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Enriqueta Felip
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ES 08 - Molecular Diagnostics and Targeted Therapy (ID 517)
- Event: WCLC 2017
- Type: Educational Session
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:Kwun M Fong, David Planchard
- Coordinates: 10/18/2017, 11:00 - 12:30, Main Hall
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ES 08.04 - Emerging Target Therapy in NSCLC (ID 7617)
11:45 - 12:00 | Presenting Author(s): Enriqueta Felip
- Abstract
- Presentation
Abstract:
As a result of recent advances, systematic genomic testing for patients with non-small cell lung cancer (NSCLC) is the new standard of care in clinical decision-making, due to the identification of driver molecular alterations that have triggered the development of new molecules targeting these specific alterations in cancer cells. Several studies have enabled to conclude that both EGFR-mutant and ALK-positive NSCLC constitute two defined subgroups of oncogene-driven tumors with potentially effective targeted therapy. Furthermore, approximately 15-20% of NSCLC diagnosed in Europe and North America bear EGFR mutations or ALK rearrangements, enhancing the significance of the development of drugs capable of interfering with their intracellular effects. Based on these results, the identification of other activating mutations has been pursued in hopes of improving survival in NSCLC by specifically treating these genomic alterations. These potential therapeutic targets include ROS1, BRAF, RET, HER2, MET exon 14 skipping mutations and NTRK, among others. Here, we seek to review the characteristics of emerging targets that enable interaction with molecules that specifically target these receptors in lung adenocarcinomas, as well as the results of preliminary studies that assess the efficacy of these new strategies applied to NSCLC. ROS1 ROS1 rearrangement characterizes a small subset (1%–2%) of NSCLC and is associated with slight/never smoking patients and adenocarcinoma histology. Crizotinib was shown to harbor relevant activity in ROS1-rearranged NSCLC. A number of agents including ceritinib, lorlatinib and entrectinib are now been developed in order to overcome the resistance to crizotinib. At present, ROS1-rearranged patients represents a clearly defined NSCLC molecular subgroup with highly active therapeutic options. BRAF BRAF mutations occur in 2%–4% of patients with NSCLC, with the most common resulting in a glutamate substitution for valine at codon 600 (V600E). Non‐V600E BRAF mutations make up the remaining BRAF mutations and may be either activating (i.e., G469A/V, K601E, L597R) or inactivating (i.e., D594G, G466V). Efforts targeting BRAF‐mutant NSCLC to date have almost exclusively focused on patients with V600E‐mutant disease. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase has led to good outcomes survival in patients with BRAF-mutant metastatic NSCLC. Dabrafenib plus trametinib achieved 63·2% response rate (RR) in BRAF(V600E)-mutant NSCLC. RET RET fusions are detected in 1-2% of lung adenocarcinomas and a number of genes, such as KIF5B, CCDC6, NCO4 and TRIMM33, can act as fusion partners. In a global registry of RET positive NSCLC patients, 41 received a RET inhibitor achieving a median progression-free survival of 2.9 months and a median overall survival of 6.8 months. Response rate was 34% for those patients receiving cabozantinib and 27% for those receiving vandetanib. Overall RET inhibitors strategies seem active in a subgroup of patients with RET-rearranged NSCLC. However, RR is lower to that observed in EGFR-mutated/ALK-positive patients. HER2 HER2 mutations are identified in about 2-4% of NSCLC and are critical for lung carcinogenesis. A number of series shows the chemosensitivity of HER2-driven NSCLC, and the potential interest of HER2-targeted agents. In a recent study, NSCLC patients with HER2 mutations were treated with T-DM1 and achieved a 44% RR. MET Approximately 2-3% of NSCLCs harbor activating mutations of the MET proto-oncogene that cause exon 14 skipping (METex14) and accumulation of c-Met lacking a juxtamembrane domain. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated in patients harboring MET exon 14 skipping lung cancer. MET seems a relevant target in NSCLC and a number of clinical trials with MET inhibitors in this population are now ongoing. NTRK TRK rearrangements represent the molecular driver of a subset of solid tumors, including 1-2% of NSCLCs. Preliminary data indicate that molecularly selected NSCLC patients harboring NTRK fusions derive an unprecedented clinical benefit from Trk-directed targeted therapies. There are two different targeted agents, entrectinib and larotrectinib, that are in phase II testing for any patients who have solid tumors with NTRK rearrangement, including NSCLC patients. Both drugs have achieved dramatic responses, regardless of histology in earlier phase I studies. In a study presented at ASCO 2017, larotrectinib has demonstrated consistent and durable antitumor activity in TRK fusion cancers, across a wide range of ages and tumor types. REFERENCES Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS-1 rearranged non-small-cell lung cancer: N Engl J Med. 2014; 371:1963-1971. Planchard D, Besse B, Groen HJ, et al. Dabrafenib plus trametininb in patients with previously treated BRAF (V600E)-mutant metastatic non-small cell lung cancer: an opne-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984-993. 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. 2017;35:1403-1410. Mazières J, Barlesi F, Filleron T, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol. 2016;27:281-286. Lu X, Peled N, Greer J, et al. MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma. Cancer Res. 2017 May 18. [Epub ahead of print]. Drilon A, Nagasubramanian R, Blake JF, et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov. 2017 Jun 3. [Epub ahead of print]. Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. J Clin Oncol. 2017;35 (suppl; abstr LBA2501). Riely GL. What, When, and How of Biomarker Testing in Non-Small Cell Lung Cancer. J Natl Compr Canc Netw. 2017;15:686-688. Jordan EJ, Kim HR, Arcila ME, et al. Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer Discov. 2017;7:596-609.
