Small Cell Lung Cancer: How I Treat Extensive Stage Disease

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1 Small Cell Lung Cancer: How I Treat Extensive Stage Disease Primo N. Lara, Jr., MD Professor of Medicine Associate Director for Translational Research

2 Pop Quiz: These deadly creatures are related in what way? You try to kill em, but they keep coming back!

3 Extensive Stage SCLC: State of the Art 2012 Platinum/Etoposide (PE) has been the standard of care for two decades Randomized trials have failed to identify more effective regimens In Japan, Cisplatin/Irinotecan (PI) is a standard Median survival time is 8-10 months, also unchanged for over 20 years The most important breakthrough in the last decade? Prophylactic cranial irradiation!

4 Prophylactic Cranial Irradiation (PCI) in Extensive SCLC PCI* No PCI HR P Value 1-year OS 27% 13% month failure free survival Symptomatic brain metastasis 23% 15.5% % 40% 0.27 <.001 * Gy in 5-12 fxs Slotman et al., NEJM 2007

5 S0124: Cisplatin/Irinotecan vs. Cisplatin/Etoposide No difference in PFS and OS Progression Free Survival Overall Survival Lara, et al. J Clin Oncol 2009 Failed to confirm Japanese results

6 Second-line SCLC therapy: Current Status 2012 Prognosis is poor Median survival 2-3 months Patients resistant to chemo (progression within 90 days) or who have received multiple prior regimens rarely respond to additional treatment Topotecan is approved as 2 nd Line therapy on basis of phase III trial vs. CAV In good performance status patients, the best option is clinical trial participation

7 Phase III Topotecan vs. CAV in Second-line SCLC Progressive SCLC > 60 days R A N D O M I Z E Topotecan 1.5 mg/m 2 x 5 days Q 21 days Cyclophosphamide 1 gm Adriamycin 45 mg/m 2 Vincristine 2 mg d1 q3 weeks Von Pawel: JCO, 1999 Primary endpoint: Response Rate

8 Phase III Topotecan vs CAV in Second-line SCLC Topotecan CAV Number Response (%) Gr 3-4 Hgb/plts (%)* 42/58 20/15 Toxic death (#) 4 3 Median survival (weeks) Symptom improvement Better - *resulting in increased transfusions Conclusion: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms Von Pawel: JCO, 1999

9 SCLC: Second Line Therapy Topotecan is approved as 2 nd Line therapy Amrubicin is a newer synthetic anthracycline Potent topoisomerase II inhibitor approved in Japan for treatment of SCLC Amrubicin and topotecan were compared as 2 nd -line treatment for SCLC patients

10 Amrubicin vs. topotecan: Randomized phase III trial 2:1 randomization N=647 Amrubicin: 40 mg/m 2 /day slow IV push over 5 min, days 1-3 of 21-day cycle Topotecan: 1.5 mg/m 2 /day IV infusion over 30 min, days 1-5 of 21-day cycle Primary Endpoint: Overall survival AMR Topo HR 95% CI P value RR (%) PFS (mo) OS (mo) Jotte, et al. ASCO 2011

11 So why has progress in SCLC been so disappointingly slow?

12 SCLC: Top Ten Reasons 1. Incomplete biologic understanding 2. Lack of biomarkers 3. Tumor heterogeneity 4. Patient heterogeneity 5. Inadequate preclinical models 6. Insufficient tumor tissue 7. Relative investigator disinterest 8. Rapid development of drug resistance 9. Lack of advocacy 10. Small (and shrinking) patient base

13 #10 Small (and shrinking!) Patient Base Lung and bronchus: 226,160 new cases per year SCLC: 25,000 30,000/year (13% of all lung cancer, decreasing in incidence) CML: 5,430; Gastric: 21,320; Myeloma: 21,700; Ovary: 22,280; HCC: 28,720 EGFR mt NSCLC: ~23,000; ALK+ NSCLC: ~9,000

