Keeping Pace with Targeted Therapies in Lung Cancer

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  • 47 patients enrolled in a continuous dosing schedule of 37.5 mg
  • High VEGF (> 161 pg/mL) at baseline correlated with shorter survival compared with patients with low VEGF (< 161 pg/mL):
    184 days compared with 292 days (P < .05)
    Notes:
    161 pg/mL is median level of plasma VEGF at baseline
    P values were not corrected for multiple sampling (Bonferroni)
  • Improvements in PFS and OS do not reach significance in this phase II study
  • Preliminary safety findings
    Incidence of grade 3-5 hemorrhage in bevacizumab-treated patients was 5.1% (4 of 79 pts)
  • AEs are Grade 1 or 2 except where noted
  • Table list most common side effects reported for each agent as listed in the agent’s Product insert (from a table or text in the AE section): where available information on monotherapy was used. In all cases it is important to educate the patient on the potential side effects of these targeted therapies. It is critical for the nurse to assess the patients for early signs of these side effects because if caught early, the majority of these can be treated so the patient can continue to receive full doses of therapy as prescribed by their oncologist and without dose delays.
  • This is a continuous of the most common side effects seen with targeted therapies
  • Bevacizumab is a monoclonal antibody and is an anti-angiogenesis agent.
    It is approved for first line treatment of colorectal cancer given in combination with a 5-FU based therapy. Most common side effects with bevacizumab when combined with chemotherapy were HTN, wound healing or bleeding complications and epistaxis. Less common but more serious are arterial thromboembolic events, GI perforation, and grade 3 or worse bleeding. These side effects were noted more often when bevacizumab was given with chemotherapy than when chemotherapy was given alone. Hypertension can be managed with standard oral anti-hypertensives, if severe hypertension, delay of treatment or discontinuing Bevacizumab therapy is recommended. In regards to wound healing, in clinical trials patients were not allowed on study until they were at least 28 days post-op, therefore it is recommended to wait at least 28 days from major surgery before initiating bevacizumab. The appropriate time to wait between bevacizumab therapy and elective surgery has not been determined. Epistaxis can be treated using standard first aid techniques.
  • This is an example of a blood pressure diary that may be used when managing a patient on bevacizumab. It is especially helpful to use with patients taking oral antihypertensives. The patient will record their blood pressure in the morning and evenings as directed and should bring this to each follow up appointment. This will help to ensure the patient is compliant with their anti-hypertensive regimen as well as give the physician and nurse a chance to monitor the patients blood pressure. Medication classes used to treat the hypertension with avastin include ACE inhibitors, calcium channel blockers, beta blockers, and diuretics. In cases of difficult to control hypertension it is important to involve a cardiologist to assist in the management of the patients care. For example a patient on three or more anti-hypertensive medications.
  • Bortezamib is an intravenously delivered proteosome inhibitor. It disrupts the homeostatis of the cell and may cause cell death. Bortezamib is approved for use in patients with multiple myeloma who have failed at least one line of treatment. The most common side effects are peripheral neuropathy, asthenia (fatigue, malaise and weakness), GI toxicities of nausea, diarrhea or constipation, vomiting,anorexia and hypotension. The peripheral neuropathy is primarily a sensory neuropathy. Patient with pre-existing neuropathy should be watched closely as bortezamib may worsen this condition. If neuropathy becomes a concern it was shown in clinical studies that adjusting the dose helped to improve the neuropathy. The incidence of hypotension was approx 11-12%. Caution should be used when treating patients with pre-existing vertigo, hypotension, dehydration or other cardiac condition where hypotension may worsen their baseline condition. Thrombocytopenia and neutropenia may be observed. It is recommended to watch a patients CBC weekly while on treatment. The incidence of febrile neutropenia was less than 1% in phase II and III trials. In addition Bortezamib should be held if platelets are less than 25, 000
  • Cetuximab is a recombinant, human/mouse chimeric monocloncal antibody against the EGFR receptor. It is approved for use in combination with Irinotecan or for single agent use for patient who may not tolerate irinotecan. The most common side effect in clinical trials were dermatologic in nature. Less common but more serious is infusion related reaction. The incidence of severe reaction was 4% or less. The incidence of grade 2 or 3 reaction was 16-19%. Approximately 90% of infusion reactions were during the first infusion. It is important for the bedside nurse to be prepared to treat a severe reaction such as bronchospasm or airway obstruction.
