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Acquired Resistance Patient Forum September 6, 2014 | Boston In ALK, ROS1 & EGFR Lung Cancers Combinations for Treating EGFR Acquired Resistance Melissa.

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Presentation on theme: "Acquired Resistance Patient Forum September 6, 2014 | Boston In ALK, ROS1 & EGFR Lung Cancers Combinations for Treating EGFR Acquired Resistance Melissa."— Presentation transcript:

1 Acquired Resistance Patient Forum September 6, 2014 | Boston In ALK, ROS1 & EGFR Lung Cancers Combinations for Treating EGFR Acquired Resistance Melissa L. Johnson, MD

2 Dx: EGFR+ lung cancer Acquired Resistance Tarceva Combination Treatments for EGFR Acquired Resistance Tarceva + NEW DRUG Gilotrif + NEW DRUG

3 Can we make 1 st Gen TKI Better? We have tried!! Selected approaches to enhancing EGFR TKI in order to overcome or prevent resistance Erlotinib + Chloroquine Erlotinib + Sirolimus Erlotinib + Onartuzumab (anti-Met) Erlotiinb + Entinostat Erlotinib + R1507 (anti IGF-1) Erlotinib + Tivantinib Erlotinib + Sorafanib Erlotinib + Dasatinib Erlotinib + MK2206 (AKT) Erlotinib + MM-121 (anti-ErbB3) Erlotinib + XL184 Erlotinib + Rilotumumab (anti-HGF) Erlotinib + Patritumumab (anti-ErbB3) Erlotinib + AUY-922 (HSP 90 inhibitor) Slide adapted, courtesy of Thomas J. Lynch, Jr., MD Combination Treatments for EGFR Acquired Resistance

4 Dx: EGFR+ lung cancer Acquired Resistance Tarceva/Gilotrif (erlotinib/afatinib) Combination Treatments for EGFR Acquired Resistance Tarceva/Gilotrif (erlotinib/afatinib) + NEW DRUG

5 Flare associated with shorter TTP Chaft, Clin Cancer Res of 61 patients (23%, 95% CI 14-35%) had a disease flare (hospitalization or death) Median time from last TKI to flare was 8 days (range 3-21 days) 3 patients went on to trial treatment Combination Treatments for EGFR Acquired Resistance

6 AUY922: An “Onco-Chaperone” Inhibitor Neckers and Workman Clin Cancer Res 2012 AUY922 (in yellow) is a synthetic isoxazole resorcinol HSP90 inhibitor, shown here bound to the deep ATP pocket of HSP90 (in blue) AUY922+ Erlotinib Melissa L. Johnson Combination Treatments for EGFR Acquired Resistance

7 Cohort Dose of AUY922 IV weekly Dose of Erlotinib PO daily # pts enrolled 1 25 mg/m 2 75 mg mg/m mg mg/m mg mg/m mg mg/m mg6 AUY922 + Erlotinib Phase I Dose-Escalation AUY922+ Erlotinib Melissa L. Johnson Combination Treatments for EGFR Acquired Resistance

8 Preliminary Activity C1D1C1D28 Patient AUY mg/m + Erlotinib 75 mg Duration of therapy: 6 months HSP90 Inhibitors in Lung Adenocarcinoma AUY922+ Erlotinib Melissa L. Johnson

9 Stage IV Adenocarcinoma +EGFR mutation Acquired Resistance Biopsy at resistance 30 day erlotinib lead-in Erlotinib 150mg PO qday AUY922 70mg/m 2 Key Inclusion Criteria Advanced lung adenocarcinoma EGFR mutation OR previous response to EGFR TKI EGFR TKI for ≥6 months and 1 full month prior to study start Biopsy at time of acquired resistance to EGFR TKI Key Exclusion Criteria Brain metastasis that are symptomatic and/or requiring escalating doses of steroids Systemic treatment within 4 weeks, RT within 2 weeks AUY922 + Erlotinib Phase II Study Design Definition of Acquired Resistance 19 Previously treated with single-agent EGFR-TKI Tumor harbors TKI-sensitive EGFR mutation (G719X, ex 19 del, L858R, L861Q) EITHER RECIST-defined PR/CR OR ≥ 6 months clinical benefit (SD) with single-agent EGFR-TKI followed by systemic POD Statistical Considerations: stage I: 16 pts (if ≥2 responses, proceed to stage II) stage II: 9 pts (if ≥ 5 responses overall, AUY922 and erlotinib are worthy of further study) α=10%; β=10%; p 0 =10%; p 1 =30% 19 Jackman JCO 2009 Primary endpoint: Overall response rate ORR (CR + PR) Secondary endpoints: Progression-free survival, Overall survival, ORR in T790M+, Toxicity Melissa L. Johnson