14 #9 Lack of Advocacy Median Survival Median Survival 2-Year Survival Untreated Patients* Treated Patients (%) (mo) (mo) Limited disease %-45% Extensive disease %-20% * historical data SCLC is a uniformly fatal disease Lack of high profile survivors = absence of advocacy Ihde DC, et al. Cancer: Principles & Practice of Oncology. 1997; Lassen U, et al. Cancer Treatment. 1995; Soriano AF, et al. Current Cancer Therapeutics. 1998;

15 Even high profile cases do not seem to raise awareness for SCLC

16 SCLC: Top Ten Reasons 1. Incomplete biologic understanding 2. Lack of biomarkers 3. Tumor heterogeneity 4. Patient heterogeneity 5. Inadequate preclinical models 6. Insufficient tumor tissue 7. Relative investigator disinterest 8. Rapid development of drug resistance 9. Lack of advocacy 10. Small (and shrinking) patient base

17 #8 Drug Resistance Despite initial high response to chemotherapy, resistance rapidly emerges Cisplatin resistance studied widely Many candidate modulators: ERCC1, XRCC1, etc. Examples of other chemoresistance studies: ECM proteins (Sethi, Nature Med 1999) GRP78 (Wang, BMC Cancer 2008) CXCR4 and nicotine (Garcia, Tox Sci 2010) Micro RNAs (Guo, Eur J Cancer 2010) and countless others

18 #8 Drug Resistance Lawson, Cancer Res 2011 Novel Determinants of Etoposide Resistance: NKX.2 and DNA polymerase beta

19 SCLC: Top Ten Reasons 1. Incomplete biologic understanding 2. Lack of biomarkers 3. Tumor heterogeneity 4. Patient heterogeneity 5. Inadequate preclinical models 6. Insufficient tumor tissue 7. Relative investigator disinterest 8. Rapid development of drug resistance 9. Lack of advocacy 10. Small (and shrinking) patient base

20 #7 Relative Investigator Disinterest Active studies on clinicaltrials.gov* SCLC 120 Ovarian 522 Myeloma CML 107 *As of March 1, 2012

21 SCLC: Top Ten Reasons 1. Incomplete biologic understanding 2. Lack of biomarkers 3. Tumor heterogeneity 4. Patient heterogeneity 5. Inadequate preclinical models 6. Insufficient tumor tissue 7. Relative investigator disinterest 8. Rapid development of drug resistance 9. Lack of advocacy 10. Small (and shrinking) patient base

22 #6 Insufficient Tumor Tissue Few surgical resections in SCLC Most diagnostic specimens FNA or cytologic Serial biopsies exceedingly rare Thus, limited tumor specimens available for research

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24 SCLC: Top Ten Reasons 1. Incomplete biologic understanding 2. Lack of biomarkers 3. Tumor heterogeneity 4. Patient heterogeneity 5. Inadequate preclinical models 6. Insufficient tumor tissue 7. Relative investigator disinterest 8. Rapid development of drug resistance 9. Lack of advocacy 10. Small (and shrinking) patient base

25 #5 Inadequate Preclinical Models Expression of tumor-specific genes in primary SCLC and xenografts lost during transition to tissue culture Gene expression NOT regained when tumors were re-established as secondary xenografts Cancer Res, 2009

26 SCLC: Top Ten Challenges 1. Incomplete biologic understanding 2. Lack of biomarkers 3. Tumor heterogeneity 4. Patient heterogeneity 5. Inadequate preclinical models 6. Insufficient tumor tissue 7. Relative investigator disinterest 8. Rapid development of drug resistance 9. Lack of advocacy 10. Small (and shrinking) patient base

27 Common Arm Comparative Toxicity Analysis: JCOG 9511 vs. SWOG 0124 Cisplatin + Etoposide Cisplatin + Irinotecan Grade 3 Toxicity J9511 S0124 p-value J9511 S0124 p-value Infection 3 (4%) 52 (16%) (5%) 36 (11%) 0.23 Neutropenia 71 (92%) 220 (68%) < (65%) 107 (34%) < Leukopenia 41 (53%) 109 (34%) (27%) 57 (18%) 0.04 Anemia 25 (32%) 39 (12%) < (28%) 18 (6%) < Lara, et al. Cancer 2010

