Treatment strategies beyond progression in EGFR mutant tumors Jürgen Wolf Lung Cancer Group Cologne & Network Genomic Medicine Center for Integrated Oncology University of Cologne

EGFR-TKIs represent a breakthrough in the treatment of EGFR mutated lung cancer with a tremendous benefit for about 12% of adenocarcinoma patients TrialEGFR- TKIEGFR mut.RR (%)PFS (m)OS (m) IPASS Mok 2009 gefitinib26171 vs. 47 P= vs. 6.3 HR vs HR 1.0 NEJ002 Maemondo 2010 gefitinib22474 vs. 31 P= vs. 5.4 HR vs WJTOG Mitsudomi 2012 gefitinib19262 vs vs. 6.3 HR vs. n.r. HR 1.64 OPTIMAL Zhou 2011 erlotinib16483 vs vs. 4.6 HR vs HR 1.04 EURTAC Rosell 2012 erlotinib vs vs. 5.2 HR vs LUX-LUNG 3 Yang 2012 afatinib vs vs. 6.0 HR vs HR 0.88 LUX-LUNG 6 Wu 2013 afatinib vs vs 5.6 HR vs HR 0.93 EU approvals: gefitinib (2009), erlotinib (2011), afatinib (2013)

... but finally all patients suffer from relapse of the disease TrialEGFR- TKIEGFR mut.RR (%)PFS (m)OS (m) IPASS Mok 2009 gefitinib26171 vs. 47 P= vs. 6.3 HR vs HR 1.0 NEJ002 Maemondo 2010 gefitinib22474 vs. 31 P= vs. 5.4 HR vs WJTOG Mitsudomi 2012 gefitinib19262 vs vs. 6.3 HR vs. n.r. HR 1.64 OPTIMAL Zhou 2011 erlotinib16483 vs vs. 4.6 HR vs HR 1.04 EURTAC Rosell 2012 erlotinib vs vs. 5.2 HR vs LUX-LUNG 3 Yang 2012 afatinib vs vs. 6.0 HR vs HR 0.88 LUX-LUNG 6 Wu 2013 afatinib vs vs 5.6 HR vs HR 0.93 PFS 9 – 13 months relapse unavoidable

Clinical decisions in relapse after EGFR-TKI therapy ① When should we change to another therapy ? ② Which therapy should we use in EGFR-TKI resistance ? - 3 rd gen. EGFR-TKI (T790M +) - MET-inh. (MET-ampl.) - immunecheckpoint-inhibitor - chemotherapy - others...

RECIST based progression: not necessarily a reason to stop TKI It is not intended that these RECIST guidelines play a role in decision making except if determined appropriate by the treating oncologist (RECIST 1.1) Several factors influence clinical decision Symptoms and clinical severity of progression Toxicity of TKI therapy Alternative therapies

Is there a biological rationale for treatment beyond progression ? Tumor growth curves of EGFR mutant tumors vary in pts. treated with TKI Nishino et al., Cancer 2013

Dynamics of progression varies in EGFR mut. patients under TKI Nishino et al., Cancer months of erlotinib 28 months of gefitinib Pat. 1 Pat. 2 8

Treatment beyond progression (TBP) Strategies: EGFR-TKI TBP only EGFR-TKI TBP + local treatment of local relapse EGFR-TKI TBP + combination with chemotherapy EGFR-TKI TBP + combination with targeted therapy

Treatment beyond progression (TBP) Strategies: EGFR-TKI TBP only EGFR-TKI TBP + local treatment of local relapse EGFR-TKI TBP + combination with chemotherapy EGFR-TKI TBP + combination with targeted therapy

Oxnard et al., ASCO 2012 Treatment beyond progression (TBP): EGFR – TKI only A series of 42 pts treated first line with erlotinib 45% of pts delayed therapy 3 m > RECIST-PD 23% delayed therapy 12 m > RECIST-PD

Treatment beyond progression (TBP): EGFR – TKI only A retrospective study of 64 Japanese patients Nishie et al., JTO 2012 small patient numbers, retrospective

Indolent course in acquired resistance may be caused by T790M Oxnard et al., CCR EGFRmut pts in acquired resistance, T790M rebiopsy proven T790M pos. and neg. pts received similiar therapy, mostly TKI beyond progression T790M pos: 19m T790M neg: 12m T790M pos: 39m T790M neg: 26m

Biological basis: slower growth of T790M resistant clones Chmielecki et al, STM 2011 Exon 19 del alone Exon 16 + T790M Discontinuation of TKI may cause flare = rapid overgrowth of EGFRmut clone without T790M

Primary endpoint: PFS1 (time to RECIST PD or death) Exclusion criteria: T790M mutations, prior chemotherapy, prior treatment with anti-HER agents, uncontrolled systemic conditions, pre-existing lung conditions, warfarin use Erlotinib PD by RECIST PD by physician assessment PFS 1 PFS 2 Erlotinib Patients ≥18 y stage IV, EGFR mut+ NSCLC ASPIRATION: first-line erlotinib until and beyond RECIST progression in ASIAN patients with EGFR mut. NSCLC Tony Mok, 2015