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.02 - Phase 2 Study of Pembrolizumab Plus CC-486 vs Pembrolizumab Plus Placebo in Previously Treated Patients with Advanced NSCLC (ID 8581)
11:05 - 11:10 | Author(s): Enriqueta Felip
- Abstract
- Presentation
Background:
Studies have demonstrated that epigenetic modifiers, such as azacitidine, may sensitize tumor cells to treatment with checkpoint inhibitors, such as pembrolizumab (pembro). Efficacy and safety results from a phase 2, randomized, double-blind study of pembro in combination with CC-486, an oral formulation of azacitidine, vs pembro+placebo (PBO) for 2L treatment of advanced NSCLC are reported.
Method:
Patients aged ≥ 18 years with stage IIIB/IV NSCLC with only 1 prior platinum-based chemotherapy were randomized 1:1 (stratified by histology) to pembro 200 mg day 1 plus either CC-486 300 mg or placebo days 1-14 of a 21-day cycle. Primary endpoint was PFS. Key secondary endpoints included OS, ORR and safety.
Result:
51 and 49 patients were randomized to the pembro+CC-486 and pembro+PBO arms. Baseline characteristics were generally balanced between treatment groups. Efficacy results are shown in Table 1. Median duration of treatment for pembro+CC-486 vs pembro+PBO was 14 vs 24 weeks, and median number of cycles was 5 vs 7. The most common grade 3/4 TEAEs associated with pembro+CC-486 were nausea (14%), vomiting (12%), asthenia (10%), and diarrhea (8%), vs diarrhea (6%), asthenia (6%) and pneumonia (6%) with pembro+PBO. Patients treated with pembro+CC-486 vs pembro+PBO experienced a higher rate of pembro dose interruptions (29% vs 16%) and discontinuations (20% vs 10%), and a higher rate of CC-486 or PBO dose interruptions (61% vs 24%) and discontinuations (33% vs 12%). Gastrointestinal events, asthenia/fatigue, and elevated transaminase levels were the most common TEAEs leading to discontinuations.
Conclusion:
The addition of CC-486 to pembro did not improve the primary endpoint of PFS compared with pembro+PBO. PD-L1 expression did not appear to be predictive of CC-486 treatment efficacy. The increase in TEAEs in the combination arm, particularly gastrointestinal (nausea and vomiting), which are known to be associated with CC-486, may have influenced treatment exposure.Efficacy Endpoints Pembro + CC-486 n = 51 Pembro + PBO n = 49 Overall PFS, median, months 3.1 4.0 ORR, n (%) 10 (19.6) 7 (14.3) By PD-L1 Level at Baseline n = 45 n = 44 PFS, median, months ≥ 50% ≥ 1%-49% 0% 5.5 1.6 3.6 8.0 1.4 3.9 ORR, % ≥ 50% ≥ 1%-49% 0% 37.5 20.0 18.5 37.5 0.0 7.1
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
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MA 15.01 - LungBEAM: A Prospective Multicenter Trial to Monitor EGFR Mutations Using BEAMing Technology in Stage IV NSCLC Patients (ID 10145)
15:45 - 15:50 | Author(s): Enriqueta Felip
- Abstract
- Presentation
Background:
Liquid biopsy is a promising approach to improve the management of NSCLC patients, offering a minimally-invasive alternative to tumor tissue testing and enabling timely monitoring of patients on-therapy. The goal of the present study was to evaluate the performance of the OncoBEAM EGFR plasma vs EGFR tissue testing across 19 Spanish hospitals and to examine the timing of T790M mutation emergence in patients during first-line EGFR TKI therapy with respect to radiological progression.
Method:
Blood samples from 112 therapy-naïve advanced NSCLC patients were collected at baseline and throughout EGFR TKI therapy. Results from OncoBEAM EGFR mutation were performed by Sysmex in Hamburg, Germany and then compared to those obtained by the initial EGFR tissue testing obtained at the referring hospital. In addition, the time at which T790M was first detected was compared to the date of progression determined by radiological imaging.