10 Molecular Characteristics N=37 AUY mg/m 2 N=12 AUY mg/m 2 N=25 Primary EGFR mutations EGFR exon 19 deletion EGFR exon 21 L858R 1129 EGFR exon 21 L861Q: 101 EGFR mutation unknown EGFR T790M found on repeat Tumor Biopsy, n (%) 16 (43%)6 (50%)10 (40%) Median duration of EGFR-TKI therapy prior to developing acquired resistance, months (range) 12 (2-42)13 (8-32)11(2-42) AUY922+ Erlotinib Melissa L. Johnson

11 Best Response to AUY922 and Erlotinib Partial Response (PR): 4/25 (16%)(95% CI 6-35%) Disease Control Rate (DCR): 14/25 (56%)(95% CI 37-73%) Best % change in target lesions Progressive disease Stable disease Partial response EGFR T790M AUY922+ Erlotinib Melissa L. Johnson N=24

12 Pt ID EGFR 19/21 T790M Best Response AUY922 + Erlotinib Cycles Completed Duration primary EGFR-TKI (prior to AR) T790MSD DLT-prolonged QTc; junctional rhythm T790M*SD Ophthalmologic tox ( gr 2 night blindness) T790MPR Ophthalmologic tox (gr 2 night blindness/blurred) —POD POD L861Q—POD POD T790MPOD POD —POD POD —POD POD T790MPOD POD —SD POD —SD Patient withdrew consent —POD POD T790MPOD POD UnkPOD Patient withdrew consent —POD POD T790MPR Patient withdrew consent 96-12_ 21—PR T790MPR Hepatic tox (gr 3 LFT elevation) —SD Opthalmologic tox (gr 2 night blindness) —NE Ω Hepatic tox (gr 3 LFT elevation) —SD Diarrhea (gr 3 colitis) T790MSD POD —POD POD —NE ∆ POD 01-20_ 19T790MNE ∆ POD Individual Responses According to EGFR Mutations and Time on Primary EGFR-TKI * Small cell transformation patient remains on study Reason withdrawn from study

13 Combination Treatments for EGFR Acquired Resistance Afatinib + Cetuximab

14 Stop erlotinib/ gefitinib for ≥72 hours 3 Disease progression 2 Pathology confirmed NSCLC with EGFR mutation 1 OR SD  6 months on erlotinib/gefitinib OR Partial or complete response to erlotinib/gefitinib MTD cohort expanded up to 80 EGFR mutation-positive patients 4 : 40 T790M+ and 40 T790M– Dose escalation schema 3–6 patients per cohort Afatinib p.o. daily + escalating doses of i.v. cetuximab q 2 weeks Dose levels starting at: afatinib 40 mg + cetuximab 250 mg/m 2 Predefined maximum dose: afatinib 40 mg + cetuximab 500 mg/m 2 ECOG PS 0-2 Age ≥ 18 years Combination Treatments for EGFR Acquired Resistance Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor-Resistant EGFR Mutant Lung Cancer with and without T790M Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

15 Tumor Regression by T790M Mutation Status at Recommended Dose Horn at al. IASLC 2011 Combination Treatments for EGFR Acquired Resistance

16 16 Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

17 Cetux/Afatanib Toxicity N=126All gradesGr 3-4 Rash114 (90%)25 (20%) Diarrhea89 (71%)8 (6%) Nail Effect72 (57%)0 (0%) Stomatitis71 (56%)1 (1%) Fatigue59 (47%)3 (2%) Nausea53 (42%)3 (2%) Xerosis53 (42%)3 (2%) Combination Treatments for EGFR Acquired Resistance Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

