective is to determine the safety profile of the combination and the recommended phase 2 dose (RP2D) based on safety assessments. Patients are selected according to tumor status; they carried an activating-EGFR mutation without secondary T790M mutation and with at least one of the following dysregulations: MET IHC3+, MET FISH 2+/3+, or AXL IHC 2+/3+.
Result:
In June 2017, molecular screening was performed in 48 EGFR/T790M-negative tumor samples to assess MET and AXL dysregulation. 17/48 met the molecular eligibility criteria: 12/17 with MET overexpression/amplification; 4/17 with both MET overexpression/amplification and AXL overexpression; and 1/17 with AXL overexpression. As regards S49076 dose levels, 4 patients were included at 500 mg and 4 at 600 mg. Five patients discontinued treatment: 4 disease progression and 1 consent withdrawal. The most frequent related AEs (≥2 patients) were asthenia (n=5), diarrhea, nausea and paronychia (n=4 each), ASAT/ALAT increase, anemia, and yellow skin (n=3 each), peripheral edema, stomatitis, blood creatinine increase, vomiting, hypoalbuminemia, and decreased appetite (n=2 each); most were grade 1-2. A DLT occurred in 1 patient at 600mg (grade 3 stomatitis). The other severe related AEs included grade 3 ALAT increase, asthenia, and neutrophil count decrease. Concomitant intake of gefitinib did not appear to modify the S49076 PK profile as compared to previous data. The best overall response rate were partial response (PR, 1/8), stable disease (SD, 6/8), and progressive disease (1/8), including 3 patients with PR/SD ≥6 months.
Conclusion:
According to preliminary data, the frequency of MET and AXL dysregulations is consistent with the literature. Combination of S49076 and gefitinib is well tolerated and safety data are consistent with the overall safety profile of each drug. The phase II part of this study will start once the RP2D is defined to evaluate the anti-tumour activity of the combination.
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MA 12.03 - Kinase Fusions as Recurrent Mechanisms of Acquired Resistance in EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC) (ID 10309)
11:00 - 12:30 | Presenting Author(s): Sai-Hong Ignatius Ou | Author(s): S.J. Klempner, B. Creelan, W.S. Hsieh, D. Costin, P.J. Stephens, Jeffrey S. Ross, V.A. Miller, Siraj M Ali, A.B. Schrock
- Abstract
- Presentation
Background:
Resistance invariably develops in EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKI). In approximately 50% of cases, resistance is mediated by the EGFR T790M mutation; however, multiple other mechanisms of resistance have also been described, including case reports of acquired kinase fusions (PMIDs: 26187428, 28089157).
Method:
Hybrid-capture based genomic profiling (FoundationOne® or FoundationACT™) was performed prospectively on DNA isolated from tissue-based FFPE samples or blood-based circulating tumor (ctDNA) samples from NSCLC patients.
Result:
From a dataset of 3,014 unique EGFR-mutated (exon 19 deletion, L858R, G719X, L861Q, or S768I) TKI naïve or relapsed NSCLCs we identified 28 (0.9%) cases with co-occurring likely activating kinase rearrangements (BRAF [12], FGFR3 [5], RET [5], ALK [4], NTRK1 [1], EGFR [1]), including 24 confirmed fusions. Treatment histories were available for 21/28 cases, and prior evidence of EGFR mutation and treatment with an EGFR TKI was evident in 21/21 (100%) cases. In 25/28 cases no other known mechanisms of acquired resistance co-occurred with the primary EGFR mutation and the kinase fusion. The 3 cases with co-occurring known resistance mechanisms (T790M or MET amplification) were those with BRAF rearrangements for which no fusion partner was identified. Additionally, our dataset included 10 paired pre- and post-EGFR TKI treatment samples where the latter sample showed an acquired kinase fusion (4 FGFR3-TACC3, 2 EML4-ALK, 2 CCDC6-RET, 1 AGK-BRAF, 1 TPM3-NTRK1) in addition to the primary EGFR alteration. Notably, in 3/10 paired cases (2 FGFR3 and 1 BRAF) the fusion was acquired in the setting of dropout of an existing T790M mutation.
Conclusion:
Acquired kinase fusions are rare yet recurrent mechanisms of acquired resistance in EGFR-driven NSCLCs, and may be enriched in the setting of resistance to T790M-specific inhibitors. Genomic profiling capable of detecting all classes of genomic alterations, including base substitutions, indels, copy number alterations, and fusions, is warranted at the time of progression on EGFR TKIs, and often provides rationale for treatment in such cases.