Result:
112 stage IV NSCLC patients (p) were enrolled between Nov 2016 and May 2017. Clinical characteristics: median age 65 y. , 81 female. Smoking pattern: never 70 p (62,5%), former 33 p (29.4%) and active 9 (8%). M1a 28 p (25%), M1b only brain 10 p (8.9%), only bone 17 p (15%). Baseline tissue samples: Exon 19 deletion 74 p (66%) , L858R 38 p (34%). Initial positive percent agreement (PPA) in 69 out of 112 p was 52/69 or 75.4%. Interestingly, the agreement between plasma and tissue EGFR mutation results for patients diagnosed at M0 was 56%, versus 81% with patients diagnosed at M1. In addition, the average number of days between tissue biopsy and blood collection for concordant cases was 128 days, versus 358 days for discordant cases. Currently, the tissue EGFR mutation status of all discordant cases is being re-examined using BEAMing. Preliminary results from serial T790M plasma analyses revealed cases where detection by OncoBEAM was observed several weeks prior to documented progression by imaging. More mature results will be available at the time of the meeting
Conclusion:
Overall, these initial results show high PPA of plasma and tissue EGFR mutation status at baseline. Moreover, early detection of T790M in blood may assist in anticipating resistance to first-line EGFR TKI therapy.
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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 05.06 - Phase 2 Study of Lorlatinib in Patients with Advanced ALK<sup>+</sup>/ROS1<sup>+</sup> Non-Small-Cell Lung Cancer (ID 8573)
16:40 - 16:50 | Author(s): Enriqueta Felip
- Abstract
- Presentation
Background:
Lorlatinib, a selective, potent, brain-penetrant ALK/ROS1 TKI, is active against most known ALK kinase domain mutations. In phase 1 of this ongoing study (NCT01970865), lorlatinib displayed robust clinical activity among patients with ALK[+]/ROS1[+] non-small-cell lung cancer (NSCLC), most of whom were heavily pretreated and had CNS metastases. Phase 2 evaluated efficacy (overall and intracranial), according to prior treatment, and safety at the recommended phase 2 dose (100 mg QD).
Method:
Patients with NSCLC ± asymptomatic CNS metastases enrolled in 6 cohorts (EXP1–5, ALK[+]; EXP6, ROS1[+]). The primary endpoint was objective response rate (ORR) and intracranial ORR by independent central review. Safety, patient-reported outcomes and molecular profiling were also assessed.
Result:
As of 15-March-2017, 227 ALK[+] patients were evaluated for ORR (Table), including 140 with CNS involvement who were evaluated for intracranial ORR.
Of 219 ALK+ patients analyzed for ALK kinase domain mutations at baseline, 46/219 (21%) had ≥1 mutation detected in circulating free DNA; most derived treatment benefit with an ORR of (27/46) 59%. Across all cohorts (N=275), the most common treatment-related adverse events (AEs) and grade 3/4 treatment-related AEs were hypercholesterolemia (81%/16%) and hypertriglyceridemia (60%/16%); 30% and 22% of patients had treatment-related AEs associated with dose interruptions and reductions, respectively. No treatment-related deaths occurred; 7 patients (3%) had treatment-related AEs leading to treatment discontinuation. 157/275 (57%) patients remained on treatment at data cutoff. Most patients reported stable/improved global quality of life (40%/43%).Confirmed ORR Confirmed IC-ORR N n (%) N n (%) ALK[+] cohorts EXP1 (treatment-naïve, no prior ALK-TKIs or CT) 30 27 (90) 8 6 (75) EXP2 (prior crizotinib only) 27 20 (74) 17 10 (59) EXP3 (1 prior ALK TKI ± CT) 59 30 (51) 32 20 (63) EXP3A (prior crizotinib + CT) 32 21 (66) 20 15 (75) EXP3B (any 1 other ALK TKI ± CT) 27 9 (33) 12 5 (42) EXP4 (2 prior ALK TKIs ± CT) 65 27 (42) 45 25 (56) EXP5 (3 prior ALK TKIs ± CT) 46 16 (35) 38 (15 (39) CT, chemotherapy; IC, intracranial.
Conclusion:
Lorlatinib showed clinically meaningful activity, including substantial intracranial efficacy, among ALK[+]/ROS1[+] patients who were either treatment-naïve or failed ≥1 prior ALK TKI. Overall lorlatinib was well tolerated and when needed, AEs were managed by dose delay/reduction or standard medical therapy.
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.02 - Updated Efficacy Results From the BIRCH Study: First-Line Atezolizumab Therapy in PD-L1–Selected Patients With Advanced NSCLC (ID 8006)
14:40 - 14:50 | Author(s): Enriqueta Felip
- Abstract
- Presentation
Background:
The anti–PD-L1 mAb atezolizumab blocks the interactions between PD-L1 and its receptors, PD-1 and B7.1, thus restoring anti-tumor immunity. A Phase II study of atezolizumab monotherapy was conducted across multiple lines of therapy in PD-L1–selected patients with advanced NSCLC (BIRCH; NCT02031458). The primary analyses showed meaningful and durable clinical benefit with atezolizumab monotherapy in 1L and 2L+ NSCLC. Here we present updated survival data (median follow-up, 29.7 months) in patients receiving 1L atezolizumab.
