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Treatment after anti-EGFR and anti-VEGF Alain J. Gelibter Regina Elena National Cancer Institute Rome Main Signaling and pathway Shc Grb2 PI3-K Sos-1 Ras AKT Raf MEKK-1 MEK mTOR MKK-7 ERK JNK Apoptosis Resistance Proliferation Angiogenesis Metastasis Selumetinib is a potent inhibitor of MEK Pathway in Cancer Growth Factors • Constitutive activation of the pathway has been implicated in driving many cancers and in resistance to cancer • Mutant Ras & Raf proteins are key activators of the Ras-Raf-MEK-ERK pathway – B-Raf Mutations Extracellular GDP GTP RAS RAS* Raf MEK1 MEK2 AZD6244 MEK Pathway ERK1 ERK2 Cytoplasm • Malignant melanomas (66%) • Papillary thyroid cancers (40%) • Colorectal cancer (8-10%) – Ras Mutations • Colon (40%) • Pancreatic cancers (90%) • NSCLC (20%) Therapies for KRAS Mutated Colorectal Cancer That Is Resistant to EGFR Monoclonal Antibody Therapy Cancer Res 2011 AS703026 and AZD6244 inhibit tumor growth of cetuximab-resistant tumor attributed by K-ras mutation Cancer Res 2011 The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm) metastatic colorectal cancer (CRC). Patients • KRASm or BRAFm Metastatic colorectal cancer • Progression during or after 1st-line bevacizumab/ oxaliplatin/ fluoropyrimidine • Measurable or nonmeasurable disease Howard S. Hochster, ASCO GI 2013: Treatment Patients (Pts) were treated with IRI 180 mg/m2 iv q2w and SEL 50 or 75 mg po bid. Dose escalation was traditional 3+3 (50 mg bid SEL, then 75 mg bid). In Part B/phase II, primary endpoint was PIdetermined response rate (RR) The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm) metastatic colorectal cancer (CRC). Patients IRI + AZD6244 (n = 31) Male/Female Median age (range) 18/13 54 (27-75) Caucasian/other race Patients IRI + AZD6244 (n = 31) Partial response (PR) 3 (10%) Stable disease 16 (52%) 24/7 SEL 50 mg BID 3 Median numbr of cycles 3.5 SEL 75 mg BID 28 Median PFS (mts) 3.4 6 pts were on study for more than 6 (up to 22) months Grade 3 AEs included (N): diarrhea 3, fatigue 2, neutropenia 2, and 1 each thrombocytopenia, enteritis, GI bleed, rash MET Pathway and MET-Inhibiting Anticancer Agents A Randomized, Phase 1/2 Trial of AMG 102 or AMG 479 in Combination With Panitumumab vs Panitumumab Alone in Patients With Wild-Type KRAS Metastatic Colorectal Cancer (mCRC): Safety and Efficacy Results Eric Van Cutsem,1 Cathy Eng,2 Josep Tabernero,3 Elzbieta Nowara,4 Anna Świeboda-Sadlej,5 Niall C. Tebbutt,6 Edith P. Mitchell,7 Irina Davidenko,8 Lisa Chen,9 Dominic Smethurst10 Introduction • Panitumumab, a fully human monoclonal antibody against epidermal growth factor receptor (EGFR), has demonstrated efficacy in patients with wild-type KRAS mCRC in clinical trials1-4 • Rilotumumab (AMG 102) and ganitumab (AMG 479) are investigational, fully human monoclonal antibodies against hepatocyte growth factor (HGF; ligand for c-Met receptor) and insulin-like growth factor 1 receptor (IGF-1R), respectively • Preclinical studies indicate that there is complex interdependence between the HGF/c-Met and IGF-1R and EGFR pathways5-10 • Combinations of agents that block these receptors are being investigated for their potential to generate additive/synergistic anticancer effects 1. Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664. 2. Amado RG, et al. J Clin Oncol. 2008;26:1626-1634. 3. Peeters M, et al. J Clin Oncol. 2010;28:4706-4713. 4. Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705. 5. Lesko E, et al. Front Biosci. 