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MA 12.04 - Discussant - MA 12.01, MA 12.02, MA 12.03 (ID 10814)
11:00 - 12:30 | Presenting Author(s): Miguel-Angel Molina-Vila
- Abstract
- Presentation
Abstract not provided
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MA 12.05 - Genomic Profiling of EGFR T790M Mutated Non-Small Cell Lung Cancer to Evaluate the Mechanisms of Resistance to Osimertinib (ID 9555)
11:00 - 12:30 | Presenting Author(s): Sonam Puri | Author(s): J.K. Hicks, T.C. Knepper, M. Smith, T.A. Boyle, Jhanelle Elaine Gray
- Abstract
- Presentation
Background:
The T790M mutation in the epidermal growth factor receptor (EGFR) gene altering the kinase domain is the most common mechanism of resistance to first or second-generation EGFR tyrosine kinase inhibitors (TKIs). Osimertinib is currently approved for treatment of metastatic EGFR T790M mutation positive non-small cell lung cancer (NSCLC). However, resistance to osimertinib is an emerging issue. Evaluation of the genomic profiles of patients with EGFR T790M mutated NSCLC treated with osimertinib is necessary to gain an understanding of the potential resistance mechanisms.
Method:
Between January 2014 and June 2017, we retrospectively reviewed DNA profiling data from blood and/or tissue (FoundationONE/ACT, Guardant 360, TruSight panel and/or Pyrosequencing) from patients with advanced NSCLC to identify those with an EGFR T790M mutation. For patients harboring the EGFR T790M mutation, electronic health records were reviewed to identify the clinical variables , outcomes and genotyping at the time of progression on osimertinib. Survival analysis was done using the Kaplan-Meier method (SPSS version 23).
Result:
We identified a total of 433 NSCLC patients who underwent genotypic profiling; EGFR T790M mutation was present in 29 (6.7%) patients. All patients received EGFR-TKIs prior to testing. Patient demographics included: Caucasian (76%), female (76%), adenocarcinoma (100%), never-smokers (52%) with a median age of 65 years and 3 median prior lines of treatment. At the time of identification of the T790M mutations, 27 (93%) patients retained their EGFR exon 19 deletion or exon 21 mutations and 24 (82%) patients received osimertinib. The median overall survival was 4.9 ± 3 months in patients not on osimertinib, and was not reachable in patients on osimertinib in the current follow up period. 7 of the 24 patients had repeat genotyping at the time of progression on osimertinib which revealed presence of acquired secondary mutations including EGFR C797S (43%, N=3), EGFR C797G (14%, N=1), amplifications in EGFR (43%, N=3), ERBB2 (HER2, 28%, N=2) and cell cycle genes (CD-K4, CCND1, CCND2, 28%, N=2), MAPK/ERK pathway alteration (KRAS amplification and Q61R mutation, 28%, N=2), PI3K/AKT/mTOR pathway alteration (ATK3 and PIK3C2B amplification, 14%, N=1) and RET fusion (NCOA4-RET, 14%, N=1).
Conclusion:
There is limited data regarding the mechanisms of resistance to osimertinib. In addition to the acquired mutations in C797S, our study identified several potential pathways for developing resistance to osimertinib including emergence of acquired amplification in EGFR and ERBB2, as well as MAP Kinase and PI3K/AKT pathway aberrations. Updated data will be presented at the meeting.
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MA 12.06 - Using Population Dynamics Mathematical Modeling to Optimize an Intermittent Dosing Regimen for Osimertinib in EGFR-Mutant NSCLC (ID 9110)
11:00 - 12:30 | Presenting Author(s): Xiuning Le | Author(s): S. Chakrabarti, F. Michor, D.B. Costa, Matthew Meyerson
- Abstract
- Presentation
Background:
Acquired resistance to therapy occurs with both first- and newer-generation epidermal growth factor receptor (EGFR) inhibitors. One strategy to delay the emergence of resistance is to use the most active/least toxic inhibitor and replace the traditional daily dosing with a biologically-rational dosing approach. Osimertinib is a covalent mutation-specific EGFR tyrosine kinase inhibitor (TKI) with activity against common EGFR plus EGFR-T790M mutations and less activity against the wild-type receptor. This drug is poised to become a 1[st] line EGFR TKI for treatment-naïve EGFR mutated lung adenocarcinomas. Therefore, it is an ideal candidate to devise rationale dosing schemes to maximize its efficacy and minimize tumor adaptation.
