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Maurice Pérol
Moderator of
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 9
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.01 - The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC (ID 10369)
11:00 - 11:10 | Presenting Author(s): Y.Y. Elamin | Author(s): Jacqulyne Ponville Robichaux, Vincent K Lam, Anne Tsao, C. Lu, G. Blumenschein, J. Kurie, Julie R Brahmer, S. Li, T. Chen, A. Estrada-Bernal, A. Truini, M. Nilsson, A.T. Le, Z. Tan, S. Zhang, Robert C. Doebele, K. Politi, Z. Yang, S. Liu, Kwok-Kin Wong, John V Heymach
- Abstract
- Presentation
Background:
Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.
Method:
We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).
Result:
In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.
Conclusion:
Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.
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OA 12.02 - Final Results of a Phase 2 Study of the hsp90 Inhibitor Luminespib (AUY922) in NSCLC Patients Harboring EGFR Exon 20 Insertions (ID 10182)
11:10 - 11:20 | Presenting Author(s): Zofia Piotrowska | Author(s): D.B. Costa, M. Huberman, Geoffrey R. Oxnard, Justin F Gainor, R. Heist, I.T. Lennes, A. Muzikansky, Alice Shaw, C.G. Azzoli, Lecia V Sequist
- Abstract
- Presentation
Background:
EGFR exon 20 insertions (ins20) comprise 4-10% of EGFR mutations in NSCLC and are refractory to 1[st]/2[nd] generation EGFR TKIs. No effective targeted therapies exist for patients with EGFR ins20. EGFR is a client protein of the molecular chaperone Heat Shock Protein 90 (hsp90). Here, we present the final results of a phase II investigator-initiated trial to assess the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20 (NCT01854034).
Method:
Between 8/2013 and 10/2016, the study enrolled 29 patients with stage IV NSCLC, EGFR ins20 identified on local testing, ECOG PS 0-2, at least one prior line of therapy and no untreated brain metastases. The study was closed on 2/28/17 when the available drug supply was exhausted. Luminespib was given at 70mg/m2 IV weekly. Response was assessed by RECIST 1.1 every 6 weeks; treatment beyond progression was allowed. Dose interruptions and dose reductions were allowed as needed for toxicity management. Primary endpoint was ORR with a target disease control rate (DCR; PR/CR plus SD lasting > 3 mos) of > 20%. Secondary endpoints were PFS, OS, safety and response by EGFR ins20 subtype.
Result:
29 patients (18 female/11 male, median age 60 (range, 31-79)) were enrolled. Median number of prior therapies = 1 (range, 1-5.) 4/29 achieved PR and 1 CR (ORR 5/29; 17%). 15 patients had SD and 9 had PD as their best response. mPFS was 2.9 mos (95% CI, 1.4-5.6,) mOS was 13 mos (95% CI, 4.9-19.5.) DCR was 11/29 (38%). Among 19 patients with baseline PS 0-1 and < 2 prior therapies, ORR = 21% and mPFS = 5.1 mos (95% CI, 2.1-11.8.) The most common luminespib-related toxicities were visual changes (22/29; 76%) diarrhea (21/29; 72%) and fatigue (13/29; 45%). Treatment-related grade 3 toxicities included ocular toxicity (1/29; 3%), hypertension (3/29; 10%) and hypophosphatemia (1/29; 3%). All study treatment was stopped on 2/28/17 due to lack of drug availability; 3 patients were on treatment without progression at study termination.
Conclusion:
The study met its primary endpoint and suggests that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other Hsp90 inhibitors in this population is warranted, as are novel systems to continue drug supply for benefitting patients when availability of experimental compounds is limited.
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OA 12.03 - Clinical Features of Advanced Lung Cancer Harboring HER2 Aberrations: A Large Prospective Cohort Study (HER2-CS STUDY) (ID 8694)
11:20 - 11:30 | Presenting Author(s): Shinobu Hosokawa | Author(s): A. Bessho, K. Ninomiya, T. Tanaka, N. Ishikawa, M. Yamasaki, T. Shibayama, K. Aoe, T. Kozuki, N. Fujimoto, K. Gemba, Y. Ueda, M. Inoue, T. Murakami, Shoichi Kuyama, H. Kawai, K. Fujitaka, K. Inoue, M. Takata, H. Yanai, K. Hotta, K. Kiura
- Abstract
- Presentation
Background:
HER2 is a potential driver oncogene. HER2-targeted precision therapy has been tested in NSCLC. However, the demographics of HER2-positive NSCLC have not been defined systematically.