2008;13:1271-1280. 6. Hynes NE, et al. Nat Rev Cancer. 2005;5:341-354. 7. Jo M, et al. J Biol Chem. 2000;275:8806-8811. 8. Ahmad T, et al. J Biol Chem. 2004;279:1713-1719. 9. Roudabush FL, et al. J Biol Chem. 2000;275:22583-22589. 10. Swantek JL, et al. Endocrinology. 1999;140:3163-3169. Rilotumumab and Ganitumab Mechanisms of Action IGF-1 Ganitumab (AMG 479) Rilotumumab IGF-2 ( AMG 102) HGF/SF IGF-1R Ras Ras Shc Grb2 SOS c-Met PI3K Survival Sos Gab1 Grb2 Proliferation PIP2 AKT/PKB PIP3 Shp2 Raf Rac1 PAK ERK/MAPK Cdc42 X X X Invasion Migration Cell Polarity Adhesion Raf IRS1 Cell proliferation PI3K PTEN MEK AKT/PKB ERK Survival mechanisms EIk-1 This depiction is believed to be the MOA of AMG 102; this compound is investigational. Rilotumumab (AMG 102) targets HGF, inhibiting downstream c-Met signaling Ganitumab (AMG 479) targets IGF1R, inhibiting downstream signaling through PI3K/AKT and MAPK pathways Study Schema • Amgen Trial 20060447; ClinicalTrials.gov identifier NCT00788957 aPanitumumab 6 mg/kg Q2W; rilotumumab (AMG 102) 10 mg/kg Q2W with dose de-escalation to 5 mg/kg as necessary; primary endpoint was incidence of dose-limiting toxicities bPanitumumab 6 mg/kg Q2W; rilotumumab (AMG 102) dose based on phase 1b; ganitumab (AMG 479) 12 mg/kg Q2W; primary endpoint was ORR cRilotumumab 10 mg/kg Q2W; ganitumab (AMG 479) 12 mg/kg Q2W; primary endpoint was ORR dPatients in the placebo arm of Part 2 with progressive disease or intolerance to treatment were eligible to participate in Part 3 DLT, dose-limiting toxicity; ORR, objective response rate; Q2W, every 2 weeks • Tumor assessments were performed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 Study Objectives Primary Objectives (Part 1 and Part 2) • Part 1: To identify a tolerable dose of rilotumumab (AMG 102) in combination with panitumumab based on the incidence and nature of dose-limiting toxicities (DLTs) • Part 2: To evaluate the efficacy as measured by the objective response rate (ORR) of rilotumumab (AMG 102) + panitumumab and ganitumab (AMG 479) + panitumumab vs panitumumab + placebo Other Key Objectives (Part 2) • Efficacy including progression-free survival (PFS) and overall survival (OS) • Safety • Pharmacokinetic analysis • Biomarker analysis Key Eligibility Criteria • Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 • Histologically or cytologically confirmed wild-type KRAS mCRC by local or central testing • Progression during or following prior treatment with irinotecan- and/or oxaliplatin-based chemotherapy for mCRC • No prior treatment with EGFR, c-Met, or IGF-1R inhibitors Part 2: Patient Demographics and Disease Characteristics at Baseline Panitumumab + Placebo (n = 48) Panitumumab + Rilotumumab (AMG 102) (n = 48) Panitumumab + Ganitumab (AMG 479) (n = 46) 28 (58) 29 (60) 25 (54) 55.0 (19-75) 62.1 (45-78) 62.0 (33-81) 15 (31) 33 (69) 24 (50) 23 (48)a 18 (39) 28 (61) 5 (10) 27 (56) 5 (10) 32 (67) 4 (9) 29 (63) Prior therapies for mCRC - n (%) First-line therapy Second-line therapy Third-line therapy and later 46 (96)b 31 (65) 14 (29) 48 (100) 33 (69) 16 (33) 46 (100) 26 (57) 12 (26) Prior chemotherapies for mCRC - n (%) Oxaliplatin Irinotecan Oxaliplatin and irinotecan 39 (81) 30 (63) 23 (48) 42 (88) 32 (67) 26 (54) 40 (87) 26 (57) 20 (44) Men - n (%) Age - mean years (range) ECOG status - n (%) 0 1 Metastatic sites - n (%) Liver only Liver + other sites aOne patient with ECOG performance score of 2 was enrolled in error; data from this patient were included in all efficacy