28 Common Arm Comparative Efficacy Analysis: JCOG 9511 vs. SWOG 0124 Cisplatin + Etoposide Cisplatin + Irinotecan Efficacy Measure J9511 S0124 p-value J9511 S0124 p-value Response Rate Progression-free Survival, median (months) 68% 57% % 60% < Lara, et al. Cancer 2010

29 Why were S0124 and J9511 results divergent? Early stopping of the J9511 trial Smaller sample size of J9511 may have significantly overestimated the treatment effect, which diminishes when the number of events accrued is large Imbalances in the distribution of patient characteristics in J9511 Fewer patients with performance status of 2, more women (who historically do better than men), and fewer brain metastases Inherent genetic differences that exist between populations Single nucleotide polymorphisms of genes involved in chemotherapy metabolism or transport may underlie racial differences Lara, et al. J Clin Oncol 2009

30 SCLC: Top Ten Reasons 1. Incomplete biologic understanding 2. Lack of biomarkers 3. Tumor heterogeneity 4. Patient heterogeneity 5. Faulty preclinical models 6. Insufficient tumor tissue 7. Relative investigator disinterest 8. Rapid development of drug resistance 9. Lack of advocacy 10. Small (and shrinking) patient base

31 the mesenchymal compartment of the tumor is generated from a separate subclone during the tumorigenic process, providing the tumor cell population as a whole with new capabilities such as metastatic potential. Cancer Cell 2011

32 SCLC: Top Ten Reasons 1. Incomplete biologic understanding 2. Lack of biomarkers 3. Tumor heterogeneity 4. Patient heterogeneity 5. Inadequate preclinical models 6. Insufficient tumor tissue 7. Relative investigator disinterest 8. Rapid development of drug resistance 9. Lack of advocacy 10. Small (and shrinking) patient base

33 #2 Lack of Biomarkers Precise cellular origin of SCLC is unknown May arise from bronchial mucosa Can undergo both neuroendocrine (NE) and non-ne differentiation: suggests common epithelial ancestor Stem cells? Reactivation of Hedgehog signaling in lung stem cells leads to NE differentiation Gazdar, Science 1985; Stovold, Lung Cancer 2011

34 Revisiting Neuroendocrine Biomarkers in SCLC POMC: hormonal precursor elevated in 30% of SCLC; potential role as secreted biomarker? Other markers: Pro-GRP NSE Synaptophysin CD56 Stovold, Lung Cancer 2011

35 CD56 as biomarker and therapeutic target CD56 a neural cell adhesion molecule (NCAM) Expressed extensively (~100%) on SCLC cell surface IMGN901 is an antibody-drug conjugate (ADC) designed to deliver a potent tubulin-acting agent (DM1) specifically to CD56- expressing cells IMGN901 has preclinical activity as single agent and in combination with platinum/etoposide in SCLC Anti-CD56 antibody (humanized IgG1) Engineered disulfide linker Randomized phase II trial of carbo/vp16 +/- IMGN901 in SCLC ongoing Conjugated to DM1 Derivative of maytansine Antimitotic inhibits tubulin polymerization

36 SCLC: Top Ten Reasons 1. Incomplete biologic understanding 2. Lack of biomarkers 3. Tumor heterogeneity 4. Patient heterogeneity 5. Inadequate preclinical models 6. Insufficient tumor tissue 7. Relative investigator disinterest 8. Rapid development of drug resistance 9. Lack of advocacy 10. Small (and shrinking) patient base

37 Fundamental Issue in SCLC Biology No actionable driver mutations OFF ON Tumor Suppressor Oncogene

38 SCLC Biologic Dilemma Oncogenes Not reliably identified in SCLC Driver vs. passenger mutations Recent advances in other solid tumors: oncogenes as targets Inherently druggable EGFR, BCR-ABL, ckit, BRAF, etc cmet mutation in SCLC previously described (Salgia): potential target