Method:
Pts with advanced NSCLC were registered. HER2-IHC and FISH assays were performed with commercial kits. HER2 mutations were identified by the direct sequencing. The aim of this study was to clarify the frequency, characteristics and outcome of HER2-positive NSCLC.
Result:
Of 1,126 tumors screened (Table A), 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 EGFR wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775_G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female pts had HER2 mutant tumors more frequently, while IHC/FISH+ tumors were detected more often in males (Table B). HER2-positive tumors had similar survival outcome to triple negative tumors, but significantly worse prognoses than EGFR-mutant and ALK-positive tumors (p < 0.05 each). The treament info will be presented at the meeting.
*including 22 pts with HER2-positive tumors with EGFR mutations, 2 with both HER2- and ALK-positive tumors, and 2 had ALK-positive tumors with EGFR-mutations. ** 1 had an IHC2+/FISH+ tumor with mutation.A. The Genotype-Specific Subsets* HER2 (n = 88) EGFR (n = 358) ALK (n = 44) Triple negative /unknown (n = 662) Total (n = 1,126) Age, median Sex (male) Smoking habit Non-Sq Stage III/IV 69 61 (69%) 58 (66%) 78 (89%) 51 (58%) 69 142 (40%) 142 (40%) 351 (98%) 220 (61%) 62 21 (48%) 19 (43%) 44 (100%) 35 (80%) 69 516 (78%) 544 (82%) 503 (76%) 423 (64%) 69 726 (64%) 754 (67%) 951 (84%) 714 (63%) MST (mo) 1-yr OS rate 17.5 59% NR 85% NR 79% 15.1 59% 19.8 67% B. The Subsets of HER2 aberrations** IHC3+ (n = 34) IHC2+/FISH+ (n = 34) Mutant (n = 21) Age, median Sex (male) Smoking habit Non-Sq Stage III/IV 71 27 (79%) 24 (71%) 30 (88%) 17 (50%) 71 27 (79%) 26 (76%) 28 (82%) 21 (62%) 65 8 (38%) 9 (43%) 21 (100%) 14 (67%) MST (mo) 1-yr OS rate 10.5 46% 16.0 70% NR 59%
Conclusion:
This is the first prospective study showing a small fraction of NSCLC possessed HER2 aberrations. HER2-positive tumors had relatively poor prognosis. NSCLCs with HER2 IHC3+ and mutation seem to be distinct subsets.
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OA 12.04 - Discussant - OA 12.01, OA 12.02, OA 12.03 (ID 10799)
11:30 - 11:40 | Presenting Author(s): Christina S Baik
- Abstract
- Presentation
Abstract not provided
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OA 12.05 - Spectrum of 1,014 Somatic BRAF Alterations Detected in Cell-Free DNA of Patients with Advanced Non-Small Cell Lung Cancer (ID 9984)
11:40 - 11:50 | Presenting Author(s): Trever G Bivona | Author(s): V.M. Raymond, R.B. Lanman, R.J. Nagy, K.C. Banks, Y.K. Chae, J.M. Clarke, Jeffrey Crawford, David R. Gandara, John V Heymach
- Abstract
- Presentation
Background:
Somatic BRAF V600E is a National Comprehensive Cancer Network clinical therapeutic target in non-small cell lung cancer (NSCLC), occurring in 6% of tumors from patients with lung adenocarcinoma. However, approximately half of BRAF alterations are non-V600E that do not respond to FDA-approved vemurafenib or dabrafenib. Emerging evidence suggests some non-V600E mutations exhibit clinical response to novel therapeutic agents. We analyzed the landscape of BRAF mutations in a very large cohort of patients with NSCLC who underwent somatic genomic testing utilizing a CLIA-certified/CAP-accredited/NYSDOH-approved 73 gene cell-free circulating tumor DNA (cfDNA) panel which evaluates single nucleotide variants, and selected indels, fusions, and copy number amplifications.
Method:
The Guardant Health laboratory database was queried for cfDNA tests from patients with a diagnosis of NSCLC where a BRAF variant was identified. Literature was queried for a description of the known function of non-V600E BRAF mutations on serine-threonine kinase activity.