and safety analyses patients had not received first-line therapy for mCRC; both patients had received oxaliplatin-based chemotherapy for non-metastatic CRC in the adjuvant setting and progressed on therapy before entering the study bTwo Part 2: Primary Endpoint Overall Response Rate Panitumumab + Placebo (n = 48) Panitumumab + Rilotumumab (AMG 102) (n = 48) Panitumumab + Ganitumab (AMG 479) (n = 46) 10 (21) 15 (31) 10 (22) 0 (0) 0 (0) 0 (0) Partial Response (PR) 10 (21) 15 (31) 10 (22) Stable Disease (SD) 17 (35) 19 (40) 18 (39) Progressive Disease (PD) 16 (33) 11 (23) 15 (33) Unevaluable/Not done 5 (10) 3 (6) 3 (6) 56 (41-71) 71 (56-83) 61 (45-75) 3.7 (3.6-NE) 5.1 (3.7-5.6) 3.7 (3.6-5.8) 0.93 0.63 Objective Response - n (%) Complete Response (CR) Disease control ratea - % (95% CI) Duration of response - median months (95% CI) Posterior probability of Odds Ratio > 1b aDisease control rate = CR + PR + SD is calculated based on ORR; an OR > 1 favors the combination arm over panitumumab alone NE, not estimable bOR • Responses were required to be confirmed at least 4 weeks after response criteria were first met Part 2: Progression-Free Survival Panitumumab ± Rilotumumab (AMG 102) (AMG 102) (AMG 102) Panitumumab ± Ganitumab (AMG 479) (AMG 479) (AMG 479) Conclusions • This is the first study to show promising evidence of efficacy by an HGF (c-Met pathway) inhibitor (rilotumumab [AMG 102]) when combined with panitumumab in patients with mCRC • The activity as assessed by ORR for patients receiving rilotumumab (AMG 102) plus panitumumab is promising (per prospectively specified Bayesian criterion) • Efficacy of ganitumab (AMG 479) plus panitumumab combination therapy as determined by ORR was indeterminate • The safety profiles of the drug combinations were generally similar to that of panitumumab alone with some exceptions, including a higher rate of grade 3/4 rash with rilotumumab and of hypomagnesemia with ganitumab ONARTUZUMAB • Onartuzumab is a monoclonal antibody designed to bind to MET and inhibit HGF/SF binding. Traditional bivalent antibodies to MET potentially activate, rather than inhibit, MET signaling by inducing MET dimerization. In contrast, the monovalent design of onartuzumab inhibits HGF/SF binding without inducing MET dimerization. Onartuzumab binds to the Sema domain of MET, an extracellular region essential for binding its ligand, HGF/SF Inhibits HGF/SF from binding to MET, thereby blocking ligandinduced MET dimerization and activation of the intracellular kinase domain Blockade of MET activation inhibits its downstream pathways, preventing cancer cell growth, survival, and metastasis PD and efficacy analysis of the B-RAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibnitor TRAMETINIB (GSK 212) in pts with BRAF V600E mutant CRC ASCO 2013 Overview of BRAF-mutant CRC • BRAF V600 mutations occur in 5-10% of CRC – Occur in K-ras wild type population – Worse prognosis than KRAS mutant or KRAS-BRAF wild type – May predict lack of response to anti-EGFR treatment • Distinct undrlying biology of BRAF-mutant CRC • Novel therapeutic strategies for BRAF-mutant CRC are critically needed. 1. Van Cutsem E, et al. ASCO 2010. Abstract 3570. 2. Tol J, et al. NEJM. 2009;361:98-99. 3. Di Nicolantonio F, et al. J Clin Oncol. 2008;26:5705-5712. 4. Laurent-Puig P, et al. J Clin Oncol. 2009;27:5924-5930. 5. Loupakis F, et al. Br J Cancer. 2009;101:715-721. 6. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019. 