Method:
We explored pulse dosing of osimertinib, to delay the emergence of acquired resistance. We applied population dynamics mathematical modeling to this question, using key parameters (“birth rate” and “death rate”), established through cellular assays. These parameters are presumed to be dose-dependent. First, we experimentally determined the “birth-rates” of PC9 lung cancer cells, PC9 cells bearing the T790M resistance mutation, and PC9 cells that were resistant to osimertinib, with increasing concentrations of osimertinib (0 - 10μM, total of eight doses at half log intervals) using cell viability assays (MTS assay). Next, we determined cellular “death-rates” using annexin V/propidium iodide (PI) fluorescence-activated cell sorting (FACS). We then applied those parameters to our population dynamics model and simulated various treatment conditions with different dosing strategies, to identify the most effective regimens at delaying or preventing the emergence of resistance to osimertinib.
Result:
Using our mathematical model, we predicted that high-dose weekly treatment of osimertinib with a low maintenance dose led to minimal cell proliferation in comparison to daily dosing. Following this in silico prediction of the superiority of pulse dose treatment, we experimentally compared the frequency of emergence of resistance with different treatment dosing regimens, using a long-term cell culture system. Indeed, weekly administration of 5uM osimertinib to PC9 cells, followed by a maintenance dose of 0.25uM, suppressed the emergence of resistance for up to 5-7 weeks in culture.
Conclusion:
We have established a population dynamics mathematical model to predict optimal dosing regimens for osimertinib in treatment-naïve EGFR mutated lung cancers. The model was experimentally validated using a long-term culture system. Future validation in additional preclinical models (cell lines, xenografts and genetically engineered mice) can lead to rationale development of pulse-maintenance clinical trials of osimertinib and eventually establish a novel paradigm for clinical use of EGFR TKIs.
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MA 12.07 - Adjusted Indirect Comparison of Osimertinib to Chemotherapy in NSCLC Patients with EGFRm T790M Who Progressed after EGFR-TKI (ID 8558)
11:00 - 12:30 | Presenting Author(s): Christopher Hoyle | Author(s): F. Andersohn, Tetsuya Mitsudomi, Tony SK Mok, James Chih-Hsin Yang, M. Green, H. Mann
- Abstract
- Presentation
Background:
Osimertinib was granted conditional marketing authorization from the EMA and accelerated approval by the FDA based on single-arm trial (SAT) data. Subsequent full FDA approval was supported by the RCT AURA3 (NCT02151981) and based on superior progression-free survival (PFS) of osimertinib versus platinum-based doublet chemotherapy (PDC) for patients with epidermal growth factor receptor (EGFRm) T790M-positive non-small-cell lung cancer (NSCLC). Accelerated and conditional approval coupled with a large treatment effect led to increased treatment switching post-progression from the control arm to the intervention arm in the RCT as clinicians and patients demanded the new treatment. This will confound analysis of overall survival (OS) benefit in the RCT. Adjusted indirect comparison from other sources can offer a robust analysis of OS without confounding owing to treatment switching and difference in subsequent therapies post-progression.
Method:
Recent SAT data (data cut-off, 1 November 2016) for osimertinib were provided by the AURA (NCT01802632) and AURA2 (NCT02094261) studies (N=405). Data for PDC were provided for a subgroup of the control arm of an RCT, IMPRESS (NCT01544179), which comprised patients with centrally confirmed EGFRm T790M-positive NSCLC whose prior treatment with an EGFRm TKI had failed and were subsequently treated with PDC (N=61). A propensity score (PS) approach was used to adjust for differences in baseline demographics and disease characteristics. Baseline characteristics of both groups were compared using statistical tests.
Result:
Following estimation of PS for each patient and adjustment for heterogeneity across the groups by matching, 288 patients from the osimertinib group and 53 patients from the PDC group were retained for analysis. Osimertinib demonstrated a statistically significant improvement in median PFS of 10.9 months versus 5.3 months for PDC (HR 0.28, 95% CI 0.19 to 0.41, P<0.0001), which was consistent with the gain in PFS from the RCT AURA3 (10.1 months versus 4.4 months; HR 0.30, 95% CI 0.23 to 0.41, P<0.001), and a statistically significant improvement in OS (HR 0.41, 95% CI 0.27 to 0.62, P<0.0001). Median OS for osimertinib was not reached and was 14.1 months for PDC.