Result:
A total of 1,014 BRAF alterations were observed in 914 tests, with 234 unique alterations identified. The majority of variants were observed only once (75.6%; N=177). 43 alterations were synonymous and excluded from analysis. Plasma-detected BRAF amplification was the most common alteration, observed in 484 tests. Of the remaining variants, 33 of 190 had functional consequence reported in the literature (17.4%), 18 with gain of function or predicted gain of function, 13 with loss of function or predicted loss of function and 2 with no effect. BRAF V600E accounted for 51.1% of occurrences of variants with gain of function or predicted gain of function (N=95 occurrences). Recurrent (>10 occurrences) non-V600E gain of function mutations included G469A (13.4%; N=25 occurrences), K601E (8.0%: N = 15 occurrences), and N581S (7.0%; N=13 occurrences). Fourteen additional gain of function variants comprised the remaining 21% of occurrences. Recurrent loss of function BRAF mutations (>10 occurrences) included G466V and D594G.
Conclusion:
This is the largest reported cohort of somatic BRAF alterations in metastatic non-small cell lung cancer. Non-V600E alterations accounted for almost 50% of the gain of function variants. The spectrum of non-V600E alterations was consistent with reports from The Cancer Genome Atlas and prior published results from tissue genomic sequencing. The recurrent non-V600E variants identified in this cohort are emerging therapeutic targets with promising early clinical data. These findings advocate for more comprehensive BRAF genomic profiling and identification of patients eligible for clinical trials targeting these non-V600E classic mutations and demonstrate the ability of plasma-based cfDNA to detect these alterations.
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OA 12.06 - Plasma Genomic Profiling and Outcomes of Patients with MET Exon 14-Altered NSCLCs Treated with Crizotinib on PROFILE 1001 (ID 9385)
11:50 - 12:00 | Presenting Author(s): Alexander Drilon | Author(s): J.W. Clark, J. Weiss, Sai-Hong Ignatius Ou, D. Ross Camidge, Ben J Solomon, G. Otterson, L.C. Villaruz, Gregory J Riely, R. Heist, G.I. Shapiro, D.A. Murphy, Y. Liu, S.C. Wang, T. Usari, K.D. Wilner, Paul K. Paik
- Abstract
- Presentation
Background:
MET exon 14 alterations occur in ~4% of non-squamous non-small cell lung cancers (NSCLCs). Treatment with the MET inhibitor, crizotinib, achieves confirmed and durable responses in patients with MET exon 14-altered NSCLCs, underscoring the need to test for these drivers (as of August 1, 2016, objective response rate was 39% and median duration of response was 9.1 months). Comprehensive molecular tumor profiling is required to detect MET exon 14 alterations that are highly heterogeneous. The utility of plasma profiling to detect these drivers has not previously been explored in a prospective trial.
Method:
Patients with advanced NSCLCs harboring MET exon 14 alterations by local tumor profiling performed in a CLIA-certified or equivalent environment were treated with crizotinib at 250 mg twice daily on an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195). Objective response was assessed by RECIST v1.0. Prospective plasma profiling of circulating tumor DNA (ctDNA) for MET exon 14 alterations was performed using the PlasmaSELECT64 targeted gene panel (sequencing and analysis output by Personal Genome Diagnostics, Boston MA).
Result:
Plasma samples were obtained for MET exon 14 alteration analysis after study amendment approval in 20 of 52 crizotinib-treated patients, of which 18 samples were deemed sufficient for analysis. MET exon 14 alterations were detected in ctDNA in 11 of 18 patients (61% agreement of plasma ctDNA testing with tumor testing) mapping to the same exon 14 splice site region in 10 of the 11 cases. Of the 11 patients with ctDNA-positive tumors, all were evaluable for response. Of these evaluable patients, a confirmed partial response and stable disease were observed in 2 and 4 patients, respectively.
Conclusion:
MET exon 14 alterations can be detected in plasma ctDNA in a subset of patients with advanced NSCLCs that harbor MET exon 14 alterations by tumor testing. Responses to crizotinib were observed in patients with ctDNA-positive testing for a MET exon 14 alteration. Plasma profiling should be considered as an adjunct to tumor profiling in screening patients for MET exon 14 alterations, pending further confirmation.