    The dermatologic side effects were the most common side effect of combination therapy and monotherapy. The rash manifests as a red ruby appearance, dry skin and also can be pustules. The rash seems to appear approximately 2 weeks after starting treatment. Patients also experienced skin drying or fissuring along the fingers and toes. Careful attention to skin care, moisturizing and avoiding over exposure to the sun is helpful. If severe rash persists a dermotologic consult may be helpful.
  • Erlotinib is an oral targeted therapy that works against the EGFR tyrosine kinase. It is approved for patients with non small cell lung cancer who have failed at least one prior chemo regimen. It is also approved for use in pancreatic cancer as first line treatment. Confounding factors for acute respiratory distress syndrome and lung infiltration in pts in lung cancer trials included: concomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, pulmonary infections
  • Gefitinib only available to pts who are or have benefited from treated with this agent
    As of September 15, 2005 new pts may be treated with gefitinib only if enrolled in a clinical trial approved by an IRB prior to June 17, 2005 or as part of a clinical study being conducted under an investigational new drug (IND) application
    Most common adverse events: diarrhea, rash, acne, dry skin, nausea, and vomiting
  • Incidence of bleeding from GIST registration trial
    Patients being treated with sunitinib should not take St. John’s Wort
    Sunitinib dose modifications recommended for pts taking concomitant strong CYP3A4 inhibitor or inducer
    Monitor adrenal insufficiency in pts who experience stress (eg, surgery, trauma, severe infection)
  • Sorafinib is an oral drug that blocks the RAF kinase that controls cell division and proliferation. It also blocks VEGFr-2 and PDGFr-beta giving it an anti-angiogenesis effect.
    Warfarin co-administration infrequently associated with bleeding events or elevations in International Normalized Ratio (INR)
    Patients taking concomitant warfarin should be regularly monitored for changes in prothrombin time, INR, or episodes of clinical bleeding
    Most common sorafenib-related AEs: rash, diarrhea, hand-foot skin reaction, fatigue
    Grade 3 AEs occurred in 37% of pts treated with sorafenib and grade 4 in 3%
  • I would like to discuss the issue of reimbursement for these new targeted therapies.
    Obviously new therapies required evidence to support effectiveness and safety. There is a clear positive impact on quality of life. The question for managed care organizations is the net impact on total cost of care. The concept of value differs among patients, providers, health plans and employers.
  • Cancer is by far the top target disease of biopharmaceuticals in late-stage development, followed by infectious diseases autoimmune disorders and rheumatoid arthritis.
    In a study done by BCBS foundatin on health care 17.8 million people in 10 blue cross blue shield plans recroded a 12.2% increase in the use of specialty pharma from 2002 to 2003 making specialty pharmaceuticals the fastest growing element in the plans’ drug budgets
  • A paper published in the American Journal of Managed Care attempts to discuss this issue in oncology as well as other diseases where biological therapies have proven to be of benefit or research is ongoing. Of the 101 late stage biopharmaceuticals in the pipeline for 169 indications in 2004, approximately 30% are already approved by the FDA. This represents one quarter of the pipeline indications. According to Herskovitz S. et al it is estimated that by 2010 between 325 and 400 biotechnology drugs will reach the market, including new drugs for common conditions such as cancer, diabetes and asthma. Although biologics improve patients quality of life and may enhance clinical outcomes, they also generate enormous costs which directly affect managed care organizations, patients and hospitals and physicians.
