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Novel Agents for Lung Cancer

Novel Agents for Lung Cancer. Suresh S. Ramalingam, MD Associate Professor Director, Division of Medical Oncology Emory University Winship Cancer Institute. Anaplastic Lymphoma Kinase (ALK).

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Novel Agents for Lung Cancer

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  1. Novel Agents for Lung Cancer Suresh S. Ramalingam, MDAssociate Professor Director, Division of Medical Oncology Emory University Winship Cancer Institute

  2. Anaplastic Lymphoma Kinase (ALK) Activation of ALK has been described as a primary oncogenic event in several different human cancers1,2 • In most cases activation is through gene rearrangement placing one of several different 5’ fusion partners upstream of the 3’ kinase domain of ALK 1Palmer et al. Biochem J 2009;420:345–361 2Mano, Cancer Sci 2008;99:2349–2355

  3. Crizotinib-Treated ALK-Positive NSCLC Cohort ALK FISH-positive NSCLC • No limit on prior lines of therapy • Brain metastases allowed if treated and stable Crizotinib 250 mg BID po administered on a continuous basis in 28-day cycles • Tumor response evaluated every other cycle (RECIST v1.0) • Safety evaluated every 2 weeks for first 8 weeks then every 4 weeks Evolving data set, previously reported at ASCO: • 2009: In 19 ALK-positive NSCLC patients1 • 2010: In 82 ALK-positive NSCLC patients2,3 • Updated data (29 October 2010 data cut-off) on 119 patients with a median duration of follow-up of 11 months are presented 1Kwak et al. J Clin Oncol 2009;27:15S abstract 3509 2Bang et al. J Clin Oncol 2010;28:18S abstract 3 3Kwak et al. New Engl J Med 2010;363:1693–1703

  4. Baseline Characteristics (N=119)

  5. Best Percent Change from Baseline in Target Lesions* Progressive disease Stable disease Partial response Complete response 100 80 60 40 20 0 % Decrease or increase from baseline –20 –40 –60 –80 –100 *excludes patients with early death and indeterminate response (n=106) **includes patients with early death and indeterminate response (n=116)

  6. Progression-Free Survival (N=119) Median PFS = 10.0 months (95% CI: 8.2, 14.7)50 events (42%; 40 PD events) 69 patients (58%) censored, 59/69 (86%) in follow-up for PFS 1.0 0.8 0.6 0.4 0.2 0 Censored 95% Hall-Wellner Band Survival distribution function 0 5 10 15 20 n at risk 119 73 29 8 1 Months

  7. Overall Survival Median OS had not been reached as of the data cut-off • 23 deaths (19%) • 2 patients (2%) censored (lost to follow up) • 94 patients (79%) remain in follow-up for OS • No deaths were related to study treatment Survival probabilities from 1st dose of crizotinib: • 6 months: 90% (95% CI 82.7, 94.4) • 12 months: 81% (95% CI 70.9, 87.2)

  8. Hsp90: Background • Heat shock proteins represent 1-2% of all cellular proteins • Facilitate protein-folding and stabilization • Induced under stress, hypoxia and oxidative damage Soti et al, J Biol Chem, 2002.

  9. Hsp90 Client Proteins Influence All Aspects of Neoplastic Transformation • > 200 Hsp90 client proteins • have been described • Many oncoproteins are relevant in • NSCLC Banerji U. Clin Cancer Res, 2009

  10. Targeting Hsp90: Rationale • Cancer cells depend on Hsp90 machinery to preserve mutated and overexpressed oncoproteins • ‘Facilitates’ oncogene addiction • Hsp90 is overexpressed in cancer cells Trepel et al, Nature Reviews, 2010; Kamal et al, Nature, 2003.