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OA 12.07 - LOXO-292, a Potent, Highly Selective RET Inhibitor, in MKI-Resistant RET Fusion-Positive Lung Cancer Patients with and without Brain Metastases (ID 10955)
12:00 - 12:10 | Presenting Author(s): Vamsidhar Velcheti | Author(s): T.M. Bauer, V. Subbiah, M.E. Cabanillas, N. Lakhani, L.J. Wirth, Geoffrey R. Oxnard, M.H. Shah, E.J. Sherman, S. Smith, T. Eary, S. Cruickshank, B.B. Tuch, K. Ebata, M. Nguyen, S. Corsi-Travali, S. Rothenberg, Alexander Drilon
- Abstract
- Presentation
Background:
RET fusions are validated therapeutic targets in human lung cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity is limited by a narrow therapeutic index from off-target effects and poor pharmacokinetics (PK). Moreover, MKIs have limited RET inhibition in the central nervous system (CNS), and patients often experience disease progression in the brain. LOXO-292 is a potent and highly selective RET inhibitor, with >100-fold selectivity versus important off-targets, and anti-tumor activity in the brain and periphery in RET-dependent tumor models in vivo.
Method:
Two RET fusion-positive lung cancer patients were treated with LOXO-292: a patient with CCDC6-RET-rearranged lung cancer with acquired resistance to RXDX-105; and a patient with KIF5B-RET-rearranged lung cancer with progressive disease in the brain while on alectinib treated under a single patient protocol with real-time, PK- guided intra-patient dose titration.
Result:
The first patient was enrolled on cohort 1 of the Phase 1 trial (20 mg daily) and was the first lung cancer patient to receive LOXO-292. She achieved a rapid, confirmed partial response (PR) by RECIST 1.1, with a 44% reduction in target lesion size. The second patient, the first to receive LOXO-292 in the setting of brain metastases, achieved a PR with escalating doses of LOXO-292 (20-60-100 mg twice daily) that included target lesion responses in both the lungs and brain (Figure 1), and resolution of cancer-related CNS symptoms. Early clinical experience with LOXO-292 has already established drug exposures that are consistent with significant RET inhibition in vitro and RET-dependent tumor regression in vivo. Importantly, LOXO-292 has been well-tolerated, with the majority of treatment-emergent adverse events reported as Grade 1-2, and none attributed to LOXO-292.
Conclusion:
LOXO-292 has demonstrated proof-of-concept tolerability, significant exposure, and efficacy in two patients with MKI-resistant, RET-dependent cancers, including a patient with progressive brain metastases after alectinib.Figure 1
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OA 12.08 - Genomic Analysis of Non-Small Cell Lung Cancer (NSCLC) Cases with Focal and Non-Focal MET Amplification (ID 9520)
12:10 - 12:20 | Presenting Author(s): Sai-Hong Ignatius Ou | Author(s): D. Pavlick, P.J. Stephens, Jeffrey S. Ross, V.A. Miller, Siraj M Ali, A.B. Schrock
- Abstract
- Presentation
Background:
MET amplification (METamp) is a known driver and a mechanism of resistance in EGFR-mutated lung cancers treated with targeted therapy. However, development of therapies targeting METamp has been hampered in part due to poor genomic stratification of patients. We investigated the natural distribution of the size of the MET amplicon and associated genomic characteristics.
Method:
Hybrid-capture based comprehensive genomic profiling (CGP) was performed prospectively on DNA isolated from FFPE samples from NSCLC. Tumor mutational burden (TMB) was calculated from 1.1 Mbp of sequenced DNA and reported as mutations/Mb, as previously described (PMID: 28420421).
Result:
We identified 545 NSCLC cases with focal, defined as <20 Mbp (n = 457, 84%), or non-focal (n = 88, 16%) amplification of the MET gene using CGP. Within this set, the size of the MET amplicon ranged from 0.095 – 158 Mbp; 25[th], 50[th] and 75[th] quartiles were 1.63 Mbp, 3.46 Mbp, and 11.66 Mbp, respectively. In cases with focal METamp the median MET copy number was 11, compared to a median of 7 copies for cases with non-focal METamp (P <0.001). Median TMB in cases with focal vs. non-focal METamp was 10.8 and 9.0, respectively (P=0.47). MET exon 14 splice site alterations co-occurred with METamp in 45 cases (8%), of which 80% had focal METamp (median amplicon size of 2.02 Mbp). EGFR mutations co-occurred with METamp in 93 cases (17%) in this dataset, of which 78% had focal METamp (median amplicon size: 3.77 Mbp). In contrast, cases with other co-occurring alterations described in the NSCLC NCCN guidelines (ALK, ROS1 or RET rearrangements, BRAF V600E, or ERBB2 mutations) METamp was more commonly non-focal (3 focal and 6 non-focal cases), with a median amplicon size of 25.5 Mbp. Clinical outcomes will be presented, including a subset of cases in the setting of resistance to EGFR inhibitors.