  • I don’t understand this slide?
  • Injectable or oral drug are covered by pharmacy benefit vs medical benefit for infused drugs
  • Keeping Pace with Targeted Therapies in Lung Cancer

    1. 1. 1 Keeping Pace with Targeted Therapies in Lung CancerKeeping Pace with Targeted Therapies in Lung Cancer Highlights from the ASCO 2006 Annual MeetingHighlights from the ASCO 2006 Annual Meeting
    2. 2. 2 IntroductionIntroduction
    3. 3. 3 Overview of Targeted TherapiesOverview of Targeted Therapies and Focus on Monoclonalsand Focus on Monoclonals Karen Kelly, MDKaren Kelly, MD Professor of MedicineProfessor of Medicine Department of Medical OncologyDepartment of Medical Oncology University of Colorado at DenverUniversity of Colorado at Denver Aurora, ColoradoAurora, Colorado
    4. 4. 4 FDA-Approved Agents BeingFDA-Approved Agents Being Investigated for Lung Cancer TreatmentInvestigated for Lung Cancer Treatment AgentAgent ClassClass TargetsTargets IndicationsIndications BevacizumabBevacizumab (Avastin(Avastin®® ; Genentech); Genentech) Monoclonal (IV)Monoclonal (IV) VEGFVEGF CRCCRC CetuximabCetuximab (Erbitux(Erbitux®® ; ImClone); ImClone) EGFREGFR Head & neck cancer, CRCHead & neck cancer, CRC ErlotinibErlotinib (Tarceva(Tarceva®® ; Genentech); Genentech) Reversible TKI (oral)Reversible TKI (oral) HER1/EGFRHER1/EGFR NSCLCNSCLC GefitinibGefitinib (Iressa(Iressa®® ; AstraZeneca); AstraZeneca) HER1/EGFRHER1/EGFR NSCLCNSCLC SunitinibSunitinib (Sutent(Sutent®® ; Pfizer); Pfizer) VEGFR-1, -2, -3; PDGFR-VEGFR-1, -2, -3; PDGFR-αα, -, -ββ;; KIT; RET; FLT3KIT; RET; FLT3 RCC, GISTRCC, GIST SorafenibSorafenib (Nexavar(Nexavar®® ; Bayer); Bayer) VEGFR-2, -3; cRAF; bRAF;VEGFR-2, -3; cRAF; bRAF; PDGFR-PDGFR-ββ; FLT3; KIT; FLT3; KIT RCCRCC BortezomibBortezomib (Velcade(Velcade®® , Millennium), Millennium) Proteasome inhibitorProteasome inhibitor (IV)(IV) ProteasomeProteasome Multiple myelomaMultiple myeloma BexaroteneBexarotene (Targretin(Targretin®® ; Ligand); Ligand) Retinoid (oral)Retinoid (oral) RXRRXRαα, RXR, RXRββ, RXR, RXRγγ Cutaneous T-cell lymphomaCutaneous T-cell lymphoma VEGF = vascular endothelial growth factor; CRC = colorectal cancer; EGFR = epidermal growth factor receptor; TK = tyrosine kinase; NSCLC = non–small-cell lung cancer; PDGFR = platelet-derived growth factor receptor; RCC = renal cell carcinoma; GIST = gastrointestinal stromal tumor; RXR = retinoid X receptor.
