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Critical Concepts in the Use of Combination Chemotherapy With Targeted Agents

Critical Concepts in the Use of Combination Chemotherapy With Targeted Agents. Lee M. Ellis, MD. The University of Texas MD Anderson Cancer Center. Combination Chemotherapy + Targeted Therapy in GI Cancers After all, I only have 20 minutes. Scientific rationale and biology

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Critical Concepts in the Use of Combination Chemotherapy With Targeted Agents

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  1. Critical Concepts in the Use ofCombination Chemotherapy With Targeted Agents Lee M. Ellis, MD The University of Texas MD Anderson Cancer Center

  2. Combination Chemotherapy + Targeted Therapy in GI CancersAfter all, I only have 20 minutes • Scientific rationale and biology • Where are we today? • Clinical trial results since ASCO 2006 • What to look for at ASCO 2007 • Where do we need to go? • Novel targets

  3. Tumors driven primarily by a single molecular event Single agent can be efficacious RCC GIST Even tumors driven by a single mutant gene can become refractory GIST Tumors driven by multiple molecular events Multiple molecular alterations requiring multi-targeted therapies Combination with chemotherapy CRC NSCLC Breast cancer Pancreatic cancer? In the Era of Targeted TherapyHow Do We Best Utilize These Agents? Two Basic Molecular Classes of Tumors:

  4. Why Combine Targeted Therapy With Chemotherapy? • Single-agent, targeted therapy has minimal efficacy in tumors driven by multiple genetic alterations • Chemotherapy intended to induce apoptosis • Most targeted therapies are designed to inhibit survival pathways, and thus enhance apoptosis • This is the foundation of EGFR targeting • Even anti-VEGF therapies may enhance chemotherapy by multiple mechanisms, including inhibition of tumor and endothelial cell survival pathways • Targeted therapies are best utilized when you have an “apoptotic hit” • Weaken the tumor cell with targeted therapy in order to maximize the benefit of CTX

  5. Current FDA-Approved, Targeted Therapies for GI Malignancies (excluding GIST) • EGFR targeting • Cetuximab • Panitumumab • Erlotinib • VEGF/R • Bevacizumab

  6. EGFR Signalling in Tumor Cells Ligand EGFR EGFR-tyrosine kinase domains K K PI3-K pY pY pY RAS RAF STAT3 AKT PTEN MEK Gene transcription Cell cycle progression Upregulation of survival mediators (Bcl-2, etc.) MAPK Proliferation /maturation Angiogenesis Chemotherapy /radiotherapyresistance Survival(anti-apoptosis)

  7. EGFR Inhibition in Cancer: A Pragmatic View • The main value of anti-EGFR therapy is to inhibit survival pathways • P-I-3K  Akt  Bcl-2 pathway • There is no such thing as an “EGFR-negative” epithelial tumor • We simply cannot detect EGFR in all specimens due to limitations of immunohistochemistry • EGFR inhibitors do not work in every tumor or every disease type • Resistance may be due to bypass pathways • Tumors driven by other receptors • Tumors driven by downstream mutations • Camp et al. Clin Ca Res, 2006

  8. Proposed Mechanisms of Action (MOA) of Anti-VEGF Therapy – and Some Comments

  9. Combination Chemotherapy + Targeted Therapy in GI Cancers • Scientific rationale and biology • Where are we today? • Clinical trial results since ASCO 2006 • CRC • Pancreas • What to look for at ASCO 2007 • Where do we need to go? • Novel Targets

  10. Recruitment June 2003 - May 2004 Recruitment Feb. 2004 – Feb. 2005 RANDOMIZATION FOLFOX4 + Placebo n=350 FOLFOX4n=317 FOLFOX4 + Bevacizumab n=350 • mCRC • No prior therapy for advanced disease • ECOG PS 0-1 XELOXn=317 XELOX + Placebon=351 XELOX + Bevacizumabn=350 Phase III Trial of FOLFOX4 or XELOX ± Bevacizumab in First-Line mCRC (NO16966) • Primary endpoints: PFS (XELOX vs. FOLFOX; bevacizumab + chemotherapy vs. chemotherapy alone) • Secondary endpoints: OS, ORR, time to response, DOR, TTF, and safety Saltz, et al. GI Cancers Symposium, 2007. Abstract 238.