18 Preliminary Efficacy Comparison RR T790M + RR T790M - PFS (months) Tarceva/AUY92230%10%1.7 Afatanib/Cetux32%28%4.66 CO %Inc.  AZD %22%  18 Combination Treatments for EGFR Acquired Resistance

19 Toxicity Comparison Any GradeDiarrheaRash Unique Toxicities Tarceva/AUY922 95%81% Night blindness, elevated LFTs, prolongation of QT c Afatanib/Cetux 71%97% Nail effects, stomatitis Tarceva/Bevacizu mab 81%99% Hypertension, Proteinuria 19

20 T+A vs T (#8005) BeTa in second line setting ATLAS as maintenance – Both with compelling results in enriched populations of never smokers, East Asians Possible EGFR regulation of VEGF in EGFR mutant cell lines (Heymach) Unselected Patient Population Combination Treatments for EGFR Acquired Resistance

21 JO25567 Study Design Primary endpoint: PFS (RECIST v1.1, independent review) Secondary endpoints: OS, tumor response, QoL, safety Exploratory endpoint: biomarker assessment R Chemotherapy-naïve Stage IIIB/IV NSCLC or postoperative recurrence Non-squamous Activating EGFR mutations* Exon 19 deletion Exon 21 L858R Age ≥20 years PS 0–1 No brain metastasis E monotherapy Erlotinib 150mg qd (n = 75) EB combination Erlotinib 150mg qd + bevacizumab 15mg/kg q3w (n = 75) PD Stratification factors: sex, smoking status, clinical stage, EGFR mutation type 1:1 *T790M excluded Abstract 8005: Presented by Terufumi Kato Combination Treatments for EGFR Acquired Resistance

22 Primary endpoint: PFS by independent review E EB Number at risk Time (months) PFS probability EB E *log-rank test, two-sided Abstract 8005: Presented by Terufumi Kato EBE Median (months) HR0.54 (95% CI: 0.36–0.79) P value* Combination Treatments for EGFR Acquired Resistance

23 PFS by EGFR Mutation Type EB groupE group Median (months) HR 0.41 (95% CI: 0.24–0.72) EB E E Number at risk E EB Number at risk EB E Time (months) Time (months) PFS probability Exon 19 deletionExon 21 L858R EB groupE group Median (months) HR0.67 (95% CI: 0.38–1.18) Abstract 8005: Presented by Terufumi Kato Combination Treatments for EGFR Acquired Resistance

24 Toxicity with Tarceva + Avastin JO25587 No unforeseen toxicities or Rx-related deaths Grade >3 toxicity 91% vs. 53% (esp. HTN, proteinuria) 41% discontinued bevacizumab for adverse effects – Primarily proteinuria (15%) or hemorrhagic (12%) – Bevacizumab discontinuation rate 10-15% in BeTa, ATLAS trials Combination Treatments for EGFR Acquired Resistance

25 EGFR + NSCLC Trials- PFS (months) 1. Rosell et al. Lancet Oncol. 2012;13:239; 11. Zhou et al. Lancet Oncol. 2011;12:735; 3. Sequist et al. J Clin Oncol. 2013;31:3327; 4. Wu et al. Lancet Oncol. 2014;15:213; 5. Kato, Proc ASCO 2014, A#8005 Med PFS (mo) EURTAC 1 OPTIMAL 2 JO Tarceva 5 JO T/A 5 LUX- Lung-3 3 LUX- Lung-6 4 Combination Treatments for EGFR Acquired Resistance

26 What’s next? Combination Treatments for EGFR Acquired Resistance Akbay et al. Cancer Discovery 3: , 2013

27 Summary TWICE the opportunity for success, but TWICE the side effects Upfront or after the development of Acquired Resistance? Future Directions: Tarceva + PDL-1 inhibitor? Combination Treatments for EGFR Acquired Resistance


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