    5. 5. 5 Examples of Novel Targeted Agents BeingExamples of Novel Targeted Agents Being Investigated for Lung Cancer TreatmentInvestigated for Lung Cancer Treatment Biologic TargetBiologic Target ClassClass Molecular TargetsMolecular Targets AgentAgent TumorigenesisTumorigenesis MonoclonalMonoclonal (IV)(IV) EGFREGFR PanitumumabPanitumumab (Amgen)(Amgen) AngiogenesisAngiogenesis ReversibleReversible TKI (oral)TKI (oral) VEGFR-1, -2, -3;VEGFR-1, -2, -3; PDGFR-PDGFR-ββ VatalanibVatalanib (Novartis/Schering AG)(Novartis/Schering AG) VEGFR-1, -2, -3;VEGFR-1, -2, -3; PDGFR; RETPDGFR; RET AMG706 (Amgen)AMG706 (Amgen) VEGFR-2VEGFR-2 AZD2171 (AstraZeneca)AZD2171 (AstraZeneca) Angiogenesis +Angiogenesis + tumorigenesistumorigenesis DualDual reversible TKIreversible TKI (oral)(oral) VEGFR-2, -3; RET;VEGFR-2, -3; RET; EGFREGFR ZD6474 (Zactima;ZD6474 (Zactima; AstraZeneca)AstraZeneca) TumorTumor VaccineVaccine (intradermal)(intradermal) TGF-TGF-ββ antisense geneantisense gene modified allogeneicmodified allogeneic tumor cell vaccinetumor cell vaccine TGFTGFββAS Vaccine (Lucanix;AS Vaccine (Lucanix; NovaRx)NovaRx) EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor; PDGFR = platelet-derived growth factor receptor; TGF = transforming growth factor.
    6. 6. 6 ASCO 2006 UpdateASCO 2006 Update Bevacizumab in NSCLCBevacizumab in NSCLC Paclitaxel + carboplatin ± bevacizumab (updatedPaclitaxel + carboplatin ± bevacizumab (updated results from randomized phase III trial E4599)results from randomized phase III trial E4599)  Sandler AB, et al.Sandler AB, et al.11  Brahmer JR, et al.Brahmer JR, et al.22  Dowlati A, et al.Dowlati A, et al.33 1. Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4. 2. Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036. 3. Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.
    7. 7. 7 Paclitaxel/Carboplatin ± BevacizumabPaclitaxel/Carboplatin ± Bevacizumab Previously Reported ECOG 4599 ResultsPreviously Reported ECOG 4599 Results Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4. PCPC (n = 427)(n = 427) PCBPCB (n = 420)(n = 420) PP-Value-Value Response rate, %*Response rate, %* 1010 27.227.2 < .0001< .0001 Median PFS, moMedian PFS, mo 4.54.5 6.46.4 < .0001< .0001 6-mo PFS, %6-mo PFS, % 32.632.6 55.055.0 1-y PFS, %1-y PFS, % 6.46.4 14.614.6 Median OS, moMedian OS, mo 10.210.2 12.512.5 .007.007 12-mo OS, %12-mo OS, % 43.743.7 51.951.9 24-mo OS, %24-mo OS, % 16.916.9 22.122.1 *As percent of patients with measurable disease, n = 350 for the PC arm and n = 357 for PCB arm. ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab; PFS = progression-free survival; OS = overall survival.
    8. 8. 8 Paclitaxel/Carboplatin ± BevacizumabPaclitaxel/Carboplatin ± Bevacizumab Possible Gender Differences in Overall SurvivalPossible Gender Differences in Overall Survival  Unplanned subgroup analysis of ECOG 4599Unplanned subgroup analysis of ECOG 4599  Key finding: compared with males, females did not appear to gainKey finding: compared with males, females did not appear to gain same overall survival benefit from addition of bevacizumabsame overall survival benefit from addition of bevacizumab PCPC PCBPCB PP-Value-Value Overall survival, moOverall survival, mo 10.310.3 12.312.3 .003.003 Overall survival males, moOverall survival males, mo 8.78.7 11.711.7 .001.001 Overall survival females, moOverall survival females, mo 13.113.1 13.313.3 .87.87 Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036. ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab.