Conclusion:
The indirect comparison estimated a statistically significant improvement in PFS and OS with osimertinib compared with PDC. The PFS benefit was consistent with that of the confirmatory RCT. The combined evidence from RCT data and indirect comparisons described may bridge the potential gap and confounding in evidence for OS produced by subsequent treatments after first progression in the RCT.
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MA 12.08 - Discussant - MA 12.05, MA 12.06, MA 12.07 (ID 10815)
11:00 - 12:30 | Presenting Author(s): Dae Ho Lee
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
EGFR TKI therapy has improved lung adenocarcinoma patients’ prognosis tremendously, but almost all of the patients inevitably develop acquired resistance, and EGFR T790M mutation is the major contributors. T790M restores the EGFR tyrosine kinase domain affinity to ATP, and therefore gefitinib is displaced from the binding pocket, and the ‘driving’ signal for proliferation is switched on again. Previous work has shown that after TKI therapy, lung adenocarcinoma patients kept the sensitive mutation and acquired resistance mutation simultaneously by sequencing methods or in vitro cell line experiments. Whether the two different type mutations are in the same cell group or in two different cell groups is unknown. None of them has observed what was happening in the tumor cells after TKI therapy.
Method:
RNA in situ hybridization methods was employed to examined EGFR T790M and L858R mutation in lung adenocarcinoma cancer tissues which was obtained before and after TKI therapy. EGFR expression was examined by immunohistochemistry. EGFR mutation were detected by ARMS PCR methods.
Result:
Twenty five patients were enrolled in this study which were divided into 3 groups. Group 1: 5 patients who had concurrent primary T790M and sensitive EGFR mutation. Group 2: 14 patients who acquired T790M mutation after receiving TKI therapy. Among them, 6 patients had biopsy tissues before and after TKI therapy. 8 patients only own tissues after TKI therapy. Group 3: 6 patients who had sensitive EGFR mutation and received TKI therapy, but re-biopsy tissues didn’t had EGFR T790M. We found that the results of RNA ISH and ARMS PCR methods was identical in the majority of the examined tissues. Only one repeated biopsy tissue didn’t identify EGFR T790M after TKI therapy by PCR in group 3, while the RNA ISH method detected T790M in this tissue which contain only 150 tumor cells. In the serial cut slides, we observed that T790M and L858R mutations were in the same cell group, not only in the primary resistance cases, but also in the acquired resistance cases. For the two cases which had tissues available after receiving third generation TKI therapy, we observed that T790M disappeared in the repeated biopsy specimen, leaving the sensitive mutation which existed from the beginning.
Conclusion:
In the primary and acquired resistance tissues, EGFR sensitive mutation and T790M co-exist in the same cell groups. EGFR sensitive mutation is a trunk and drive mutation, while T790M is a passenger mutation during the treatment process by TKI therapy.
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MA 12.10 - Clinical Utility of Plasma EGFR T790M Mutation Detection in Advanced Non-Small Cell Lung Cancer Patients According to RECIST Criteria (ID 9620)
11:00 - 12:30 | Presenting Author(s): Lourdes Barrera | Author(s): J.R. Borbolla-Escoboza, E. Montes-Servin, E.O. Macedo-Perez, Feliciano Barron, C. Molina Romero, J.M. Hernandez Martinez, Oscar Arrieta
- Abstract
- Presentation
Background:
Circulating tumor DNA (ctDNA) has emerged as a specific and sensitive blood based biomarker for detection of several mutations in non–small cell lung cancer (NSCLC). Other clinical applications for ctDNA include molecular assessment of patients at diagnosis and serial (real-time) monitoring of biomarker status or the development of resistance mutations.
Method:
Eighty patients with advanced NSCLC who either (Group 1) had a new diagnosis or (Group 2) had developed acquired resistance to an EGFR kinase inhibitor were analyzed with highly sensitive Biocept, Inc. TargetSelector[TM] Real Time PCR based plasma assays genotyping for the detection of EGFR mutations L858R, Del19 and T790M. In addition, group 1 was analyzed for KRAS, BRAF, ROS1 and ALK and circulating tumor cells (CTCs) before and after TKI treatment.