Method:
Eligible patients had chemotherapy-naive, locally advanced or metastatic NSCLC without CNS metastases. Prior TKI therapy was required in patients with EGFR mutation or ALK rearrangement. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was centrally evaluated (VENTANA SP142 IHC assay). Patients who were TC2/3 or IC2/3 (PD-L1 expression on ≥ 5% of TC or IC) were enrolled. Atezolizumab 1200 mg was administered IV q3w until disease progression or unacceptable toxicity. The primary endpoint was independent review facility (IRF)–assessed ORR. Secondary endpoints included investigator (INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.
Result:
With a median follow-up of 29.7 months, median OS was 26.9 months (TC3 or IC3 subgroup) and 24.0 months (all treated patients); INV-assessed ORR was 35% (TC3 or IC3 subgroup) and 26% (all treated patients; Table). Among evaluable patients, the ORR was 31% for mutant EGFR (4/13) vs 23% for wild-type EGFR patients (24/103), and 31% for mutant KRAS (10/32) vs 24% for wild-type KRAS patients (16/66). No new safety signals were observed.
Conclusion:
With more than 2 years of follow-up, atezolizumab continued to demonstrate durable clinical activity in 1L NSCLC, regardless of EGFR and KRAS mutational status. These data suggest that atezolizumab monotherapy has promising activity as a frontline therapy. Ongoing Phase III trials are evaluating atezolizumab-based regimens vs chemotherapy in 1L NSCLC.Endpoint (95% CI) TC3 or IC3[a ](n = 65) TC2 or IC2[b] (n = 73) All Treated Patients (N = 138) INV-assessed ORR, % 35% (23.9, 48.2) 18% (9.8, 28.5) 26% (19.0, 34.2) EGFR mutant/wild-type, % 25%/33% 33%/15% 31%/23% KRAS mutant/wild-type, % 38%/33% 25%/15% 31%/24% mDOR, mo 16.5 (8.5, NE) 12.5 (8.3, 17.9) 13.1 (9.9, NE) mOS, mo 26.9 (12.0. NE) 23.5 (18.1, NE) 24.0 (18.1, 31.9) 12-mo OS rate, % 61% (49.0, 74.0) 71% (59.8, 81.5) 66% (58.1, 74.6) 24-mo OS rate, % 52% (39.3, 65.2) 49% (37.0, 61.1) 50% (41.5, 59.2) 30-mo OS rate, % 48% (35.3, 61.5) 39% (27.2, 51.2) 43% (34.3, 52.1) mPFS, mo 7.3 (4.9, 12.0) 7.6 (4.0, 9.7) 7.6 (5.7, 9.7) 12-mo PFS rate, % 38% (25.1, 49.9) 30% (19.2, 41.2) 34% (25.3, 41.9) 24-mo PFS rate, % 28% (16.5, 40.0) 13% (4.5, 21.5) 20% (12.9, 27.5) 30-mo PFS rate, % 19% (5.4, 33.5) 9% (1.4, 16.4) 14% (6.5, 21.9) NE, not estimable. [a ]TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells.[b ]TC2/3 or IC2/3 excluding TC3 or IC3.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-012 - Ceritinib in Anaplastic Lymphoma Kinase (ALK)+ NSCLC Patients Pretreated With Only Crizotinib: ASCEND-1 Subgroup Analysis (ID 8972)
09:30 - 09:30 | Author(s): Enriqueta Felip
- Abstract
Background:
In phase 1 ASCEND-1 study (NCT01283516), ceritinib 750 mg/day (fasted) demonstrated durable whole-body and intracranial responses in both anaplastic lymphoma kinase inhibitor (ALKi)-naïve and ALKi-pretreated patients with ALK-rearranged non-small cell lung cancer (NSCLC). Here, we report the efficacy and safety of ceritinib in patients who were pretreated with crizotinib only from the ASCEND-1 study.
Method:
Patients with ALK+ NSCLC who were enrolled globally received ceritinib 750 mg/day (fasted). Efficacy and safety were evaluated in a subset of patients who had received prior crizotinib only (no other prior antineoplastic therapy). Data cut-off was May 03, 2016.
Result:
Overall, 246 patients with ALK+ NSCLC (83 ALKi-naïve and 163 ALKi-pretreated) received ≥1 dose of ceritinib, of whom, 26 had received prior crizotinib only. Among the 26 crizotinib-pretreated patients, 11 (42.3%) had baseline brain metastases, of which, 7 received prior radiotherapy, 6 (23.1%) had an ECOG performance status of 0, and 24 (92.3%) patients had stage IV disease. The median time from initial diagnosis to ceritinib initiation was 10.5 months (range, 2.4-33.0). At data cut-off, the median duration of exposure (range) was 41.0 weeks (2.9-180.4). In the 26 crizotinib-pretreated patients, per investigator assessment, the overall response rate was 65.4% (95% confidence interval [CI]: 44.3, 82.8), and the disease control rate was 80.8% (95% CI: 60.6, 93.4) (Table). The most frequently reported grade 3/4 adverse events (AEs), regardless of study drug relationship, were ALT increased (30.8%), AST increased (15.4%), diarrhea (11.5%), nausea (7.7%), fatigue (7.7%), and blood alkaline phosphatase increased (7.7%). All 26 patients discontinued treatment due to disease progression (n=12), consent withdrawal (n=6), AEs (n=2), administrative problems (n=4), or death (n=2).