  11. HR=0.83 [97.5% CI, 0.72-0.95] (ITT) P=0.0023 8.0 9.4 Phase III Trial of FOLFOX4 or XELOX ± Bevacizumab in First-Line mCRC (NO16966): PFS FOLFOX + placebo/XELOX + placebo N=701; 547 events FOLFOX + bevacizumab/XELOX + bevacizumab N=699; 513 events Saltz, et al. GI Cancers Symposium, 2007. Abstract 238

  12. FOLFOX subgroupHR=0.89 [97.5% CI 0.73-1.08] (ITT) P=0.1871 XELOX subgroupHR=0.77 [97.5% CI 0.63-0.94] (ITT) P=0.0026 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 PFS Estimate 8.6 9.4 7.4 9.3 0 5 10 15 20 25 0 5 10 15 20 25 Months Months FOLFOX + placebo N=351; 277 events FOLFOX + bevacizumab N=349; 255 events XELOX + placebo N=350; 270 events XELOX + bevacizumab N=350; 258 events Phase III Trial of FOLFOX4 or XELOX ± Bevacizumab in First-Line mCRC (NO16966): Subgroup PFS Saltz, et al. GI Cancers Symposium, 2007. Abstract 238

  13. Cetuximab/Irinotecan N=648 Failure of Oxaliplatin-Based Therapy Survival Irinotecan Stratified by: • Study site • ECOG PS (0-1, 2) N=650 Randomized Phase III Trial of Cetuximab Plus Irinotecan vs. Irinotecan Alone for mCRC After Failing Prior Oxaliplatin-Based Therapy: The EPIC Trial • Primary endpoint: survival • Secondary endpoints: PFS, RR, DCR, safety, QoL • Sample size: 1,298 patients in 221 centers Sobrero, et al. AACR 2007.

  14. PFS OS 1.0 1.0 HR=0.975 (95.03% CI 0.854–1.114) HR=0.692 95% CI=0.617–0.776 0.8 0.8 Stratified Log Rank P Value = < 0.0001 Stratified Log Rank P Value = 0.7115 0.6 0.6 4.0 mo Proportion Alive Proportion Progression Free 2.6 mo 0.4 0.4 47% of pts on the irinotecan-alone arm subsequently received cetuximab 0.2 0.2 0.0 0.0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Months Randomized Phase III Trial of Cetuximab Plus Irinotecan vs. Irinotecan Alone for mCRC After Failing Prior Oxaliplatin-Based Therapy: The EPIC Trial Cetuximab + irinotecan; N=648 Irinotecan alone; N=650

  15. 1.0 Cetuximab + Irinotecan; N=575 0.9 Irinotecan; N=345 | | | | | | | | | | | | | | | | | | | | | 0.8 | | | | | | | | 47% of pts subsequently received cetuximab | | | | 0.7 | | | | | | | | | 10.2 mo | 0.6 | | | | | | | | | | | | | | | Survival Probability | | | | | | | | | | 0.5 | | | | | 6.2 mo | | | | | | | | | | | | | | | | | | | | 0.4 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.3 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.2 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.1 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.0 | | | 0 3 6 9 12 15 18 21 24 27 30 Survival Time (months) Post-Hoc Survival Analysis: Subjects Who Received Post-Study Cetuximab Were Excluded

  16. N=1080; primary endpoint: PFS – statistically improved over chemo alone* FOLFIRI+ Cetuximab EGFR-expressing mCRC; no previous chemotherapy except adjuvant PFS, OS, ORR, duration of response, safety, QoL FOLFIRI CRYSTAL: Phase III FOLFIRI± Cetuximabin First-Line mCRC • FOLFIRI: 5-FU: 400mg/m2 as bolus and 2400 mg/m2 over 46 h Folinic acid: 400 mg/m2 Irinotecan: 180 mg/m2 • Cetuximab: 400 mg/m2 initial dose (week 1) • 250 mg/m2 weekly dose (starting week 2) * Press Release - PFS top line data; detailed data will be presented at ASCO 2007. Tuesday 11:00 AM - 11:15 AM Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. Abstract 4000. Presenter: Eric Van Cutsem, MD, PhD

  17. Is More Better? • If you use all of your agents up front, what do you use second line after progression/resistance? • Simultaneous targeting of multiple pathways may lead to increased toxicity • Remember, these targets also play a role in physiology

  18. RANDOMIZATION Bevacizumab FOLFOX FOLFIRI N=1,000 Bevacizumab + Panitumumab PACCE Phase III Trial in First-Line mCRC

  19. Phase III Trial CTX + Bev +/- Panitumumab in mCRC: PACCE Study • Preliminary announcement in January 2007 reported an increased incidence of grade 3 diarrhea, dehydration, and infections in the panitumumab arm • In March 2007, Amgen announced discontinuation of panitumumab treatment based on pre-planned interim analysis showing PFS and OS in favor of the control arm Not Presented at ASCO Will be presented at the World Congress on GI Cancers, Barcelona, Spain, June 2007

  20. Cetuximab Patients with untreated metastatic colorectal cancer (N=2,289) Patient/physician choice: mFOLFOX6 or FOLFIRI Bevacizumab Cetuximab Bevacizumab Primary endpoint: OSSecondary endpoints: PFS, RR CALGB/SWOG 80405: Study Design