Conclusion:
The size of the MET amplicon in MET-amplified NSCLCs is largely variable. Focal amplification is associated with a higher estimate of MET copy number. Neither TMB or co-occurring MET or EGFR mutations significantly correlated with size of the MET amplicon; however, other co-occurring known drivers were associated with non-focal METamp. Additional investigation is warranted to determine the clinical significance of the size of the MET amplicon in NSCLC.
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OA 12.09 - Discussant - OA 12.05, OA 12.06, OA 12.07, OA 12.08 (ID 10800)
12:20 - 12:30 | Presenting Author(s): Julien Mazieres
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
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MA 03.06 - Effect of 2L Ramucirumab after Rapid Time to Progression on 1L Therapy: Subgroup Analysis of REVEL in Advanced NSCLC (ID 7947)
11:35 - 11:40 | Author(s): Maurice Pérol
- Abstract
- Presentation
Background:
In REVEL, ramucirumab+docetaxel in the second-line (2L) treatment of patients with advanced NSCLC led to improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), independent of histology. This exploratory, post-hoc analysis focuses on patients who progressed rapidly on first-line (1L), and who traditionally have a poor prognosis in the 2L setting. In REVEL, treatment benefit was observed in patients with progressive disease as their best overall response to 1L and in patients who were on 1L for only a short time (Reck M, ASCO 2017, Abstr 9079). Here, we report outcomes from patients who participated in REVEL according to their time to tumor progression (TTP) on 1L (ClinicalTrials.gov, NCT01168973).
Method:
Patients with advanced NSCLC of squamous or nonsquamous histology with disease progression during or after 1L platinum-based chemotherapy were randomized (1:1) to receive docetaxel 75 mg/m[2] and either ramucirumab 10 mg/kg or placebo on day 1 of a 21-day cycle. OS was the primary endpoint. Secondary endpoints included PFS, ORR, safety, and patient-reported quality-of-life (QoL). Response was assessed according to RECIST v1.1. QoL was assessed with the Lung Cancer Symptom Scale. TTP on 1L, defined as the time from start of 1L until progressive disease, was assessed for the REVEL intent-to-treat population.
Result:
Of 1253 patients in REVEL, 11% had TTP ≤9 weeks, 17% had TTP ≤12 weeks, and 28% had TTP ≤18 weeks on 1L therapy. Baseline characteristics of each subgroup generally were balanced between treatment arms. Efficacy, safety, and QoL outcomes by TTP are shown in the table.Outcomes in Patients From the REVEL Study by Time to Tumor Progression on First-Line Therapy
≤9 Weeks ≤12 Weeks ≤18 Weeks INTENT-TO-TREAT POPULATION Ramucirumab+Docetaxel N = 71 Placebo+Docetaxel N = 62 Ramucirumab+Docetaxel N = 111 Placebo+Docetaxel N = 98 Ramucirumab+Docetaxel N = 182 Placebo+Docetaxel N = 172 Median OS, months (95% Confidence Interval [CI]) 8.28 (5.19, 10.84) 4.83 (3.09, 6.90) 9.10 (6.70, 10.84) 5.78 (4.30, 7.49) 8.51 (6.97, 9.95) 5.95 (4.44, 6.97) Unstratified Hazard Ratio (HR) (95% CI) 0.69 (0.47, 1.01) 0.74 (0.54, 1.00) 0.80 (0.63, 1.01) 12-month survival rate, % (95% CI) 47 (35, 58) 32 (20, 44) 34 (25, 43) 23 (15, 32) 30 (23, 37) 24 (18, 31) 18-month survival rate, % (95% CI) 20 (11, 31) 12 (5, 24) 17 (10, 26) 13 (6, 22) 17 (11, 23) 13 (8, 20) Median PFS, months (95% CI) 3.01 (2.66, 4.07) 1.48 (1.41, 1.87) 3.61 (2.76, 4.21) 1.61 (1.45, 2.60) 3.22 (2.79, 4.14) 1.61 (1.48, 2.60) Unstratified HR (95% CI) 0.69 (0.48, 0.98) 0.73 (0.55, 0.97) 0.72 (0.58, 0.89) ORR (complete response [CR]+partial response [PR]), %, (95% CI) 18.3 (10.1,29.3) 3.2 (0.4, 11.2) 18.9 (12.1, 27.5) 9.2 (4.3, 16.7) 19.2 (13.8, 25.7) 10.5 (6.3, 16.0) Disease Control Rate (CR+PR+stable disease), % (95% CI) 50.7 (38.6, 62.8) 30.6 (19.6, 43.7) 49.5 (39.9, 59.2) 37.8 (28.2, 48.1) 50.5 (43.1, 58.0) 36.0 (28.9, 43.7) Average Symptom Burden Index, time to deterioration HR (95% CI) 0.60 (0.30, 1.22) 0.49 (0.27, 0.88) 0.74 (0.49, 1.12) Total Score Lung Cancer Symptom Scale, time to deterioration HR (95% CI) 0.89 (0.45, 