Result:
Our results showed concordance rates of EGFR, KRAS and ALK mutations for up to 90% between the tissue and blood samples in newly diagnosed patients (Group 1). Paired analysis of mutations status monitoring in this group (P= 0.016) showed that the pattern of mutant ctDNA and CTCs changed in response to systemic therapy in 83% of the cases (Partial response or disease progression; R2=0.808). Plasma ctDNA analysis of multiple mutations showed that 40% of patients had at least one more mutation besides the one detected in tissue biopsy; 28% of EGFR tissue positive patients also had a KRAS mutation. In addition, 75% of KRAS positive patients had a BRAF mutation. These results demonstrate that plasma ctDNA analysis may even detect mutations missed by standard tissue genotyping due to tissue heterogeneity. Plasma EGFR T790M mutation was analyzed in patients with clinical progression to TKI inhibitors. Considering the RECIST criteria, 58% of progressive disease, 10% of stable disease and 16% of partial response patients were positive for T790M. According to metastatic disease type (locoregional, oligometastatic, polimetastatic), the T790M mutation was found on 64.3% of polimetastatic patients, 30.8% of oligometastatic patients and 17.6% of loco-regional patients.
Conclusion:
TargetSelector[TM] ctDNA assay is capable of rapidly detecting EGFR, KRAS and ALK mutations and is highly concordant with mutations present in tumor tissue with the robustness needed for real world testing to identify patients who progress on first line TKI therapy as well as for real-time monitoring of patients’ clinical status. Our findings highlight the importance of the RECIST criteria to define the progressive disease and determine the right moment to test for T790M mutation regardless the metastatic disease type.
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MA 12.11 - The Alteration of T790M Prevalence Between 19 Deletions and L858R in NSCLC After EGFR-TKIs Therapy, a Meta-Analysis (ID 10077)
11:00 - 12:30 | Presenting Author(s): Hengrui Liang | Author(s): D. Chen, J. He, W. Liang
- Abstract
- Presentation
Background:
Pre-treatment EGFR T790M mutation is more likely to coexist with L858R mutation than with exon 19 deletions (19del) in NSCLC. However, EGFR-TKIs might alter this status. We sought to compare the prevalence of T790M upon acquired resistance to EGFR-TKIs between 19del and L858R by assembling all existed data.
Method:
Electronic databases were comprehensively searched for eligible studies. The primary endpoint was the odds ratio (OR) of T790M mutation in NSCLC co-existing with L858R mutation and 19del upon resistance to first-generation EGFR-TKIs. A random effects model was used. Stratified analysis was performed based on study type (retrospective and prospective), race (Asians and Caucasians) and sample type (tissue and plasma).
Result:
A total of 25 studies involving 1,770 patients were included. The overall T790M existent rate was 45.25%. Post-resistance T790M was more frequent in 19del than in L858R mutated patients (53% vs. 36%; OR 1.87; p=0.00). All outcomes of subgroup and overall analyses were similar. In contrast, we re-analyzed the previous meta-analysis, finding that the pooled rate of pretreatment T790M was 14% and 22% in 19del and L858R respectively (OR 0.59; p<0.01). The increase of T790M rate was 2.79-fold in 19del and only 0.63-fold in L858R in the course of EGFR-TKIs therapy.
Conclusion:
Opposite to the situation of de novo T790M, it was observed that T790M was more frequent in exon 19del than in L858R among EGFR-TKI resistant acquired patients. The difference in T790M alteration between 19del and L858R encourages development of specific resistance mechanism detection or treatment strategies.
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MA 12.12 - Discussant - MA 12.09, MA 12.10, MA 12.11 (ID 10816)
11:00 - 12:30 | Presenting Author(s): Kenneth Obyrne
- Abstract
- Presentation
Abstract not provided
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Author of
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MS 16 - Future Direction of Chemoradiotherapy for Inoperable Non-small Cell Lung Cancer (ID 538)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Radiotherapy
- Presentations: 1
- Moderators:Yuko Nakayama, Cecile Le Pechoux
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 502
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MS 16.02 - Selection of Chemotherapeutic Agents (ID 7717)
15:45 - 17:30 | Presenting Author(s): Nobuyuki Yamamoto
- Abstract
- Presentation
Abstract not provided
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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 - 16:00 | Author(s): Nobuyuki Yamamoto
- 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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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-008 - Phase I/II Study of Intermitted Erlotinib in Combination with Docetaxel in Patients with Recurrent NSCLC with Wild-Type EGFR: WJOG 4708L (ID 7556)
09:30 - 16:00 | Author(s): Nobuyuki Yamamoto
- Abstract
Background:
Erlotinib (ERL) is modestly active to non-small cell lung cancer (NSCLC) with wild type epidermal growth factor receptor (EGFR). We hypothesized that an intermittent delivery of erlotinib and docetaxel (DOC) would increase efficacy.