39 SCLC Biologic Dilemma Tumor Suppressor Genes Commonly seen in SCLC P53, RB Deleted, silenced, inactivated Not easily druggable Need to instead target effector pathways VEGF, cell cycle kinases, signal transduction

40 Small Cell Lung Cancer 3p (del) Molecular Profile p53 mutations: 80-90% Rb abnormalities: 100% High Expression of c-kit* High Expression of BCL2* Biologic Behavior High cellular proliferation Short cell cycle time Rapid doubling time Early metastases Chemo-radiation sensitive * Oncogenes

41 Median OS = 3 months JTO 2006 Tumor tissue not available for further interrogation

42 ABT-263 in SCLC Phase I/II Monotherapy Thrombocytopenia doselimiting Tolerable Limited efficacy as monotherapy Phase I in combination with cisplatin and etoposide Cisplatin 75mg/m 2 D1, Etoposide 100mg/m 2 D1-3 ABT-263 doses explored: Starting dose: 150mg D1-5; adjusted to 150mg D1-3 Adverse effects: Grade 4 neutropenia, neutropenic fever 39 patients with recurrent SCLC; 26 evaluable: - 1 PR Closed due to futility - 9 SD (23%) - 16 PD Hann/Rudin, Targeted Therapies 2012

43 Obatoclax in SCLC Phase 2b Trial Design R Investigational Arm (CbEOb) * Carboplatin AUC 5 IV day 1 Etoposide 100 mg/m2 days 1, 2, 3 Obatoclax 30 mg/3 hr days 1, 2 and 3 Tx every 3 wks X 6, followed by Maintenance obatoclax [same schedule until PD] Control Arm (CbE) * Carboplatin AUC 5 IV day 1 Etoposide 100 mg/m2 days 1, 2, 3 Tx every 3 wks X 6 * PCI: permissible in both arms Langer, ASCO 2011

44 Response Rate Analysis* PS 0-2 CR/PR CbEOb CbE Total Odds Ratios 50/77 65% 42/78 55% P value (Fisher s; 1- sided) PS 0-2 CR/PR/SD 64/77 83% 54/78 69% PS 0-1 CR/PR 47/69 68% 41/72 57% PS 0-1 CR/PR/SD 61/69 88% 53/72 74% All responses, including SD, confirmed by 2 nd evaluation 6 + wks later CR/PR/SD = Disease Control Rate Langer, ASCO 2011

45 Percent survival Kaplan-Meier Actuarial Estimated Survival Median 9.8 mos 10.5 mos CbE CbeOb CE CEO Overall H.R CEOb/CE P value (1-sided): Time

46 Targeting Pathways in Absence of Actionable Oncogenic Mutations Example: PI3K/AKT/mTOR pathway is defective in SCLC pakt expression = 70% pten mutations = 15% D Angelo, Cancer Biol & Ther 2010; Krystal, Mol Ther 2002

47 SCLC Cell Line Panel Cell line p53 RB PTEN PI3K EGFR KRAS BRAF ALK H526 Mt Mt wt wt wt wt wt wt H69 Mt Mt wt Mt wt wt wt wt H2196 Mt Mt Mt wt wt wt wt wt Mack lab, UC Davis *Provided by Cancer Genome Project (Sanger Institute)

48 CI CI Combination Indices (CI) show additivity or synergy for Topotecan + MK Fa-CI plot H526: PTEN wt, PI3K wt Fa-CI plot H69: PI3Kmt Effect Effect Combination CI = 1.0 ED25 CI Values Combination CI = 1.0 ED25 CI Values ED ED ED ED Median Effect Analysis Unpublished data: Mack lab, UC Davis

49 Conclusions SCLC presents both universal and unique challenges to drug development Investments in SCLC research and therapy remain underwhelming Defining biology = optimizing treatment

50 LOST IN TRANSLATION