  11. STA-9090 in NSCLC: Salient Findings • Phase II study in advanced NSCLC • Patients had progressed following 2-3 prior regimens • STA-9090 was tolerated well and there were no undue safety concerns • Objective responses seen exclusively in ALK+ positive patients (all 4 responders were ALK+) • Disease stabilization noted in EGFR and KRAS mutated patients Wong, Shapiro et al, ASCO 2011, Abs # 7500

  12. Significance • Among the earliest signs of success with Hsp90 inhibition in lung cancer • Clear signal in a molecularly selected subset of adenocarcinoma patients • Improved safety profile over first-generation Hsp90 inhibitors

  13. IPI-504 in Advanced NSCLC • Eligibility: • Histologically confirmed NSCLC, stage IIIb (with effusion) or IV. • Failed prior EGFR TKI therapy. • No limit to the number of prior therapies. • Dose and schedule: • Days 1, 4, 8 and 11 of each 21 day cycle; 225 mg/m2 iv Mutant EGFR Cohort If >1 CR, PR, or SD for at least 3 months Enroll 10 patients Expand to a total of 29 patients Wild-Type EGFR Cohort If >1 CR, PR, or SD for at least 3 months Enroll 10 patients Expand to a total of 29 patients Sequist et al, J Clin Oncol, 28:4953-4960, 2010

  14. Salient Results • Two out of 3 patients with ALK positive NSCLC had major responses • Activity noted in patients with mutated EGFR and wild-type KRAS

  15. Clinical Results: HSP90 Inhibition in ALK+ NSCLC IPI-504 STA-9090 *simulated waterfall plot based on reported results *Durability of responses not reported N=11

  16. Hsp90 Inhibtion in ALK + NSCLC • There is now clear evidence of robust anti-cancer effects with Hsp90 inhibitors in ALK+ NSCLC • Durability of responses is not established yet (mPFS?) • Next steps • Combination of Crizotinib with Hsp90 inhibitors • Hsp90 inhibition in Crizotinib-resistant ALK +NSCLC

  17. Hsp90 Inhibition in NSCLC • It is likely that other genetic backgrounds beyond ALK+ disease are susceptible to Hsp90 inhibition • The effects in KRAS mutated tumors provides the rationale for combining Hsp90 inhibitors with other novel agents • Patients with HER-2 and RAF mutated tumors are also potential candidates

  18. Rationale for Combining Hsp90 inhibitors and Taxanes • Hsp90 inhibitors are synergistic with taxanes • 17-AAG sensitizes tumor cells to taxane-induced apoptosis by inhibition Akt activation • STA-9090 and docetaxel have synergistic effects • Phase I study of 17-AAG and paclitaxel • Tolerated well • No objective response Solit et al, Cancer Res, 2003; Sawai et al, Cancer Res, 2008; Proia et al, AACR 2010; Ramalingam et al, Clin Cancer Res, 2008.;

  19. Emory Univ. Docetaxel + STA-9090 Combination Phase I Study • Phase I study in patients with advanced solid organ malignancies (ongoing) • Docetaxel – day 1 • Ganetespib- days 1 & 15 • N=20 patients to date • Recommended phase II dose: Docetaxel 75 mg/m2; Ganetespib 150 mg/m2 • DLTs- myelosuppression and diarrhea (with 200 mg/m2) • Promising anti-cancer activity PI: Drs. Harvey and Ramalingam

  20. Vascular Disrupting Agents (VDAs) • Unique class of anti-neoplastic therapy • Designed to destroy established vessels of actively proliferating tumors - Leads to blood flow arrest and tumor necrosis • Mechanism has relevance to solid tumors such as non-small cell lung cancer (NSCLC)

  21. Study Design • Stage IIIB/IV NSCLC • All histologies • First-line chemotherapy-naïve • PS 0 or 1 • Stratification: • Sex • Squamous vs non-squamous Paclitaxel + carboplatin + ASA404 N=1200 Randomization 1:1 Paclitaxel + carboplatin + placebo • Paclitaxel 200 mg/m2, carboplatin AUC 6, and ASA404 1800 mg/m2 or placebo • Day 1, q3w, up to six cycles • ASA404 maintenance treatment (after completion of six cycles of ASA404 + P/C up to progression)

  22. Progression Free Survival

  23. Overall Survival Study closed by DSMC on 3.29.10 (interim analysis) for futility; final OS results from 6.1.10 shown

  24. Conclusions • Although tolerable, the addition of ASA404 to frontline chemotherapy failed to improve outcomes in advanced NSCLC patients • Median OS in either study arms was > 12.5 months, exceeding a priori assumptions • Vascular disruption as a therapeutic anti-cancer strategy remains unproven - ASA404 drug development has been halted • Molecular target of VDAs remains unknown; further clinical development of VDAs requires this knowledge • Patients with high likelihood of benefiting from VDAs, as identified by a putative biomarker, should be the focus of any future study