1.78) 0.71 (0.41, 1.23) 0.90 (0.60, 1.36) SAFETY POPULATION Ramucirumab+Docetaxel N = 70 Placebo+Docetaxel N = 61 Ramucirumab+Docetaxel N = 109 Placebo+Docetaxel N = 97 Ramucirumab+Docetaxel N = 179 Placebo+Docetaxel N = 171 Any Treatment-Emergent Adverse Event (TEAE), n (%) 67 (95.7) 58 (95.1) 105 (96.3) 92 (94.8) 173 (96.6) 159 (93.0) Grade ≥3 50 (71.4) 46 (75.4) 80 (73.4) 69 (71.1) 134 (74.9) 113 (66.1) TEAE leading to discontinuation 4 (5.7) 2 (3.3) 5 (4.6) 3 (3.1) 13 (7.3) 6 (3.5) TEAE leading to dose adjustment 24 (34.3) 19 (31.1) 39 (35.8) 28 (28.9) 70 (39.1) 47 (27.5) TEAE leading to death 5 (7.1) 4 (6.6) 7 (6.4) 6 (6.2) 9 (5.0) 8 (4.7) TESAE 25 (35.7) 30 (49.2) 46 (42.2) 46 (47.4) 80 (44.7) 71 (41.5)
Conclusion:
Efficacy, toxicity, and QoL outcomes among ramucirumab+docetaxel patients who have aggressive disease with rapid TTP on 1L therapy appear consistent with the intent-to-treat population. The benefit/risk profile for these rapid progressors suggests that such patients may derive meaningful benefit from ramucirumab+docetaxel in the 2L setting.
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MS 13 - How to Deal with CNS Metastases (ID 535)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Martin Schuler, Nir Peled
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 502
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MS 13.01 - Strategic Approach to CNS Metastasis (ID 7701)
11:00 - 11:15 | Presenting Author(s): Maurice Pérol
- Abstract
- Presentation
Abstract:
Brain metastases (BMs) concern more than 10-15% of patients with stage IV NSCLC at baseline and more than 40% during the disease course. The wider use of MRI and improvement of extra-cranial systemic disease control contribute to increase the BMs incidence. The issue of BMs is critical in the management of NSCLC patients in the perspective of the neurological consequences of brain lesions. BMs occurrence is synonymous of a poor outcome in NSCLC but reflects in fact many different situations. Establishing a therapeutic strategy needs first to assess their prognosis; the most appropriate scale is the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers including as prognostic factors EGFR mutations and ALK rearrangement in addition to age, number of BMs, extra-cranial disease and Karnofsky status, with a median survival varying from 3.0 months for the worse subgroup (GPA 0.5-1) to 46.8 months for patients with oncogene addiction and good prognostic factors (GPA 3.5-4). The second step is to evaluate the indications, efficacy and side effects of available therapeutic "weapons". Corticosteroids are active against cerebral edema and improve symptoms. Whole brain radiotherapy (WBRT) has been for decades the treatment "reflex" of BMs but the emergence of stereotactic radiosurgery (SRS) or radiotherapy (SRT) and the issue of neurocognitive complications led to deferral or omission of WBRT in an increasing number of patients. WBRT remains indicated in patients with symptomatic, large (≥3 cm) and numerous BM. However, palliative WBRT did not provide any benefit in terms of survival, quality of life and QUALYs compared to supportive care alone in the Quartz trial; the subgroup analysis suggests a benefit only in patients with better prognostic factors. Neuroprotective strategies as sparing hippocampi during WBRT are currently evaluated. SRS defined by invasive contention with sub-millimeter accuracy or noninvasive SRT with millimeter accuracy are indicated in case of 1 to 3 BMs (but now up to 10 lesions) with a diameter <3 cm, alone or as a boost on the top of WBRT. SRS/SRT alone avoids neurocognitive toxicity of WBRT and provides a similar OS to that of surgical resection when using SRS/SRT for patients with operable lesions. Radionecrosis is observed in 10-17% of patients treated with SRS/SRT, making difficult the distinction with a tumor relapse. In spite of reduction in local and distant brain failures or in death from neurological causes, adjuvant WBRT after SRS/SRT does not improve overall survival and has a detrimental effect on neurocognitive functions