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Lucio Buffoni ONCOLOGIA POLMONARE

Lucio Buffoni ONCOLOGIA POLMONARE AZIENDA OSPEDALIERO-UNIVERSITARIA SAN LUIGI GONZAGA DI ORBASSANO. Le strategie terapeutiche a progressione dopo gli Inibitori di EGFR di Ia e IIa generazione. 29-30 Aprile 2016 – Camogli. Background. Virtually all NSCLC EGFRmut will progress during TKIs;

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Lucio Buffoni ONCOLOGIA POLMONARE

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  1. Lucio Buffoni ONCOLOGIA POLMONARE AZIENDA OSPEDALIERO-UNIVERSITARIA SAN LUIGI GONZAGA DI ORBASSANO Le strategie terapeutiche a progressione dopo gli Inibitori di EGFR di Ia e IIa generazione. 29-30 Aprile 2016 – Camogli

  2. Background • Virtually all NSCLC EGFRmut will progress during TKIs; • Median PFS of 9-13 mos; • Progression = Primary Resistance -> “immediate” Secondary Resistance -> “acquired”

  3. Kind of Progressions: notallprogressions are made equal!!! Symptomatic vs Asymptomatic progression

  4. Different Progression -> Different behaviour Asymptomatic/symptomatic CNS progression: continue TKIs + local treatment Particular value in those w/CNS as first site of PD Weickhardt, J Thorac Oncol 2013

  5. Different Progression -> Different behaviour Asymptomatic oligoprogression (eg new lung nodule or local asymptomatic progression): continue TKIs or continue TKIs + local treatment (SBRT).

  6. Different Progression -> Different behaviour • Asymptomatic systemic progression-> continue TKIs • Symptomatic systemic progression –> -continue TKIs + CT; -switch to CT; -switch to CT ->rechallange TKIs

  7. Erlotinib Erlotinib Patients ≥18 y stage IV, EGFR mut+ NSCLC PD by physician assessment PD by RECIST PFS 1 PFS 2 Continue TKIs to avoid “Flare”: ASPIRATION • Primary endpoint: PFS1 (time to RECIST PD or death) PD definita come: • PD lenta (stabilità di malattia o risposta parziale per > 6 mesi) • Minima PD asintomatica • Nuove secondarietà encefaliche controllabili con trattamenti locali Tony Mok, 2015

  8. 1.0 0.8 0.6 Survival probability 0.4 0.2 0.0 0 10 20 30 Progression-free survival time (months) La prosecuzione di erlotinib post-PD aumenta il 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 PFS1 PFS2 11.0 months 14.1 months Tony Mok, 2015

  9. On-study erlotinib versus post-PD erlotinib inthe EGFR-mutant cohort. 1st-line erlotinib Post-progression erlotinib Treatment break Surgery Radiation • Feasibility of delaying a change in systemic • Treatment after RECIST-PD on TKI. • Support ASPIRATION conclusion and became • NCCN G-Lines at TKIs-PD for: • Longer TTP; • Slow rate of progression; • No new extra-thoracic mts. 0 12 24 36 48 60 72 Months from start of first-line erlotinib until failure of treatment strategy 84 96 Lo et al. Cancer 2015

  10. Continue TKIs + CT:IMPRESS Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 (≤6 cycles) + Gefitinib 250 mg Patients Endpoints • 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 Primary • Progression-free survival Secondary • Overall survival • Objective response rate • Disease control rate • Safety and tolerability • Health-related quality of lifec Exploratory • Biomarkersd Objectives 1:1 randomisationb Cisplatin 75 mg/m2 IV + Pemetrexed 500 mg/m2IV (≤6 cycles) + Placebo 250 mg Enrollment period: March 2012‒December 2013 T Mok ESMO 2014

  11. 1.0 0.9 0.8 0.7 0.6 Probability of PFS 0.5 0.4 0.3 0.2 Gefitinib (n=133) Placebo (n=132) 0.1 0.0 0 2 4 6 8 10 12 14 Time of randomisation (months) Patients at risk: Gefitinib Placebo 133 132 110 100 88 85 40 39 25 17 12 5 6 4 0 0 IMPRESS: PFS (primary endpoint; ITT) aPrimary cox analysis with covariates A HR <1 implies a lower risk of progression with gefitinib

  12. Different Progression -> Different behaviour LUX Lung 1 – Afatinib vs Placebo BR.26 – Dacomitinib vs Placebo PFS: 3.3 vs. 1.1 months RR < 10% PFS: 2.7 vs. 1.4 months RR < 10% (Miller et al. Lancet Oncol 2013; Ellis et al. Lancet Oncol 2014)

  13. Vertical pathway: Combined EGFR blockade Janjigian ESMO 2012

  14. Horizontal pathway: EGFR inhibition + bypass signalingJO25567: bevacizumab + erlotinib first-line Erlotinib 150mg • Eligibility • Stage IIIB/IV NSCLC, chemo-naïve • EGFR exon 19 deletion or L858R • mutation • ECOG PS 0–2 • Treated brain metastases allowed • Bevacizumab-eligible 1.0 1:1 Avastin + Tarceva Tarceva 0.8 Bevacizumab 15mg/kg + erlotinib 150mg n=150(Chugai)* 0.6 PFS probability 0.4 HR=0.54 (0.36–0.79) Log-rank p<0.0015 0.2 9.7 16.0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Es 19 PFS 10.3 vs 18 Es 21 PFS 7.1 vs 13.9 Time (months) Beva added to TKIs in I line NSCLC EGFR+ prolongs PFS. Some evidence of major hypertension, proteinuria, haemorragic events. Seto et al, Lancet Oncol 2014