*Median value derived from summary statistics; **Median value estimated by Kaplan-Meier method.Investigator Assessment N=26 Blinded Independent Review Committee Assessment N=26 Best overall response Complete response (CR), n (%) 1 (3.8%) 1 (3.8%) Partial response (PR), n (%) 16 (61.5%) 15 (57.7%) Stable disease (SD), n (%) 4 (15.4%) 5 (19.2%) Progressive disease (PD), n (%) 2 (7.7%) 1 (3.8%) Unknown, n (%) 3 (11.5%) 4 (15.4%) Overall response rate (ORR), % [95% CI] 65.4% [44.3-82.8] 61.5% [40.6-79.8] Disease control rate (DCR), % [95% CI] 80.8% [60.6-93.4] 80.8% [60.6-93.4] Median time to response*, weeks [95% CI] 6.1 [5.1-23.6] 6.4 [5.1-14.0] Median DOR**, months [95% CI] 8.3 [4.2-11.2] 8.5 [3.0-13.6] Median PFS**, months [95% CI] 8.5 [5.3-9.9] 8.2 [4.4-15.2]
Conclusion:
Ceritinib demonstrated durable efficacy in crizotinib-pretreated patients with ALK-rearranged NSCLC. Safety was consistent with the overall ASCEND-1 study population.
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P1.05 - Early Stage NSCLC (ID 691)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.05-015 - Major Pathological Response as a Predictive Value of Survival in Early-Stage NSCLC After Chemotherapy: Cohort of NATCH Phase III Trial (ID 9893)
09:30 - 09:30 | Author(s): Enriqueta Felip
- Abstract
Background:
In early-stage non-small cell lung cancer (NSCLC) patients, randomized phase III NATCH trial reported no statistically differences in disease-free survival (DFS) or overall survival (OS) with the addition of preoperative or adjuvant chemotherapy to surgery. In pre-operative arm, those patients who achieved a complete response obtained a benefit in 5-year DFS rate (59% vs. 38%). Recently, major pathological response (MPR) to preoperative therapy (10% or less of residual viable tumor after preoperative chemotherapy) has reported as surrogate marker of OS. We assess to validate this prognostic factor in a cohort of patients included the NATCH trial.
Method:
Retrospectively MPR was collected in a cohort of 57 early-stage NSCLC patients treated in the preoperative arm into NATCH trial from 2 institutions. OS according to MPR was analysed (long-rank test) in the whole population and by histologic subtype
Result:
In this cohort, median age was 67 years (47-78), 48 (84%) were males, 26 (46%) squamous subtype. By stage according to 6[th] TNM: 9 (16%) stage IA, 35 (61%) stage IB, 12 (21%) stage IIB and 1 (2%) stage IIIA. All except 3 completed 3 cycles of preoperative treatment. Surgical procedures: 81% lobectomies or bi-lobectomies, 14% pneumonectomies, 5% no surgery. In the whole population, there was a trend toward 5-year OS benefit among those patients with MPR (84.6% vs. 58.5%, p=0.106). According to histologic subtype, squamous tumours with MPR had significantly better 5-year OS (100% vs. 47.1%, p=0.026), but not in adenocarcinoma subtype (66.7% vs. 66.7%, p=0.586).
Conclusion:
MPR is a prognostic value in squamous NSCLC patients who receive preoperative chemotherapy. Validation in extended cohort merits further evaluation.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 3
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-004 - IMpower010: A Phase III Study of Atezolizumab vs Best Supportive Care Following Adjuvant Chemotherapy in Completely Resected NSCLC (ID 8896)
09:30 - 09:30 | Presenting Author(s): Enriqueta Felip
- Abstract
Background:
Atezolizumab is an anti–PD-L1 mAb that blocks PD-L1 from interacting with its receptors PD-1 and B7.1 and restores anti-cancer immunity. In patients with 2L/3L advanced NSCLC, the OAK trial showed improved mOS in the atezolizumab arm (13.8 mo) vs the docetaxel arm (9.6 mo), with survival benefit observed across all PD-L1 expression levels on tumor cells (TC) or tumor-infiltrating immune cells (IC). In patients with fully resected NSCLC (stages IB [tumors ≥ 4 cm]-IIIA), adjuvant chemotherapy remains the standard of care, but survival benefit is limited. Therefore, more effective therapies are still needed for patients with early-stage NSCLC. IMpower010 (NCT02486718) is a global Phase III, randomized, open-label trial conducted to evaluate the efficacy and safety of atezolizumab vs best supportive care (BSC) following adjuvant cisplatin–based chemotherapy in patients with resected stage IB (tumors ≥ 4 cm)-IIIA NSCLC.
