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Jürgen Wolf
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ES 04 - Biology of Lung Cancer (ID 513)
- Event: WCLC 2017
- Type: Educational Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Vera Luiza Capelozzi, Akihiko Gemma
- Coordinates: 10/17/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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ES 04.02 - Resistance Mechanism in TKI (ID 8118)
11:20 - 11:40 | Presenting Author(s): Jürgen Wolf
- Abstract
- Presentation
Abstract:
The implementation of mutation-directed therapy has revolutionized systemic treatment of non-small cell lung cancer (NSCLC). In particular in lung adenocarcinoma targetable driver mutations can be found in a substantial proportion of patients allowing therapy with specific tyrosine kinase inhibitors (TKI) with higher efficacy and better tolerability compared to chemotherapy. Such personalized treatment approaches partly have already become first line standard therapy (EGFR, ALK, ROS1, BRAF V600), other driver mutations are currently evaluated in clinical trials (MET, RET, HER2, NTRK). Also with these new treatment options, however, we are still far away from cure and, mostly after a median progression free survival (PFS) of 10 – 12 months, resistance develops and the patients suffer from relapse. Different mechanisms may underlie primary as well as secondary resistance, which can be subdivided in two major groups: (I) pharmacological resistance, caused by reduced absorption or increased metabolism of the drug or, as a particular challenge in patients with CNS-metastases, by inadequate CNS penetration; (II) biological resistance by molecular changes in the target molecule (resistance mutations or gene copy number gain) or by activation of oncogenic bypass pathways (1). Impressive progress in treating NSCLC patients resistant to TKI therapy has been achieved by a deep understanding of the molecular mechanisms underlying biological resistance, in particular in EGFR mutated and ALK positive NSCLC. In about 60% of patients with acquired resistance (AR) to first- or second generation EGFR-TKIs resistance is caused by the secondary EGFR point mutation T790M leading to reduced TKI binding affinity and conferring growth advantage to the cancer cells. The resistance mechanisms include activation of bypass pathways e.g. by amplification of CMET or HER2 and transition to small cell carcinoma (2). Osimertimib, a third-generation EGFR-TKI, can overcome resistance caused by the T790M mutation and, based on its high clinical activity and favorable tolerability, now has become standard treatment for patients with T790M positive AR to EGFR-TKIs (3). However, resistance also occurs under osimertinib therapy and the molecular mechanisms, which are partly different to those conferring reistance to first generation EGFR inhibitors, are increasingly understood on the molecular level. They include occurrence of the EGFR C797S mutation, activation of the RAS/RAF/MEK/ERK pathway, CMET amplification and HER2 amplification (4,5). Dependent on the molecular mechanism underlying resistance to third generation EGFR inhibitors treatment strategies include the development of next generation inhibitors with activity against C797S positive cancer cells (6) as well as the evaluation of combination therapy approaches e.g. EGFR-TKI plus MET- or MET-inhibitors. These combination approaches are evaluated in the clinical setting of manifest relapse (to overcome resistance) but also as first line treatment (to prevent or postpone relapse). Similarly, also osimertinib is being evaluated in the first line setting and a substantial higher PFS has been reported in this clinical situation. A particular challenge for molecular diagnostics as well as for the development of resistance-overcoming therapeutic strategies is clonal heterogeneity, i.e. the occurrence of different driver mutations within the same patient (7). Also in ALK positive patients substantial progress has been achieved in understanding and overcoming the molecular mechanisms underlying resistance to therapy with ALK-directed TKIs. Similarly to AR to EGFR-TKIs also in AR to ALK-TKIs resistance can be caused by resistance mutations in the ALK receptor itself or by the activation of transforming bypass pathways. A series of resistance mutations has been identified and several next-generation ALK-inhibitors are either already approved or in clinical evaluation. These ALK inhibitors differ in their activity against distinct ALK mutations providing a basis for moleculary guided sequential therapy (8). Already now, impressive prolongation of survival has been reported by the sequential use of the first generation ALK inhibitor crizotinib and the next generation ALK inhibitors alectinib and ceritinib (9,10). Also for other driver mutations like ROS1, BRAF V600 or CMET resistance to TKI therapy is increasingly understood on the molecular level enabling the development of resistance-overcoming treatment strategies for these patients. The development of molecularly guided treatment strategies in AR to TKIs also poses a challenge to molecular