Targeted therapy in NSCLC: do we progress? Prof. Dr. V. Surmont Masterclass 27 september 2018
Outline Introduction EGFR TKI ALK TKI TKI for uncommon driver mutations Take home messages
The promise of genotype directed therapy EGFR mutation Erlotinib or gefitinib ALK (or ROS) Crizotinib, other ALK TKIs NSCLC Treatment C Treatment D
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Succes Failure-resistance 9 /
EGFR TKI first generation second generation third generation
EGFR receptor and EGFR mutations 10-15% NSCLC woman adenoca never smoker 11 /
12 / VOETTEKST
EGFR pathway and resistance mechanisms 13 / Cancer Discovery, 2014c
Tyrosine kinase inhibitors
15 / EGFR TKI
first generation TKI
Pivotal trials with first generation EGFR TKI 17 / Translational Lung Cancer Research 2015
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19 / Skin toxicity
Case presentation women, 57 years never smoker weight loss, malaise january 2009: diagnosis of stage IV adenocarcinoma left upper lobe with liver and bone metastases
Mutation in exon 19 (liver biopsy)
After 6 weeks Tarceva confirmed CR for 2 years
second generation TKI
25 / second generation EGFR TKI: afatinib
LUX-LUNG 7: afatinib versus gefitinib Patients with Advanced adenocarcinoma of the lung Documented common EGFR mutations (del19 or L858R) First line (no prior treatment) Global study: 57 sites (currently recruiting) N = 264 Randomization Afatinib 40 mg Gefitinib 250 mg Coprimary endpoints: PFS, TTF and OS ClinicalTrials.gov. NCT01466660.
11 m vs 10.9 m RR: 73% vs 56% 27 / A:exon 21 B:exon 19
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third generation TKI
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31 / N Engl J Med 2017; 376:629-640
FLAURA: osimertinib vs first generation EGFR-TKI 32 /
erlotinib, gefitinib osimertinib 33 /
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ALK TKI crizotinib next generation TKI sequence
ALK positive NSCLC Guidelines recommend testing for ALK gene rearrangements in all patients with adenocarcinoma or in whom adenocarcinoma cannot be excluded. ALK Rearrangements - 3-5% of NSCLC - adenocarcinoma - younger patients - never smokers
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Rapid clinical development and success in a short time Solomon & Soria Ann Oncol 2016
crizotinib
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Crizotinib superior to standard chemotherapy PFS probability (%) 100 80 60 40 20 1 st Line therapy 2nd Line therapy Pfizer 1014: Crizotinib vs. Platinum/Pemetrexed Crizotinib (N=172) Chemotherapy (N=172) Events, n (%) 100 (58) 137 (80) Median, months 10.9 7.0 HR (95% CI) 0.45 (0.35 0.60) P b <0.0001 Pfizer 1007: Crizotinib vs. Chemotherapy No. at risk Crizotinib Chemotherapy 0 0 5 10 15 20 25 30 35 Time (months) 172 120 65 38 19 7 1 0 171 105 36 12 2 1 0 0 ORR: Crizotinib 65% vs. Chemo 20% Mediaan PFS 7.7 m vs. 3 m Mok et al. ASCO 2014, abstr 8002 Shaw et al., NEJM 2013
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But acquired resistance to ALK inhibitors April 2009 September 2010 Progression following initial Crizotinib 1L??? September 2011
Slide 17 Presented By Christine Lovly at 2015 ASCO Annual Meeting
15% 20-40% 30% Slide 18 Presented By Christine Lovly at 2015 ASCO Annual Meeting
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Next generation ALK TKI
Next generation ALK inhibitors Ceritinib Alectinib Brigatinib LorlatinibBriga 53 /
ceritinib
ALK TKI : Toxicity Perol, ESMO 2016
alectinib
Alectinib, a potent CNS-active ALK inhibitor ALK secondary mutation Crizotinib Alectinib G1123S - Sensitive I1151Tins Resistant Resistant L1152P/R Resistant Sensitive C1156Y/T Resistant Sensitive I1171T/N Resistant Resistant F1174L/C Resistant Sensitive V1180L Resistant Resistant L1196M Resistant Sensitive G1202R Resistant Resistant S1206Y Resistant Sensitive G1269A/S Resistant Sensitive
ORR ORR 48% 48% SD: 32% SD: 32% PD: 16%% PD: 16%
NR 11.1 m 59 / VOETTEKST N Engl J Med 2017; 377:829-838
60 / N Engl J Med 2017; 377:829-838
brigatinib
RR 45% RR 54% Robust PFS 62 / VOETTEKST
Best Change From Baseline in Target Lesions (%) ORR Brain Mets to brigatinib 40 20 Phase 1/2 40 20 ALTA, Arm A 90 mg qd 40 20 ALTA, Arm B 90 mg 180 mg qd b 0 20 Confirmed ORR, n (%) 8 (53) 0 20 Confirmed ORR, n (%) 12 (46) 0 20 Confirmed ORR, n (%) 12 (67) 40 a 40 40 60 60 60 80 80 80 100 a 100 100 Progressive disease Stable disease c Confirmed partial response Confirmed complete response Last scan date: 8 October 2015 (phase 1/2), 13 July 2016 (ALTA); dotted line at 30% indicates threshold for partial response per RECIST v1.1 a Crizotinib-naive patients (n=2); b 180 mg qd with 7-d lead-in at 90 mg; c Includes single responses not confirmed OA08.06: Brigatinib Activity in Patients With ALK+ NSCLC and Intracranial CNS Metastases Scott N Gettinger
lorlatinib
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Response to Lorlatinib in a patient with an ALK G1202R Mutation ALK+ NSCLC Post crizotinib, ceritinib, and alectinib Started lorlatinib at 75 mg QD on April 23, 2015 Baseline 11 months on lorlatinib Reduced to 50 mg QD on May 14, 2015 * Continues on treatment
Clinical Responses to Lorlatinib in Patients with ALK G1202R Mutation Patient 1 Patient 2 19 Nov 2014 17 Jan 2015 18 Dec 2014 01 Sep 2015 Post crizotinib and ceritinib Post crizotinib and alectinib Started at 75 mg QD on 21 Nov 201467 Started 100 mg QD on 24 Dec 2014
ALK TKI : Toxicity Perol, ESMO 2016
optimal sequence
Role for Multiple Sequential ALK Inhibitors 1L Crizotinib 2L 2 ND Generation Ceritinib ALKi e.g Ceritinib Alectinib Brigatinib 3L PD??? CNS progression? Resistant mutation?