  21. Combination Chemotherapy + Targeted Therapy in GI Cancers • Scientific rationale and biology • Where are we today? • Clinical trial results since ASCO 2006 • CRC • Pancreas • What to look for at ASCO 2007 • Where do we need to go? • Novel Targets

  22. Primary endpoint: OS Secondary endpoints: PFS, ORR, DR, toxicity RANDOMIZATION • Unresectable pancreatic adenocarcinoma • No prior chemotherapy for metastatic disease • No prior VEGF inhibitors • ECOG PS 0-2 n=300 Gemcitabine + placebo N=602 n=302 Gemcitabine + bevacizumab Phase III Trial of Gemcitabine ± Bevacizumab in First-Line Metastatic Pancreatic Cancer (CALGB 80303) Kindler,et al. GI Cancers Symposium, 2007. Abstract 108.

  23. PFS OS 1.0 1.0 Gemcitabine + bevacizumab Gemcitabine + placebo Gemcitabine + bevacizumab Gemcitabine + placebo 0.8 0.8 HR=1.00 P=0.99 HR=1.09 P=0.40 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 5 10 15 20 0 5 10 15 20 Months From Study Entry Months From Study Entry Phase III Trial of Gemcitabine ± Bevacizumab in First-Line Metastatic Pancreatic Cancer (CALGB 80303): PFS and OS Kindler,et al. GI Cancers Symposium, 2007. Abstract 108.

  24. RANDOMIZATION Gemcitabine + placebo • Stratify • Stage • Prior pancreatectomy • PS N=~760 Gemcitabine + cetuximab Phase III Trial of Gemcitabine ± Cetuximab in First-Line Advanced Pancreatic Cancer (SWOG 0205) • Primary endpoint: OS; completed accrual at N=760 • Secondary endpoints: TTF, RR, safety, QOL, EGFR + tumors and compare survival in EGFR + subset • Tumor samples to SWOG central lab for EGFR IHC; registration independent of EGFR status Sunday, 06/03/2007, 3:15 PM - 3:30 PM Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. Abstract LBA4509. Presenter: Philip A. Philip, MD, PhD, FRCP

  25. What’s Next • As targeted therapies become the mainstay of therapy in the frontline setting, we need to be prepared for resistance • Is resistance to chemo or targeted therapies or both • We use 5-FU through multiple lines of therapy • Should targeted therapies continue after progression on a regimen? • We need therapies for subsequent lines of therapy • Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Results from a large observational study (BRiTE). • Abstract No: 4036 Presenter: Axel Grothey, MD • Saturday, 2:00 PM - 6:00 PM Poster Display Location:S403

  26. Functions of Cell Surface Receptors The most efficacious targeted therapies may be those that mediate cell survival

  27. P P P P Angiogenesis VEGF P P P P Mitogenic Ras MAPK Survival PI-3-K/Akt Migration/ Invasion IGF-IR as a Central Mediator of Cellular Functions IGF-1R EGFR

  28. Direct Liver Injection (1 x 106 HT29 cells) Liver harvested (3/12 mice moribund) Days 0 4 7 10 11 13 14 16 18 19 21 22 25 28 54 oxaliplatin IGF-IR MoAB Effect of an IGF-IR MoAB +/- Oxaliplatin on Growth of Liver Tumors Treatment: MoAB IGFR oxaliplatin Groups: 1. control 2. Oxaliplatin 3. MoAB IGFR 4. MoAB IGFR + oxali 5. MoAB IGFR + oxali (start d 19) (“delayed”) Bauer et al. Ann Surg Onc, In press, 2007

  29. Effect of MoAB IGF-IR and Oxaliplatin on Colon Cancer Growth in the Liver 1 cm Bauer et al. Ann Surg Onc, In press, 2007

  30. IGF-IR Inhibitors in Development Hofmann, DDT 10, 2005. *All TKIs (tyrosine kinase inhibitors) have the potential to inhibit the insulin receptor (kinase homology = 84%, ATP-binding pocket homology 100%). Insulin-like Growth Factor Receptor Targeting: An Exciting New Strategy for Cancer Therapeutics: Monday AM- Location: S100a

  31. Other Promising Targets cMET* uPAR* Src* Akt/PKB MAPK (MEK, JNK, Raf) HSP90 * mTOR* Proteosome NFkB HDAC * Ongoing studies in the lab with promising results in combination with chemotherapy

  32. Conclusions: CTX and Targeted Therapies • Anti-EGFR and anti-VEGF MoABs have lead to incremental improvements in RR and PFS in metastatic CRC • At the present time, combining multiple targeted therapies simultaneously with CTX has not been shown to be of benefit • Detriment? • Little progress has been made in pancreatic cancer with the addition of targeted therapies to CTX • Is gemcitabine the right foundation? • We urgently need predictive markers of efficacy, toxicity, and resistance

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