7. Bokemeyer C, et al. ASCO 2010. Abstract 3506. BRAF Mutations in First-Line Setting • CRYSTAL and OPUS combined analysis – Patients with wild-type KRAS/mutated BRAF • Worse outcomes vs wild-type KRAS/wild-type BRAF • Still experienced non-significant improvements (small N) Outcome Wild-type KRAS/ Mutated BRAF Wild-type KRAS/ Wild-type BRAF Cetuximab + CT CT Only P Value Cetuximab + CT CT Only P Value Median PFS, mos 7.1 3.7 .267 10.9 7.7 < .001 Median OS, mos 14.1 9.9 .079 24.8 21.1 .041 Median ORR, % 21.9 13.2 .4606 60.7 40.9 < .0001 Bokemeyer C, et al. ASCO 2010. Abstract 3506. B-RAF mutation: Melanoma vs CRC B-RAF mutant melanoma Response rate 60-80% B-RAF mutant CRC Response rate less than 10% Same target, same drug, different disease…….different response!!! Flaherty et al NEJM 2010 Kopetz et al ASCO 2010 PD and efficacy analysis of the B-RAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibnitor TRAMETINIB (GSK 212) in pts with BRAF V600E mutant CRC • Dabrafenib (150mg BID) • Trametinib (2mg QD) PD and efficacy analysis of the B-RAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibnitor TRAMETINIB (GSK 212) in pts with BRAF V600E mutant CRC Patients (n = 40) Patients Gender:Female 32 (80%) Number of lines of prior systemic anticancer therapy ECOG 1 18 (45%) 0 2 (5%) B-RAF V600E Mutation 40 (100%) 1 5 (13%) 2 12 (30%) Disease sites at screening n (%) (n = 40) <3 sites 18 (45%) >3 21 (53%) > 3 sites 19 (48%) Prior EGFR inhibitor 18 (45%) PD and efficacy analysis of the B-RAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibnitor TRAMETINIB (GSK 212) in pts with BRAF V600E mutant CRC • 1 (3%) achieved a complete response (confirmed, on study >12m), • 3 (9%) achieved a partial response and 18 (53%) had stable disease (SD). Efficacy Median PFS was 3.5 mo (95% CI: 1.8-4.9); 7 pts (24%) remained on study for ≥6 cycles with 9 pts still on study. Toxicity Any grade (n = 40) AE any grade Grade3-4 Pyrexia 10% 67% Nausea 5% 56% Fatigue 8% 53% Chills 3% 47% Vomiting 5% 39% Headache 0 31% Anemia 20% 28% Diarrhea 3% 25% 2 pts discontinued due to AEs. pERK reduction • Decreased pERK staining vs pre-dose samples was seen in all post-dose samples leading to absolute (49% ±29%) and relative (69% ±28%, normalized to total ERK) reduction in pERK. Study conclusions • Treatment with D and T combine safetely in B-RAF mutant CRC patients • Clinical activity is seen in a subset of patients • About 1/3 of PTS with at least a minor response • 25% of PTS with PFS > 6 mts • Biomarker analyses • Reduction in pERK observed in all patients. • PIK3CA mutations do not preclude clinical activity • MSI and low EGFR may be associated with better outcomes Next step for BRAF/MEK Inhibition? BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer An open-label, three-part Phase 1/2 study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) and dabrafenib (GSK2118436) when administered in combination with the anti-EGFR antibody panitumumab in subjects with BRAF-mutation V600E or V600K positive colorectal cancer (CRC). The phosphatidylinositol 3-kinase (PI3K) signaling cascade Activation Inhibition Inhibition of PI3K signaling can diminish cell proliferation, and in some circumstances, promote cell death Activation of PI3K signaling in Cancer • PI3K signaling is activated in human cancers via several different mechanisms. • Increased PI3K signaling is often due to direct mutational activation or amplification of genes encoding key components of the PI3K pathway such as PIK3CA and AKT1, or loss of PTEN Philip AJ Cancer Research Genetic