    9. 9. 9 Paclitaxel/Carboplatin ± BevacizumabPaclitaxel/Carboplatin ± Bevacizumab No Gender Differences in Overall SurvivalNo Gender Differences in Overall Survival  Females on PCB arm had higher response rate and progression-freeFemales on PCB arm had higher response rate and progression-free survival compared with females in the PC armsurvival compared with females in the PC arm MalesMales FemalesFemales PCPC (n = 230)(n = 230) PCBPCB (n = 191)(n = 191) PP-Value-Value PCPC (n = 162)(n = 162) PCBPCB (n = 190)(n = 190) PP-Value-Value Overall responseOverall response rate (CR + PR), %rate (CR + PR), % 15.715.7 28.828.8 .001.001 14.214.2 41.141.1 < .0001< .0001 Progression-freeProgression-free survival, mosurvival, mo 4.34.3 6.36.3 < .0001< .0001 5.35.3 6.26.2 .002.002 Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036. P = paclitaxel; C = carboplatin; B = bevacizumab; CR = complete response; PR = partial response.
    10. 10. 10 Paclitaxel/Carboplatin ± BevacizumabPaclitaxel/Carboplatin ± Bevacizumab Perspective on Unplanned Analysis by GenderPerspective on Unplanned Analysis by Gender  Treatments at time of disease progression were not different, except that inTreatments at time of disease progression were not different, except that in the PCB arm, females were slightly less likely than males to getthe PCB arm, females were slightly less likely than males to get chemotherapy as 2chemotherapy as 2ndnd -line therapy-line therapy  Reasons for observed differences in overall survival are unclear, possibilitiesReasons for observed differences in overall survival are unclear, possibilities includeinclude – Random chanceRandom chance – Pitfalls of unplanned subgroup analysisPitfalls of unplanned subgroup analysis  These results contrast with results in CRC trials where no gender differencesThese results contrast with results in CRC trials where no gender differences reported in overall survivalreported in overall survival  PCB remains ECOG reference treatment in NSCLCPCB remains ECOG reference treatment in NSCLC Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036. Laskin JJ. 42nd ASCO; June 2-6, 2006. Lung Cancer I Poster Discussion. Discussant. Hurwitz H, et al.Hurwitz H, et al. N Engl J MedN Engl J Med. 2004;350:2335.. 2004;350:2335. Genentech data on fileGenentech data on file PCB = paclitaxel/carboplatin/bevacizumab; CRC = colorectal cancer; ECOG = Eastern Cooperative Oncology Group; NSCLC = non–small-cell lung cancer.
    11. 11. 11 Prospective Correlative Assessment ofProspective Correlative Assessment of Biomarkers from ECOG 4599Biomarkers from ECOG 4599 Biomarkers studiedBiomarkers studied  Endothelial leukocyte adhesion molecule-1 (E-selectin)Endothelial leukocyte adhesion molecule-1 (E-selectin) – Expressed only on endothelial cell after activation by inflammatoryExpressed only on endothelial cell after activation by inflammatory cytokinescytokines – Elevated E-selectin seen in disorders characterized by endothelialElevated E-selectin seen in disorders characterized by endothelial cell apoptosis and malignanciescell apoptosis and malignancies  Intercellular adhesion molecule-1 (ICAM-1; CD54)Intercellular adhesion molecule-1 (ICAM-1; CD54) – Expressed on endothelial, epithelial, lymphocytes, monocytes,Expressed on endothelial, epithelial, lymphocytes, monocytes, hepatocytes, and hemapoietic cellshepatocytes, and hemapoietic cells – Elevated levels seen in many malignancies and alterations seenElevated levels seen in many malignancies and alterations seen with vascular targeting and antiangiogenic agentswith vascular targeting and antiangiogenic agents  Vascular endothelial growth factor (VEGF) and basic-fibroblast growthVascular endothelial growth factor (VEGF) and basic-fibroblast growth factor (b-FGF)factor (b-FGF) – Well-known angiogenic factorsWell-known angiogenic factors Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.