Continuation of erlotinib post-PD extended PFS In patients receiving post-PD erlotinib (n=93) –PFS1 was 11.0 months –the difference between PFS1 and PFS2 was an additional 3.1 months Survival probability Progression-free survival time (months) PFS1 PFS months 14.1 months Tony Mok, 2015

Post-PD erlotinib versus no post-PD erlotinib Post-PD E N=93 No post-PD E N=78 P value Recurrent disease at baseline, n (%) 15 (16.1)3 (3.8) Median PFS1, months11.0 (95% CI 9.1– 11.0) 7.4 (95% CI 5.6–9.2) Median depth of response *, % † ‡ Median time from baseline to BOR, days Median time from BOR to PFS1, days ECOG 0/1 at PFS1, % Ongoing grade ≥3 AEs at PFS1,% *Depth of response is the maximum % decrease from baseline for each patient in the 'sum of diameters of target lesions' prior to the date of the first occurrence of PD. † n=90, ‡ n=70 Tony Mok, 2015

ASPIRATION: Conclusions Continuing erlotinib post-PD resulted in an additional PFS of 3.1 months Treating physicians may consider continuing erlotinib post-PD in certain patients –patients who respond well to first-line erlotinib (assessed by median PFS1, depth of response or time from BOR to PD) –those who maintain a good ECOG PS (0/1) at PFS1 –patients with recurrent disease at baseline –patients with exon 19 deletions may benefit more from post-PD erlotinib compared with patients who have L858R mutations Open questions: Is there a survival benefit ? How to precisely identify the patients with benefit from TBP ?

Treatment beyond progression (TBP) Strategies: EGFR-TKI TBP only EGFR-TKI TBP + local treatment of local relapse EGFR-TKI TBP + combination with chemotherapy EGFR-TKI TBP + combination with targeted therapy

Govindan, Science 2014 Tumor heterogeneity: different clones may drive different metastastatic sites and escape from EGFR-TKI control

Local ablative therapy of OMD prolongs disease control by TKIs in oncogene-addicted lung cancer Weickhardt et al, JTO 2012 PFS benefit 6.2 m PFS benefit 4.0 m PFS benefit 7.0 m

Local ablative therapy of OMD prolongs disease control by TKIs in oncogene-addicted lung cancer Weickhardt et al, JTO 2012

Treatment beyond progression (TBP) Strategies: EGFR-TKI TBP only EGFR-TKI TBP + local treatment of local relapse EGFR-TKI TBP + combination with chemotherapy EGFR-TKI TBP + combination with targeted therapy

IMPRESS Study Objectives Enrollment period: March 2012 ‒ December 2013 Primary Progression-free survival Secondary Overall survival Objective response rate Disease control rate Safety and tolerability Health-related quality of life c Exploratory Biomarkers d Age ≥18 years WHO PS 0-1 Histologically confirmed stage IIIB / IV EGFR mutation-positive advanced NSCLC Chemotherapy-naïve Achieved CR / PR ≥4 months or SD >6 months with first-line gefitinib Disease progression (RECIST) a <4 weeks prior to study randomisation Patients Cisplatin 75 mg/m 2 + Pemetrexed 500 mg/m 2 (≤6 cycles) + Gefitinib 250 mg Cisplatin 75 mg/m 2 IV + Pemetrexed 500 mg/m 2 IV (≤6 cycles) + Placebo 250 mg 1:1 randomisation b 1 Jackman et al 2010 Endpoints T Mok ESMO 2014

IMPRESS: duration of different treatment regimens Gefitinib (n=132) (day) Placebo (n=132) (day) Median duration of chemotherapy Median duration of gefitinib / placebo in combination with chemotherapy Median number of chemotherapy cycles (lower quartile, upper quartile) 5 (3, 6)5 (2, 6)

Gefitinib (n=133) Placebo (n=132 ) Probability of PFS Time of randomisation (months) Patients at risk: Gefitinib Placebo IMPRESS: PFS (primary endpoint; ITT) identical a Primary cox analysis with covariates A HR <1 implies a lower risk of progression with gefitinib Gefitinib (n=133) Placebo (n=132) Median PFS, months5.4 Number of events, n (%) 98 (73.7)107 (81.1) HR a (95% CI) = 0.86 (0.65, 1.13); p=0.273

IMPRESS: OS (ITT; 33% of events) in favour of placebo a Primary cox analysis with covariates A HR <1 implies a lower risk of death with gefitinib Gefitinib (n=133) Placebo (n=132) Median OS, months Number of events, n (%) 50 (37.6)37 (28.0) HR a (95% CI) = 1.62 (1.05, 2.52); p= Probability of OS Time of randomisation (months) Patients at risk: Gefitinib Placebo Gefitinib (n=133) Placebo (n=132)