Method:
Eligibility criteria include complete tumor resection 4-12 weeks prior to enrollment for pathological stage IB (tumors ≥ 4 cm)-IIIA NSCLC, adequate recovery from surgery, ability to receive cisplatin-based adjuvant chemotherapy and ECOG PS 0-1. Patients with other malignancies, autoimmune disease, hormonal cancer or radiation therapy within 5 years and prior chemotherapy or immunotherapy will be excluded. Approximately 1127 patients will be enrolled regardless of PD-L1 status. Patients will receive up to four 21-day cycles of cisplatin-based chemotherapy (cisplatin [75 mg/m[2] IV, day 1] + vinorelbine [30 mg/m[2] IV, days 1, 8], docetaxel [75 mg/m[2] IV, day 1] or gemcitabine [1250 mg/m[2] IV, days 1, 8], or pemetrexed [500 mg/m[2] IV, day 1; only non-squamous NSCLC]). Adjuvant radiation therapy is not permitted. Eligible patients will be randomized 1:1 to receive 16 cycles of atezolizumab 1200 mg q3w or BSC post-adjuvant chemotherapy. Stratification factors include sex, histology (squamous vs non-squamous), disease stage (IB vs II vs IIA) and PD-L1 status by IHC (TC2/3 [≥ 5% expressing PD-L1] and any IC vs TC0/1 [< 5%], and IC2/3 vs TC0/1 and IC0/1 [< 5%]). The primary endpoint is disease-free survival, and secondary endpoints include OS and safety. Exploratory biomarkers will be evaluated, including PD-L1 expression and immune- and tumor-related biomarkers before, during and after treatment with atezolizumab and at radiographic disease recurrence or confirmation of new primary NSCLC.
Result:
Section not applicable
Conclusion:
Section not applicable
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P2.04-005 - GEOMETRY Mono-1: Phase II, Multicenter Study of MET Inhibitor Capmatinib (INC280) in EGFR Wt, MET-Dysregulated Advanced NSCLC (ID 8961)
09:30 - 09:30 | Author(s): Enriqueta Felip
- Abstract
Background:
Amplification of MET leading to oncogenic signaling occurs in 3‒5% of newly diagnosed EGFR wild type (wt) non-small cell lung cancer (NSCLC) cases with decreasing incidence at higher levels of amplification. Mutations in MET leading to exon 14 deletion (METΔ[ex14]) also occur in 2–4% of adenocarcinoma and 1–2% of other NSCLC subsets. Capmatinib (INC280) is a potent and selective MET inhibitor that has shown strong evidence of antitumor activity in a phase I study in patients with EGFR wt advanced NSCLC harboring MET amplification and METΔ[ex14].
Method:
This phase II, multicenter study (NCT02414139) was designed to confirm the clinical activity of capmatinib in patients with advanced NSCLC by MET amplification and METΔ[ex14] status. Eligible patients (≥18 years of age, Eastern Cooperative Oncology Group Performance Status 0–1) must have ALK-negative, EGFR wt, stage IIIB/IV NSCLC (any histology). Centrally assessed MET amplification (gene copy number [GCN]) and mutation status is used to assign patients to one of the below cohorts: Pretreated with 1–2 prior systemic lines of therapy for advanced setting (cohorts 1–4): 1a: MET amplification GCN ≥10 (n=69) 1b: MET amplification GCN ≥6 and <10 (n=69) 2: MET amplification GCN ≥4 and <6 (n=69) 3: MET amplification GCN <4 (n=69) 4: METΔ[ex14] mutation regardless of MET GCN (n=69) Treatment naïve (cohorts 5a and 5b): 5a: MET amplification GCN ≥10 and no METΔ[ex14] mutation (n=27) 5b: METΔ[ex14] mutation regardless of MET GCN (n=27) Capmatinib 400 mg tablets are orally administered twice daily on a continuous dosing schedule 12 hours apart. Primary and key secondary endpoints are overall response rate (ORR) and duration of response (DOR), respectively (blinded independent review assessment). Other secondary endpoints include investigator-assessed ORR, DOR, time to response, disease control rate, progression-free survival (independent and investigator assessment), safety, and pharmacokinetics. Enrollment is ongoing in 25 countries. Cohorts 1b, 2, and 3 are now closed to enrollment; cohorts 1a and 4 continue to enroll patients who have received 1–2 prior lines of therapy in the advanced setting, and cohorts 5a and 5b are open for enrollment of treatment-naïve patients. Responses have been seen in both MET-amplified and MET-mutated patients irrespective of the line of therapy.