  15. ACCRU: bevacizumab + erlotinib first-line study in EGFR mutation-positive patients Erlotinib 150mg • Eligibility* • Stage IIIB/IV NSCLC, chemo-naïve • EGFR exon 19 deletion or L858R mutation • ECOG PS 0–2 • Treated brain metastases allowed • Bevacizumab-eligible 1:1 Bevacizumab15mg/kg + Erlotinib 150mg n=112 (CALGB)n=150 (Chugai) BELIEF (MO29711): phase II study Previously untreatedstage IIIb–IV non-squamous NSCLC EGFR mut+ (Ex19/21) ± T790M (n=102) Erlotinib 150 mg po + bevacizumab15 mg/Kg iv PD Sub-study 1: T790M mutated Sub-study 2: T790M non-mutated mPFS 16 mos mPFS 10.5 mos

  16. BE-POSITIVE: “Real Life Data” Strategy at TKIs PD: 60% received chemotherapy 40% no further treatment Chemotherapy: 21% single agent 9.2%switch to afatinib 68% platinum-based treatment 60% platinum/pemetrexed Efficacy: ORR 28.9% PFS 5.2 mos OS 26.3 mos At oligoPD: continue TKIs and local treatment. 4.3% re-biopsy at PD! Novello S. et al, Lung Cancer 2016

  17. New Insights in Epidermal Growth Factor Receptor Resistance • 50-60% T790M resistance mutation Es.20; • bypass or alternative activation: 5-10% MET amplification, 5% PI3Kmut; 12%HER2 ampl; 1% BRAF mut • 3-14% histological transformation to SCLC. Camidge DRet al.NatRevClinOncol.2014;11:473–81

  18. NSCLC Molecular Heterogeneity

  19. NSCLC Molecular Heterogeneity: Spatial Variation

  20. NSCLC Molecular Heterogeneity: Temporal Variation

  21. 3 rd generation TKIs: Osimertinib (AZD9291): mono-anilino-pyrimidine compound, irreversible mutant selective EGFR-TKI Rociletinib (CO-1686) a 2,4-disubstituted pyrimidine molecule, irreversible mutant-selective EGFR-TKI

  22. 3 rd generation TKIs: Slide 11 Presented By Christine Lovly at 2015 ASCO Annual Meeting

  23. 3rd generation TKIs: Slide 10 Presented By Christine Lovly at 2015 ASCO Annual Meeting

  24. All-causality Adverse Events

  25. ORR by medical history of brain metastasesAZD9291 data from phase II studies Median PFS, months (95% CI) Full analysis set: 9.7 (9.7, NC) With brain metastases: 8.0 (6.9, 8.5) Without brain metastases: 9.7 (9.7, NC) Myung-ju Ahn et al, ECCO 2015

  26. Osimertinib: PFS in T790M positive cohort Presented by Kenneth O’Byrne at ELCC 2016

  27. Osimertinib/Rociletinib in T790M-

  28. EGFR mut Lung Cancer Patient TIGER3 1 st/ 2 nd generation TKIs PD T790M- Chemotherapy EGFR MUT Death R E B I O P S Y 1 st/ 2 nd generation TKIs PD T790M+ 3rd generation TKIs Chemotherapy Death EGFR MUT

  29. EGFR mut Lung Cancer Patient TIGER3 Death 1 st/ 2 nd generation TKIs PD T790M- Chemotherapy EGFR MUT R E B I O P S Y 1 st/ 2 nd generation TKIs PD T790M+ 3rd generation TKIs Chemtherapy Death EGFR MUT PFS1 9.2-13.7mos PFS2 Osimertinib 13.5mos PFS2 Rociletinib 8 mos PFS1+PFS2 17.2 TO 27.5 mos OS

  30. Acquired resistance/3rd generation TKIs: • Which is the best sequence : -sequential use of 1st/2nd TKIs -> 3 rd generation TKIs till PD; -3rd generation TKIs at first (Better in 1° line AZD9291 RR 73%, PFS? Ramalingan); • Sequence them for better survival?

  31. Best Sequence: “HITTING HARDER” EGFR mut. TIGER3 1 st/ 2 nd generation TKIs PD T790M- Chemotherapy Death EGFR MUT R E B I O P S Y PD T790M+ 3rd generation TKIs Chemotherapy Death 1 st/ 2 nd generation TKIs EGFR MUT Chemotherapy EGFR MUT 3rd generation TKIs PFS = PFS1+PFS2 OS

  32. Rociletinib Osimertinib PFS1 PFS3 PFS2

  33. OVERCOME THE RESISTANCE: WHICH STRATEGY? ? First/2nd gen TKI Third gen TKI +/- EGFR del19/L858R +/- T790M Third gen TKI ? +/- Erlotinib+bev Third gen TKI ? +/- Horizontal Pathways Inhibition Immuno AntiMET Antiangio

  34. Future perspectives

  35. Conclusions: • Oligoprogression: -continue TKIs + local treatment still valid option; then 3rd TKIs; • At systemic progression: - investigate mechanism of resistance by RE-BIOPSY is MANDATORY! (solid re-biopsy; cfDNA…); • Systemic progression: T790M+ ->3rd TKIs T790M- -> TIGER (trials) Met/Her2/BRAF -> specific inhibitors +/- TKIs? SCLC -> Cisplatin/etoposide • Monitor resistance (cfDNA).

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