alterations of the PI3K Signaling Pathway in Cancer PI3K inhibitors in Clinical trials. mTOR inhibitors A Phase II Trial of Bevacizumab plus Everolimus for Patients with Refractory Metastatic Colorectal Cancer Altomare The Oncologist 2011 A Phase II Trial of Bevacizumab plus Everolimus for Patients with Refractory Metastatic Colorectal Cancer 8 patients had minor responses (16%) and an additional 15patients (30%) had stable disease (SD). No CR, not PR. PFS was 2.3 months; Altomare The Oncologist 2011 A Phase II Trial of Bevacizumab plus Everolimus for Patients with Refractory Metastatic Colorectal Cancer Conclusions • Bevacizumab plus everolimus is generally tolerable but may have risks related to mucosal damage and/or wound healing. • Bevacizumab plus everolimus appears to have modest activity in refractory mCRC in patients. Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus (RAD001) for Patients With Refractory, Metastatic Colorectal Cancer Methods • The phase Ib study followed a 3+3 dose-escalation design with three dose levels. • The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer. Wolpin BM The Oncologist 2013 Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus (RAD001) for Patients With Refractory, Metastatic Colorectal Cancer Wolpin BM The Oncologist 2013 Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus (RAD001) for Patients With Refractory, Metastatic Colorectal Cancer • By independent radiologic review, 50% of 40 patients with refractory metastatic colorectal cancer had stable disease as their best response. • Nearly 20% of patients remained on study treatment for 6 months. • The disease control rate (DCR) of 50% and median PFS of 3.0 months compare favorably to trials in similar patient populations with refractory colorectal cancer, Including a 99-patient phase II trial of everolimus alone (DCR: 25.3%; median PFS: 1.7 months), a 50-patient phase II trial of bevacizumab and everolimus (DCR: 46%; median PFS: 2.3 months). Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus (RAD001) for Patients With Refractory, Metastatic Colorectal Cancer • The phase II study met its primary endpoint, with 50% of patients achieving PFS at 2 months. • Outcomes did not appear to differ by tumor KRAS mutation status. • In contrast, better outcomes in patients who developed grade 1 hypertension while receiving tivozanib and everolimus. (predictive biomarker for antiangiogenenic agents in colorectal cancer?). • Thus, modest efficacy was suggested for this drug combination in a patient population that greatly needs novel treatment programs. PI3K pathway: Conclusions • It remains unclear whether single-agent PI3K pathway inhibitors will promote dramatic responses (comparable to gefitinib in EGFR-mutant lung Cancers even in sensitive cancers. • Most models of cancers that are sensitive to single-agent PI3K pathway inhibitors have demonstrated tumor stasis in vivo rather than frank tumor regressions. • Data suggest that cancers with KRAS mutations may be fairly resistant to PI3K pathway inhibitors. • Consequently, necessary to combine PI3K pathway inhibitors with other agents Conclusions and Future directions • Predictive biomarkers have the potential to improve selection of the right drug for the right patient, but, aside from K-RAS (n-RAS), there has been little progress in incorporating these into clinical practice in CRC. • Identification of Biomarkers strongly needed • Multitarget treatment are needed after preclinical and pharmacodynamic studies