  25. MetMAb is an anti-Met monovalent antibody that inhibits HGF-mediated activation • Rationale for targeting Met: • Met is amplified, mutated, overexpressed or uniquely activated in many tumors • Met expression is associated with worse prognosis in many cancers including NSCLC • Met activation is implicated in resistance to erlotinib/gefitinib in pts with activating EGFR mutations • MetMAb: • One-armed format designed to prevent HGF-mediated stimulation of pathway • Preclinical activity across multiple tumor models HGF HGF MetMAb Met Met GrowthMigrationSurvival Noactivity HGF: Hepatocyte growth factor HGF: Hepatocyte growth factor

  26. Phase II: MetMAb +/- erlotinib in 2nd/3rd line NSCLC 1:1 RANDO M IZ A T I O N MetMAb (15 mg/kg IV q3w) Arm A n=69 Erlotinib (150 daily) • Key eligibility: • Stage IIIB/IV NSCLC • 2nd/3rd line NSCLC • Tissue required • PS 0–2 • Stratification factors: • Tobacco history • Performance status • Histology Placebo (IV q3w) n=137* n=68 Erlotinib (150 daily) Arm B • Co-primary objectives: • PFS in ‘Met Diagnosticpositive’ patients (est. 50%) • PFS in overall ITT population Other key objectives: • OS in ‘Met Diagnostic positive’ patients • OS in overall ITT patients • Overall response rate • Safety/tolerability PD add MetMAb n=27 Must be eligible to be treated with MetMAb *128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010

  27. Development of Met IHC for use as a companion diagnostic • Technical metrics • Tissue was obtained from 100% of patients. • 93% of patients had adequate tissue for evaluation of Met by IHC • Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories Met Dx Negative Met Dx Positive 1000 Negative (0) Weak (1+) Met Dx Negative 100 10 MET mRNA (2-Dct) Moderate (2+) Strong (3+) 1 Met Dx Positive 0 0 1 2 3 MET IHC score • Met diagnostic status was assessed after randomization and prior to unblinding • ‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong staining intensity 52% patients enrolled were ‘Met Diagnostic Positive’

  28. 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0 3 6 9 12 15 18 0.2 0.2 0 3 6 9 12 15 18 21 0.0 0.0 Effective MetMAb plus erlotinib in ITT population PFS: HR=1.09 OS: HR=0.8 Placebo +erlotinib 2.6 56 MetMAb +erlotinib 2.2 1.09 (0.73–1.62) 0.69 48 Placebo +erlotinib 7.4 41 MetMAb +erlotinib 8.9 0.80 (0.50–1.3) 0.34 34 Median (mo) HR (95% CI) Log-rank p-value No. of events Median (mo) HR (95% CI) Log-rank p-value No. of events Probability of survival Probability of progression free Note: + = censored value. Note: + = censored value. Time to progression (months) Overall survival (months) Control arm was consistent with previous studies in a similar population (Br21 PFS 2.2 mo, OS 6.7 mo, ORR 8.9%)

  29. 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0 3 6 9 12 15 18 0.2 0.2 0 3 6 9 12 15 18 21 0.0 0.0 Effective MetMAb plus erlotinib in Met Diagnostic Positive NSCLC patients PFS: HR=0.53 OS: HR=0.37 Placebo + erlotinib 1.5 27 MetMAb + erlotinib 2.9 0.53 (0.28–0.99) 0.042 20 Placebo + erlotinib 3.8 26 MetMAb + erlotinib 12.6 0.37 (0.19–0.72) 0.002 16 Median (mo) HR (95% CI) Log-rank p-value No. of events Median (mo) HR (95% CI) Log-rank p-value No. of events Probability of survival Probability of progression free Time to progression (months) Overall survival (months) The addition of MetMAb to erlotinib doubled the progression free survivaland nearly tripled the overall survival in this population

  30. Summary / conclusions • MetMAb is a potent, selective inhibitor of the Met pathway • Combination of MetMAb+erlotinib was well-tolerated; there were no new significant safety findings • Met Diagnostic Positive expression was associated with a worse outcome in control arm • MetMAb+erlotinib showed improved PFS (HR 0.53) and OS (HR 0.37) in Met Diagnostic Positive NSCLC patients • Different outcomes in ITT population vs Met Diagnostic Positive NSCLC patients support the importance of patient selection • MetMAb+erlotinib will be tested in a Phase III NSCLC trial

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