Method:
This was a multi-center, single-arm phase I/II study in patients with wild type EGFR NSCLC who failed one prior chemotherapy. The phase I was designed a standard 3+3 dose escalation design to determine feasibility, the maximum tolerated dose (MTD) and phase II recommend dose (RD) of ERL on days 2 to 16, in combination with a fixed dose of 60mg/m[2] DOC on day 1. The phase II primary endpoint was objective response rate (ORR) by independent review committee. This study required 41 patients with expected ORR of 30% and threshold ORR of 10% (one-sided α= 0.025; β=0.1). The target number was 45 patients assuming the loss of follow-up cases. All eligible patients had ECOG performance status of 0/1 and adequate organ functions.
Result:
Between Mar 2009 and Dec 2010, 12 patients were enrolled in the phase I, and between May 2011 and Feb 2015, 46 patients in the phase II. Five patients were excluded from per protocol set, because of deviation of entry criteria. Planned dose escalation was completed without reaching a MTD. The RD was determined as 150 mg/dose of ERL. In the phase II, the ORR was 17.1% (95%CI, 7.2-32.1). The median progression free survival and median overall survival were 3.48 months (95%CI, 3.06-4.50) and 11.27 months (95%CI, 8.61-16.56), respectively. Gender, smoking status, or concomitant drugs which influence the ERL metabolism had no significant differences in ORR, or disease control rate. All 46 patients were evaluable for toxicity. The grade 3 non-hematological toxicities included 9 (19.6%) febrile neutropenia, 7 (15.2%) appetite loss, 3 (6.5%) oral mucositis and 3 (6.5%) infections. The grade 4 hematological toxicities were 31 (67.4%) neutropenia. Two treatment related deaths were observed; interstitial lung disease, and pleural infection.
Conclusion:
Intermittent dosing of ERL plus DOC is clinically feasible, but has no statistically significant improvement of ORR, in patients with recurrent NSCLC with wild type EGFR.
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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 - 16:00 | Author(s): Nobuyuki Yamamoto
- 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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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-035 - Correlation Between Immune-Related Adverse Events and Efficacy in Non-Small Cell Lung Cancer Treated with Nivolumab (ID 9403)
09:30 - 16:00 | Author(s): Nobuyuki Yamamoto
- Abstract
Background:
Nivolumab has been established as a novel standard of care in patients with pre-treated non-small-cell lung cancer (NSCLC). Patients treated with nivolumab sometimes experience its unique adverse events, called immune-related Adverse Events (irAEs). Given the mechanisms of action of immune-checkpoint inhibitors (ICIs), occurrence of irAEs may potentially reflect antitumor response. Here, we report the clinical correlation between irAE and efficacy in NSCLC patients treated with nivolumab.
Method:
Between Dec 2015 and Feb 2017, 38 advanced NSCLC patients were treated with nivolumab at our institution. All patients were enrolled in our single-institutional observational cohort study (UMIN000024414). We divided the patients into two groups: irAEs group and no-irAEs group and evaluated the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Efficacy was assessed by RECIST version 1.1, and toxicity was graded based on CTCAE version 4.0.
Result:
Of thirty-eight, median age was 68.5 (range, 49 to 86), 74% was male, 68% was non-squamous cell carcinoma, and 82% was performance status of 0-1. Among overall population, ORR was 23.7%, and median PFS was 91 days. Eleven patients (29%) experienced irAEs and median time to onset irAEs was 53 days (range, 14 to 213 days). There was no significant correlation observed between PD-L1 expression on tumor and occurrence of irAEs. Most common irAE was pneumonitis (n = 5) and others were hypothyroidism (n = 4), hyperthyroidism, hypopituitarism, hepatitis, rash and elevated thyroid stimulating hormone (one, each). Patients with irAEs had significantly higher efficacy compared with those without (ORR: 63.6% versus 7.4%, p < 0.01 (Fisher’s exact test), mPFS: not reached (NR) versus 49 days, p < 0.01 (log-rank test). Landmark analysis in patients who achieved progression free ≥ 12 weeks showed a similar trend (p = 0.07). Next, we performed additional analyses on correlation with specific irAEs. Patients with pneumonitis and those without demonstrated similar outcome (p = 0.95 (log-rank test)). With regard to endocrine irAEs, the similar result was also observed (p = 0.95 (log-rank test)).