IMPRESS: Post-discontinuation therapy (ITT) Anti-cancer therapy ITT population Gefitinib (n=133)Placebo (n=132) Any, n (%)61 (45.9)72 (54.5) Platinum alone, a n (%) 0 (0)2 (1.5) Platinum-based regimen (doublet or triplet), n (%) 5 (3.8)17 (12.9) Single-agent cytotoxic, b n (%) 27 (20.3)27 (20.5) EGFR TKI, c n (%) 30 (22.6)44 (33.3) Others, n (%) 16 (12.0)14 (10.6) a Platinum: carboplatin, cisplatin, nedaplatin b Single agent: docetaxel, paclitaxel, pemetrexed, gemcitabine, vinorelbine c EGFR TKI (gefitinib, erlotinib, AZD9291 [n=2 gefitinib arm; n=3 placebo arm])

IMPRESS: Conclusions No statistically significant improvement in PFS with continuation of gefitinib in addition to cisplatin / pemetrexed beyond RECIST progression OS was immature (secondary endpoint; 33% of events): Imbalances in post study treatment in favour of the placebo plus cisplatin / pemetrexed arm No treatment differences found in ORR or DCR Safety profile for gefitinib plus cisplatin / pemetrexed in line with that known IMPRESS does not support the combination of chemotherapy and EGFR-TKI after disease progression (by RECIST criteria)

Treatment beyond progression (TBP) Strategies: EGFR-TKI TBP only EGFR-TKI TBP + local treatment of local relapse EGFR-TKI TBP + combination with chemotherapy EGFR-TKI TBP + combination with targeted therapy

Molecular understanding of relapse enables the development of effective therapies Ohashi et al, J Clin Oncol 31, 2013 Takezawa et al, Cancer Disc 2, 2012 EGFR-resistance mutation 3 rd gen. EGFR-TKIs with high T790M specificity alternative pathways combination therapies: continue initial blockade, add new drug

Patient with activating EGFR mutation and good response for about 2 years: now presenting with acquired resistance and massive progression Rebiopsy left arm: EGFR L858R, high-level METamp, TP53 C277*, TP53 R110C start crizotinib continue erlotinib Scheffler et al., JTO in press

Patient with activating EGFR mutation and good response for about 2 years: now presenting with acquired resistance and massive progression Rebiopsy left arm: EGFR L858R, high-level METamp, TP53 C277*, TP53 R110C start crizotinib continue erlotinib after 8 days of crizotinib + erlotinib Scheffler et al., JTO in press

Patient with activating EGFR mutation and good response for about 2 years: now presenting with acquired resistance and massive progression Rebiopsy left arm: EGFR L858R, high-level METamp, TP53 C277*, TP53 R110C start crizotinib continue erlotinib after 8 days of crizotinib + erlotinib Molecular analysis pleural effusion: EGFR L858R T790M, low-level METamp stop crizotinib and erlotinib start AZD9291 Scheffler et al., JTO in press

stop AZD9291 restart crizotinib (without erlotinib) Patient with activating EGFR mutation and good response for about 2 years: now presenting with acquired resistance and massive progression Scheffler et al., JTO in press

stop AZD9291 restart crizotinib (without erlotinib) Patient with activating EGFR mutation and good response for about 2 years: now presenting with acquired resistance and massive progression Molecular analysis pleural effusion EGFR L858R, EGFR T790M, TP53 R110C no METamp Patient died due to progression of disease Scheffler et al., JTO in press

stop AZD9291 restart crizotinib (without erlotinib) Patient with activating EGFR mutation and good response for about 2 years: now presenting with acquired resistance and massive progression Molecular analysis pleural effusion EGFR L858R, EGFR T790M, TP53 R110C no METamp Patient died due to progression of disease Tumor disease was driven by two clones The MET driven clone was inhibited with crizo + erlotinib, but also with crizo alone This patient would have had a benefit from 3 rd gen EGFR-TKI + MET-inh. (not from treatment with the 1 st gen. TKI beyond progression) Scheffler et al., JTO in press

Conclusions: EGFR-TKI treatment beyond progression Treatment beyond RECIST progression in certain patients is suggested by differences in growth kinetics and clinical course. Feasibilty of TBP and prolongation of PFS have been shown (ASPIRATION), not, however, survival prolongation. Locally treatable progress should be treated locally with ongoing EGFR-TKI. TBP + chemotherapy provides no benefit (IMPRESS). For TBP + additional targeted therapy no benefit has been shown so far. During TBP careful and continuous clinical supervision is mandatory to change treatment in time. Rebiopsy before treatment change should become routine to allow rational therapy of acquired resistance.

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Thanks ! to all the patients and their families Clinical Trials & NGM Study Center Sebastian Michels Rieke Fischer Diana Abdullah Vanessa Brandes Christian Mattonet Matthias Scheffler Lucia Nogova Elisabeth Bitter Anna Kostenko Jürgen Wolf Translational Genomics Florian Malchers Martin Sos Roman Thomas Network Genomic Medicine … all NGM partners Molecular Pathology Katharina König Sabine Merkelbach-Bruse Andreas Scheel Reinhard Büttner / / Molecular Imaging Deniz Kahraman Carsten Kobe Markus Dietlein Alexander Drzezga Thorsten Persigehl David Maintz CCC Amsterdam Egbert Smit Ronald Boellaard Adriaan Lammertsma Spanish Lung Cancer Group Rafael Rosell Bartomeu Massuti