Sequence is associated with prolonged survival Median combined PFS: 18.2 months Median OS: 51.1 months Median combined PFS: 17.4 months Median OS: 49.4 months Gainor Clin Cancer Res 2015; Watanabe Clin Lung Cancer 2016
What is the optimal first-line treatment? 1L Crizotinib 2L Next gen ALK TKI 1L Next gen ALK TKI Sequence (J-)ALEX: alectinib vs crizotinib ALTA-1L: brigatinib vs. crizotinib (recruiting) exalt3: ensartinib vs. crizotinib (recruiting) CROWN: lorlatinib vs. crizotinib (recruiting)
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Current practice in Belgium first line: Alectinib (1 september 2018) second line: crizotinib after failure crizotinib ceritinib alectinib lorlatinib Medical Need Evolving landscape Evolving landscape!e
Case Female 51 yr 18 py, stop 2003 April 2011 ct3n3m1b NSCLC (stage IV) adenocarcinoma LUL with mediastinal lymphadenopathy, liver metastases and pericarditis carcinomatosa (proven)
the choice at that time First line cisplatinum / pemetrexed SD after 4 cycles July 2011: hospitalization in France with PD
second line treatment 13-07-2011 3-10-2011 25-07-2013 July 2011 start crizotinib 250 mg BID in medical need program
T1 T1+gado September 2013 A symptomatic brain metastasis frontal right 1 cm with oedema T2 T2*
the choice at that time A symptomatic brain metastasis frontal right 1 cm with oedema SABRT + WBRT Continuation of crizotinib 250 mg BID
24-04-2014 16-06-2014 enlargement of lymph nodes April 2014 Progressive disease After 3y10m crizotinib Continuation until end of June 2014 Screening for ASCEND-5 Randomisation between second line chemotherapy and ceritinib
third line ceritinib 19-08-2014 First response evaluation: partial response Liver toxicity, dose adjustments After 1y4m headache and nausea: new symptomatic brain metastases PD also in the lungs TT needle rebiopsy showed: ALK G1202R Mutation
the choice at that time 13-10-2015 (re)wbrt lorlatinib 07-01-2016
Lorlatinib since december 2015 13-10-2015 07-01-2016 08-11-2016
Case April 2011 NSCLC adenocarcinoma ALK+ stage IV, ct3n3m1b 3 m cisplatinum / pemetrexed: SD after 2y3m oligoprogression brain: SABRT (+WBRT) + crizotinib continuation in total 3y10m on crizotinib 1y4m ceritinib:pr PD October 2015 in brain and lungs: R/ WBRT followed by lorlatinib 2018: ongoing SD
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TKI for uncommon mutations BRAF V600E MET exon 14
Dabrafinib plus Trametinib for BRAF V600E 89 /
male 63 years BRAF V600E mutation, WHO 2-3 90 / July 2017 September 2017
MET-inhibitors in MET exon 14 mutant NSCLC 91 /
male, 73 years stage IV NSCLC, adenocarcinoma liver and bone mets R/ platinum-pem with PD after 4 cycles nivolumab with PD start MET-TKI in clinical trial a After 4 cutamtalen 92 /
In summary, promizing new drugs for old or new targets NGS is important Refer these patients for trials Presented By David Planchard at 2018 ASCO Annual Meeting
Take home messages EGFR TKI first, second and third generation optimal sequens? rebiopsy, liquid biospy future perspectives: third generation TKI (EGF816, ASP8273 ), combo with anti-angiogenesis, chemo, checkpoint inhibitors, adjuvant setting.. ALK TKI first, next generation TKI optimal sequens? rebiopsy, liquid biopsy future perspectives: new combinations: with anti-angiogenesis, Hsp90 inhibitors, checkpoint inhibitors, adjuvant setting uncommon mutations important to detect 94 / refer for clinical trials