Conclusion:
In our study, there was a correlation between irAEs and efficacy in NSCLC patients treated with nivolumab. Occurrence of specific irAE was not necessarily associated the efficacy.
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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 - 16:00 | Author(s): Nobuyuki Yamamoto
- 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: 4
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-026 - Analysis of Long-Term Response to First-Line Afatinib in the LUX-Lung 3, 6 and 7 Trials in Advanced EGFRm+ NSCLC (ID 9051)
09:30 - 16:00 | Author(s): Nobuyuki Yamamoto
- Abstract
Background:
In patients with advanced EGFR mutation-positive (EGFRm+) NSCLC, first-line afatinib significantly improved PFS and objective response rate (ORR) versus platinum-doublet chemotherapy in the phase III LUX-Lung (LL) 3 and LL6 studies, and PFS, time-to-treatment failure (TTF) and ORR versus gefitinib in the phase IIb LL7 study. Here, we present post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in LL3/6/7.
Method:
Treatment-naïve patients with stage IIIb/IV EGFRm+ NSCLC who were randomized to 40mg/day afatinib in LL3/6/7 and remained on treatment for ≥3 years were defined as LTRs. In these patients, we assessed efficacy and safety outcomes, as well as PROs measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire and the EQ-5D™ health status self-assessment questionnaire; these included scores on the EORTC Global Health [GH]/QoL scale (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:
In LL3/6/7, there were 24/229 (10%)/ 23/239 (10%)/ 19/160 (12%) afatinib-treated LTRs; 6/9/14 remained on treatment at time of analysis. Baseline characteristics were similar to the overall study populations, except for the proportion of women (LL3/6 only [LTRs versus overall]: 92/78% vs 64/64%) and Del19+ patients (LL3/6/7: 63–79% vs 49–58%). In LL3/6/7, 4–11% of LTRs had brain metastases at enrolment. Median (range) duration of treatment in LL3/6/7 LTRs was 50 (41–73)/56 (37–68)/42 (37–50) months. Due to few deaths, median OS could not be estimated. Median follow-up for OS in LL3/6/7 was 64.6/57.0/42.1 months. ORR among LTRs in LL3/6/7 was 70.8% (complete response: 4.2%; n=1)/78.3% (13.0%; n=3)/89.5% (5.3%; n=1). The frequency of afatinib dose reductions due to treatment-related AEs, and the frequency/duration of subsequent treatments were similar to the overall LL3/6/7 populations. In afatinib-treated LTRs in LL3/6/7, PROs appeared stable between ~Week 24 to ~Week 160, with slight improvements after ~3 years afatinib treatment versus scores at the start of treatment.
Conclusion:
In LL3/6/7, 10%–12% of afatinib-treated patients were LTRs. Afatinib was well tolerated among these patients. Long-term treatment was independent of tolerability-guided dose adjustment or presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment. In afatinib-treated LTRs, PROs were not negatively affected by long-term treatment, and were slightly improved after ~3 years of treatment versus scores at treatment initiation.
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P3.01-035 - Post-Marketing Observational Study of Japanese Patients with EGFR Mutation-Positive (EGFRm+) NSCLC Treated with Daily Afatinib (Final Report) (ID 9250)
09:30 - 16:00 | Presenting Author(s): Nobuyuki Yamamoto
- Abstract
Background:
This is a prospective, post-marketing surveillance study (NCT02131259) to evaluate safety and effectiveness of the irreversible ErbB family blocker, afatinib, which is approved in Japan for the treatment of inoperable/recurrent EGFRm+ NSCLC.
Method:
Patients with inoperable/recurrent EGFRm+ NSCLC received afatinib at the approved dose (20–50 mg/day) and were observed following treatment initiation for 52 weeks/until premature discontinuation. Data were included for all patients who received afatinib during the investigational period of this study, thus minimizing patient selection bias. The incidence/severity of adverse drug reactions (ADRs)/serious ADRs (sADRs) was the primary endpoint. Other endpoints included effectiveness (objective response rate [ORR]) and the incidence/severity of ADRs of special interest (diarrhea, rash/acne, nail effects [NEs] and interstitial lung disease [ILD]).