and quality of life. Surgical resection of BMs achieves survival and functional benefit in addition to WBRT. Surgery is indicated in case of a symptomatic lesion, larger than 2 cm, with a mass effect, allowing fast improvement of symptoms. The invasive edge of BMs explains the high local recurrence rate after resection and the need for adjuvant radiotherapy. WBRT is progressively less used in favor of SRS/SRT despite a better intracranial control rate because of a higher rate of cognitive deterioration. Systemic treatment remains critical for extracranial systemic control of the disease. Brain-blood barrier limits the brain penetration of systemic agents, especially with efflux transporters as P-gp, for which many TKIs and cytotoxic agents are substrates. BMs usually cause brain-blood barrier disruption with heterogeneous drug penetration. Cytotoxic chemotherapy provides similar response rates in BMs to those of extracranial disease. Anti-PD-1 antibodies seem to be active in the brain but available data are scarce. First and second-generation EGFR TKIs have a low brain penetration but sufficient to obtain response rates similar to those achieved for systemic disease; duration of response might be inferior. Osimertinib has a better CNS penetration. For ALK+ disease, crizotinib is a P-gp substrate with a low blood/CSF concentration ratio and brain is the most frequent site of progression. Next-generation ALK TKIs have a better CNS diffusion; alectinib largely decreases the cumulative incidence of BMs compared to crizotinib. Concurrent administration of TKIs with brain radiotherapy is controversial and is not recommended outside of a clinical trial. Defining an optimal multidisciplinary strategy needs to take into account many parameters, including number, location and size of brain metastases, leptomeningeal lesions, neurological symptoms, risk factors for neurocognitive alteration, extracranial metastases and their control, primary lung tumor control, and identification of a targetable oncogenic addiction. In absence of a targetable genomic alteration, BMs at baseline can benefit from systemic treatment alone in selected patients with no neurological symptoms, small intracranial tumor burden, low risk of impending neurologic issues, on the condition that they are closely monitored; brain radiotherapy can be safely deferred to intracranial progression. Symptomatic BMs require local treatment, by favoring SRS/SRT rather than WBRT; adjuvant WBRT is not recommended but further close monitoring is mandatory to detect new intra-cranial lesions. Surgery is preferred for large lesions, posterior fossa location or diagnosis; adjuvant SRS/SRT is mandatory to avoid local recurrences. WBRT remains indicated for multiple symptomatic lesions not eligible for SRS/SRT except in poor PS patients. In case of EGFR mutations, asymptomatic patients with BMs are treated with first or second-generation EGFR TKIs but must be closely watched with repeated brain imaging. A recent retrospective study suggests that front-line SRS/SRT might improve overall survival as CNS remains a sanctuary site in oncogene-addicted disease. Symptomatic patients are locally treated, favoring SRS/SRT requiring only a short interruption of systemic treatment. For patients with ALK+ disease, the advent of alectinib as standard front-line treatment should change the management approach to BMs: the low incidence of BMs should allow spacing brain monitoring while the high intra-cranial response rate should permit to delay local treatment. For ALK+ patients developing BMs on ALK TKI, local treatment with SRS/SRT or surgery if necessary is the first option; switching to another TKI with a better brain penetration is another option for patients candidates to WBRT. The longer life expectancy of ALK+ patients leads to defer as far as possible the use of WBRT. However, improvement of intracranial control should be considered in patients at preferential risk of dying from intracranial progression, independently on mutational status.
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