Result:
Section not applicable
Conclusion:
Section not applicable
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P2.04-013 - ElevatION:NSCLC-101 – A Phase 1b Study of PDR001 Combined with Chemotherapy in PD-L1 Unselected, Metastatic NSCLC Patients (ID 8936)
09:30 - 09:30 | Presenting Author(s): Enriqueta Felip
- Abstract
Background:
PDR001 is a high-affinity, humanized antiprogramed cell death-1 (PD-1) antibody that blocks interaction with programmed cell death ligands, PD-L1 and PD-L2. Results from phase 1/2 study have shown that PDR001 has a manageable safety profile and preliminary antitumor activity in advanced solid tumors. ElevatION:NSCLC-101 is the first study to evaluate the safety and preliminary efficacy of PDR001 plus platinum-doublet chemotherapy in patients with PD-L1 unselected, advanced NSCLC.
Method:
ElevatION:NSCLC-101 is an open-label, multicenter, phase 1b study (NCT03064854) of PDR001 plus platinum-doublet chemotherapy in patients (≥18 years) with squamous or nonsquamous, stage IIIB (not a candidate for definitive multimodality therapy) or stage IV or relapsed locally advanced or metastatic NSCLC, lacking EGFR-sensitizing mutation and/or ALK- or ROS1-rearrangements. Other inclusion criteria: ECOG PS 0-1, ≥1 measurable lesion (per RECIST v1.1), relapse for >12 months from the end of neoadjuvant or adjuvant systemic therapy. PD-L1 expression will be assessed but will not be used to determine eligibility. This study comprises 2 parts (dose-confirmation and dose-expansion) and 4 treatment groups (A, B, C, and D). Groups A, B, and C (dose-confirmation and dose-expansion parts) will include treatment-naïve patients. Group D (dose-expansion part) will include second line patients – those who have received only 1 prior systemic therapy consisting of a PD-1 and/or PD-L1 inhibitor ± CTLA-4 inhibitor (last dose of prior immunotherapy, ≥6 weeks prior to start of study treatment). The treatment-naïve patients will receive gemcitabine/cisplatin (group A) or pemetrexed/cisplatin (group B) or paclitaxel/carboplatin (group C) plus PDR001 (initially 300 mg q3w; if intolerable, a provisional dose level (−1) of 300 mg q6w will be explored) for up to 4 cycles followed by maintenance with PDR001 ± pemetrexed (group B). The second-line patients (group D) will be randomized (1:1) to either platinum-doublet chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) alone/combined with PDR001. Primary endpoints: dose-confirmation part – MTD and/or recommended dose for expansion (DLTs during first 6 weeks of therapy; for groups A, B, and C); dose-expansion part – investigator-assessed ORR per RECIST v1.1 (for groups A, B, and C). Secondary endpoints: ORR (for group D); PFS, DCR, DOR, TTR (for groups A, B, C, and D); OS, PK, and safety. The study enrollment is still ongoing. Approximately 6 to 20 treatment-naïve patients will be assigned to each group (A, B, C) and once MTD/RDE is established, ~20 additional patients will be enrolled in each treatment group; ~60 pretreated patients will be enrolled in group D.
Result:
Not-applicable.
Conclusion:
Not-applicable.
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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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P3.01-043 - Impact of ErbB Mutations on Clinical Outcomes in Afatinib- or Erlotinib-Treated Patients with SCC of the Lung (ID 9457)
09:30 - 09:30 | Author(s): Enriqueta Felip
- Abstract
Background:
In LUX-Lung 8 (LL8), second-line afatinib (an irreversible ErbB family blocker) significantly improved OS (median 7.9 versus 6.8 months; HR [95% CI]: 0.81 [0.69‒0.95]; p=0.0077), and PFS (2.6 versus 1.9 months; 0.81 [0.69‒0.96]; p=0.0103) versus erlotinib in lung SCC (N=795). Comprehensive genetic analysis in LL8 patients assessed whether afatinib efficacy varied according to genetic aberrations in cancer-related genes, including ErbB family mutations.
Method:
Tumor genetic analysis (TGA) was performed using Foundation Medicine FoundationOne™ next-generation sequencing (NGS). The cohort was enriched for patients with PFS >2 months, reflecting a range of responsiveness to EGFR-TKIs. EGFR expression was assessed by immunohistochemistry (IHC) in a largely separate cohort. Cox regression analysis correlated PFS/OS with genetic mutations (individual/grouped) and EGFR expression.
Result:
Of 440 patients selected for TGA (PFS >2 months: n=320; ≤2 months: n=120), samples from 245 were eligible (afatinib: n=132; erlotinib: n=113). In the selected TGA population, PFS/OS outcomes were improved in the afatinib versus erlotinib arm. Baseline characteristics were similar in TGA and IHC cohorts and LL8 overall. In the TGA subset, 53 patients (21.6%) had ≥1 ErbB family mutation (EGFR: 6.5%; HER2: 4.9%; HER3: 6.1%; HER4: 5.7%). Beyond the benefit seen for afatinib in the overall population, in afatinib-treated patients, PFS/OS were longer when ErbB mutations were present (PFS: 4.9 versus 3.0 months; OS: 10.6 versus 8.1 months). Conversely, survival outcomes in erlotinib-treated patients were similar with/without ErbB mutations. Presence of HER2 mutations predicted favorable PFS/OS with afatinib versus erlotinib. The Table shows outcomes in patients with/without ErbB family mutations, and by EGFR expression levels (afatinib: n=157; erlotinib: n=188).