Result:
As of February 2017, 1,602 patients were included in the analysis (59% female, 81% aged <75 years, 86% ECOG PS 0–1, 83% BMI <25 kg/m[2]). 97% of patients had adenocarcinoma, and 64%/26% had EGFR Del19/L858R mutations. 70% had ≥1 line of prior chemotherapy; 48%/30% had prior gefitinib/erlotinib. Afatinib starting dose was 40 mg in 77% of patients. 95% had ADRs (36% grade ≥3). The most frequently reported ADRs (all grade/grade 3–4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and NEs (38%/4%). ILD (all grade/grade 3–4/grade 5) occurred in 4%/2%/1% of patients. Median (range) time to initial onset was 5.0 (1–316) days for diarrhea, 11.0 (1–406) days for rash/acne, 9.0 (1–327) days for stomatitis, 38.0 (1–526) days for NEs, and 35.5 (3–329) days for ILD. Four patients (<1%) had creatinine elevation following grade ≥3 diarrhea. Dose reductions/permanent discontinuations occurred in 8%/7% of patients following diarrhea, 6%/4% following rash/acne, 3%/2% following stomatitis, 5%/2% following NEs, and <1%/4% following ILD. 33% of patients experienced sADRs. ADR frequency was associated with starting dose (96%/91% with 40/<40 mg afatinib), but was not unfavorably impacted by age, ECOG PS, number of prior chemotherapies, or previous EGFR TKIs. ORR with afatinib was higher in EGFR TKI-naïve patients than those who had previously been treated with EGFR TKIs (68% versus 21%).
Conclusion:
Consistent with previous studies, afatinib was effective in inoperable/recurrent EGFRm+ NSCLC, particularly as first-line targeted treatment (ORR ~70%). ADRs were predictable and generally manageable. ADR frequency was not notably affected by age, ECOG PS or number of previous therapies. In clinical practice, patients should be closely monitored and ADRs, particularly diarrhea and ILD, treated early to prevent sADRs.
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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 - 16:00 | Author(s): Nobuyuki Yamamoto
- 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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P3.01-088b - Is Efficacy Result in Phase 2 Trial Replicated in Phase 3 Trial in Advanced NSCLC: A Meta-Analysis (ID 9125)
09:30 - 16:00 | Author(s): Nobuyuki Yamamoto
- Abstract
Background:
Phase 3 trial has been mandatory to establish new treatment. However, molecular targeted agents were often approved based on phase 2 trials. There have not been fully investigated whether efficacy data in phase 2 would be replicated in phase 3.
Method:
We extracted phase 2 and 3 trials for advanced non-small cell lung cancer (NSCLC) using platinum doublet (Plt) or EGFR-tyrosine kinase inhibitor (TKI) monotherapy, published between 2005 and 2015. Overall response rate (ORR) and median progression-free survival (PFS) in each study were collected. We compared these data between phase 2 and 3.
Result:
155 phase 2 trials and 13 phase 3 trials were adopted as Plt trials, while 21 phase 2 trials and 6 phase 3 trials were adopted as TKI trials. Plt trials had larger sample size (median number of patients: 47 in phase 2, and 203 in phase 3) than TKI trials (median number of patients: 29 in phase 2, and 101.5 in phase 3). In Plt trials, median ORR and median of median PFS were 31% and 5.2 months in phase 2, while 27% and 4.7 months in phase 3. There was statistically significant difference between phase 2 and phase 3 in ORR and mPFS (p = 0.03 and 0.03, respectively). In TKI trials, median ORR and median of median PFS were 64.0% and 9.7 months in phase 2, while 64.5% and 10.9 months in phase 3. There were not significant difference between phase 2 and phase 3 either in ORR and mPFS (p = 0.88 and 0.31, respectively). Among TKI trials, equivalence of efficacy data between phase 2 and phase 3 was also investigated in ORR and mPFS, but not proved (p = 0.30 and 0.45, respectively).
Conclusion:
Efficacy of TKI in phase 2 trial was well replicated in phase 3 trial.
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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: 1
- 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 - 16:00 | Author(s): Nobuyuki Yamamoto
- 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.