diagnostics. In view of the numerous mechanisms which might underly resistance, the implementation of rebiopsies and molecular multiplex diagnostics using next-generation-sequencing (NGS) technologies in clinical routine becomes increasingly important. In addition, the particular challenge of clonal heterogeneity might be addressed already in the near future by the development of highly sensitive NGS-based liquid biopsy diagnostics. References Camidge R et al. Nat Rev Clin Oncol 11, 473-481 (2014) Yu HA et al. Clin Cancer Res 8, 2240-2247 (2013) Mok TS et al. NEJM 7, 629-640 (2017) Thress KS et al. Nat Med 6, 560-562 (2015). Ortiz-Cuaran et al. Clin Cancer Res 19, 4837-4847 (2016) Jia Y et al. Nature 534, 129-132 (2016) Scheffler et al. J Thorac Oncol 10, 40-43 (2015) Gainor et al. Cancer Disc 10, 1118-1133 (2016) Gainor et al. Clin Cancer Res 21, 2745-2752 (2015) Duruisseaux et al. Oncotarget 8, 21903-21017 (2017)
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GR 01 - What to Do at the Time of Progression on Targeted Therapy (ID 520)
- Event: WCLC 2017
- Type: Grand Rounds
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:D. Kim, Lecia V Sequist
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 303 + 304
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GR 01.06 - ALK-Positive NSCLC Cases who Failed Previous ALK Inhibitors (ID 7630)
12:10 - 12:30 | Presenting Author(s): Jürgen Wolf
- Abstract
- Presentation
Abstract not provided
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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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P1.01-013 - Patient-Reported Outcomes and Safety from the Phase III ALUR Study of Alectinib vs Chemotherapy in Pre-Treated ALK+ NSCLC (ID 9007)
09:30 - 09:30 | Author(s): Jürgen Wolf
- Abstract
Background:
Alectinib demonstrated superior efficacy versus chemotherapy in ALK+ NSCLC after crizotinib failure (ALUR; NCT02604342). We present PROs and safety in the ITT population and in patients with baseline CNS disease (C-ITT).
Method:
Patients (n=107) with pre-treated ALK+ NSCLC (randomised 2:1) received alectinib (600mg BID) or chemotherapy (pemetrexed 500mg/m[2] or docetaxel 75mg/m[2] q3w) until PD/death/withdrawal. Primary endpoint: investigator-assessed PFS. Secondary endpoints: safety and PROs. Symptoms, functioning, and HRQoL were reported using questionnaires: EORTC QLQ-C30; lung module QLQ-LC13; BN-20 (3 items, CNS symptoms). Pre-specified endpoints included time-to-deterioration (TTD) in lung cancer symptoms, longitudinal analyses of mean score changes from baseline, proportion of patients with clinically meaningful change (≥10-point change from baseline) during treatment.
Result:
High compliance with assessment completion (alectinib 91.7%, chemotherapy 88.6% at baseline); compliance remained ≥70% with alectinib, and decreased with chemotherapy (64.3%, Week 6; ≤70% thereafter). Deterioration of patient-reported fatigue (median TTD 2.7 vs 1.4 months) and arm/shoulder pain (median TTD 8.1 vs 1.9 months) was delayed with alectinib versus chemotherapy. Median TTD in composite symptom endpoint (cough, dyspnoea, chest-pain) was similar between arms. Alectinib patients reported improvement in lung cancer symptoms from baseline (least square [LS] mean) during treatment: fatigue (-6.2), single-item dyspnoea (-6.0), multi-item dyspnoea scale (-2.3), coughing (-4.9), chest pain (-4.2), pain in other parts (-5.3). More patients reported improvement in baseline symptoms (nausea/vomiting, diarrhoea, peripheral neuropathy) with alectinib versus chemotherapy, except constipation. More alectinib patients reported improvements in cognitive function versus chemotherapy (ITT 19% vs 3%; C-ITT 24% vs 4%); average change from baseline in cognitive function favoured alectinib (LS means difference 10.0, 95% CI 2.2–17.7). Median treatment duration: 20.1 weeks alectinib (95% CI 0.4–8.2), 6 weeks chemotherapy (95% CI 1.9–47.1). For alectinib versus chemotherapy: AEs leading to discontinuation, 5.7% vs 8.8%; dose reductions, 4.3% vs 11.8%; dose interruptions due to AEs, 18.3% vs 8.8%. AEs: 77.1% alectinib (grade 3–5, 27.1%); 85.3% chemotherapy (grade 3–5, 41.2%); one fatal AE (chemotherapy); grade ≥3 AEs: 41.2% chemotherapy versus 27.1% alectinib. TEAEs occurring in ≥10% patients: constipation (alectinib 18.6%, all grade 1–2; chemotherapy 8.8% [grade ≥3 2.9%]), nausea (alectinib 1.4%, all grade 1–2; chemotherapy 17.6% [grade ≥3 2.9%]) and fatigue (alectinib 5.7%, all grade 1–2; chemotherapy 26.5% [grade ≥3 8.8%]).
Conclusion:
Alectinib improved HRQoL, functioning, and symptom burden versus chemotherapy (except constipation). Safety of alectinib compared favourably to chemotherapy. Alectinib patients (ITT and C-ITT populations) derived benefit versus chemotherapy.
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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: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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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 | Presenting Author(s): Jürgen Wolf
- 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