Conclusion:
These data are provocative and suggest that NGS may enable identification of lung SCC patients who would derive additional clinical benefit from afatinib. Differential outcomes with respect to ErbB mutations for afatinib and erlotinib are hypothesized to reflect afatinib’s broader mechanism of action.Subgroup n Afatinib vs erlotinib PFS OS HR (95% CI) p~interaction~ HR (95% CI) p~interaction~ ErbB mutation-positive ErbB mutation-negative 53 192 0.56 (0.29–1.08) 0.70 (0.50–0.97) 0.718 0.62 (0.35‒1.12) 0.76 (0.56‒1.03) 0.683 EGFR mutation-positive EGFR mutation-negative 16 229 0.64 (0.17–2.44) 0.67 (0.50–0.91) 0.981 1.01 (0.32–3.16) 0.72 (0.54–0.95) 0.529 HER2 mutation-positive HER2 mutation-negative 12 233 0.06 (0.01–0.59) 0.72 (0.54–0.97) 0.006 0.06 (0.01–0.57) 0.76 (0.58–1.00) 0.004 HER3 mutation-positive HER3 mutation-negative 15 230 0.52 (0.16–1.72) 0.69 (0.51–0.94) 0.692 0.84 (0.27–2.59) 0.73 (0.56–0.97) 0.998 HER4 mutation-positive HER4 mutation-negative 14 231 0.21 (0.02–1.94) 0.67 (0.50–0.91) 0.909 0.22 (0.05–1.04) 0.75 (0.56–0.99) 0.272 EGFR IHC positive EGFR IHC negative 292 53 0.74 (0.56–0.97) 0.76 (0.41–1.40) 0.985 0.82 (0.63–1.06) 0.75 (0.41–1.40) 0.882 EGFR amplification present EGFR amplification absent 17 228 0.72 (0.18–2.90) 0.68 (0.50–0.92) 0.994 0.50 (0.15–1.65) 0.76 (0.58–1.00) 0.413 HER2 amplification present HER2 amplification absent 9 236 0.94 (0.20–4.38) 0.68 (0.50–0.91) 0.861 1.10 (0.27–4.48) 0.72 (0.54–0.94) 0.388
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P3.07 - Immunology and Immunotherapy (ID 723)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.07-012 - Nivolumab Versus Docetaxel in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer and Liver Metastases (ID 8484)
09:30 - 09:30 | Author(s): Enriqueta Felip
- Abstract
Background:
Patients with non-small cell lung cancer (NSCLC) who have metastasis to the liver have poor prognosis. The phase 3 trials CheckMate 017 and 057 demonstrated improved overall survival (OS) and a favorable safety profile with nivolumab, an anti-programmed death-1 antibody, versus docetaxel in patients with previously treated advanced squamous and non-squamous NSCLC, respectively. A prior subgroup analysis from these trials evaluated and demonstrated efficacy and safety with nivolumab in patients with asymptomatic central nervous system metastases (Goldman J. ASCO 2016). Here we report subgroup analyses from these trials of patients with baseline liver metastases.
Method:
In both trials, patients were randomized 1:1 to nivolumab 3 mg/kg every 2 weeks or docetaxel 75 mg/m[2] every 3 weeks until progression or discontinuation. The primary endpoint of each study was OS. Patients from CheckMate 017 and 057 with baseline liver metastases reported as either target or non-target lesions were identified and pooled across studies by treatment.
Result:
Baseline characteristics were generally similar between patients with liver metastases randomized to nivolumab (n=99) and docetaxel (n=94). In the nivolumab group, 26% of patients had squamous and 74% had non-squamous NSCLC; in the docetaxel group, 36% had squamous and 64% had non-squamous NSCLC. The minimum follow-up was 24.2 months (Feb 2016 database locks). Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio [HR]=0.68; 95% confidence interval [CI]: 0.50, 0.91), similar to findings from the ITT group (HR=0.72; 95% CI: 0.62, 0.84). Median OS in patients with liver metastases was 6.83 months with nivolumab versus 5.93 months with docetaxel, both of which were lower than those observed in the overall pooled intent-to-treat (ITT) population (11.14 months vs 8.11 months). Two-year OS rates were 18% with nivolumab versus 6% with docetaxel in patients with liver metastases. Rates of grade 3−4 treatment-related adverse events in patients with liver metastases were lower with nivolumab compared with docetaxel (7% vs 53%), and similar to those in the ITT population (10% vs 55%).
Conclusion:
The lower median OS observed in this subgroup of patients with previously treated advanced NSCLC and baseline liver metastases corroborates previous findings that metastasis to the liver is an unfavorable prognostic factor. However, nivolumab demonstrated sustained OS benefit versus docetaxel in these patients, similar to the ITT population. The safety profile of nivolumab was favorable versus docetaxel in this subgroup, with no new safety concerns identified.