    12. 12. 12 Prospective Correlative Assessment ofProspective Correlative Assessment of Biomarkers From ECOG 4599—ResultsBiomarkers From ECOG 4599—Results Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027. Reprinted with permission from Dr. Dowlati. Hirsch F. 42nd ASCO; June 2-6, 2006. Lung Cancer III. Discussant.  Baseline plasma ICAM may beBaseline plasma ICAM may be prognostic for response and survivalprognostic for response and survival in advanced NSCLCin advanced NSCLC – This might be useful stratificationThis might be useful stratification factor in future trialsfactor in future trials – Low levels indicate a 2-foldLow levels indicate a 2-fold increase in likelihood of responseincrease in likelihood of response to chemotherapy (unclear if thisto chemotherapy (unclear if this is prognostic or predictive)is prognostic or predictive)  Future trials are needed to determineFuture trials are needed to determine if these will be better markers forif these will be better markers for clinical outcome than conventionalclinical outcome than conventional radiographic response assessmentradiographic response assessment Probability Months 1.0 - 0.8 - 0.6 - 0.4 - 0.2 - 0.0 - Survival by Baseline ICAMSurvival by Baseline ICAM 0 10 20 30 40 <260.5 (62 deaths/75 cases) >260.5 (70 deaths/75 cases) P = .000050 1 y 60% 1 y 25%
    13. 13. 13 Risk Factors for Pulmonary Hemorrhage (PH)Risk Factors for Pulmonary Hemorrhage (PH) in Bevacizumab-Treated Patientsin Bevacizumab-Treated Patients Retrospective study of ECOG 4599 data examining associationRetrospective study of ECOG 4599 data examining association between baseline clinical factors and incidence of early onsetbetween baseline clinical factors and incidence of early onset (< 150 d from initial treatment) PH(< 150 d from initial treatment) PH  GradeGrade ≥≥ 3 PH occurred in 2.3% of patients3 PH occurred in 2.3% of patients  Of 10 cases identified, 6 met criteria for early onset PH relatedOf 10 cases identified, 6 met criteria for early onset PH related to bevacizumabto bevacizumab  Pretreatment cavitation may be associated with increased riskPretreatment cavitation may be associated with increased risk of PHof PH  Hemoptysis was predicative of possible future PHHemoptysis was predicative of possible future PH Sandler AB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7068.
    14. 14. 14 ASCO 2006 Update onASCO 2006 Update on Cetuximab in NSCLCCetuximab in NSCLC  SWOG 0342 phase II trial of chemotherapy +SWOG 0342 phase II trial of chemotherapy + cetuximab vs chemotherapy followed bycetuximab vs chemotherapy followed by cetuximabcetuximab11  FLEX phase III trial of cisplatin/vinorelbine ±FLEX phase III trial of cisplatin/vinorelbine ± cetuximabcetuximab22 elly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. on Pawl, J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.
    15. 15. 15 Preliminary Results of SWOG 0342 Phase IIPreliminary Results of SWOG 0342 Phase II Trial of Paclitaxel/Carboplatin + CetuximabTrial of Paclitaxel/Carboplatin + Cetuximab Primary objectivesPrimary objectives  Compare response rate and toxicity of concurrent vs sequentialCompare response rate and toxicity of concurrent vs sequential platinum-based chemotherapy + cetuximab regimens as 1platinum-based chemotherapy + cetuximab regimens as 1stst -line-line treatment for advanced NSCLCtreatment for advanced NSCLC  Select regimen for future trials based on overall survivalSelect regimen for future trials based on overall survival Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly. Randomize stage IIIB/IV NSCLC Paclitaxel/ carboplatin × 4 cycles (n = 119) Paclitaxel/ carboplatin + cetuximab × 4 cycles (n = 106) Cetuximab weekly × 1 year Cetuximab weekly × 1 year
    16. 16. 16 Phase II Trial ofPhase II Trial of Paclitaxel/Carboplatin + CetuximabPaclitaxel/Carboplatin + Cetuximab Preliminary Efficacy ResultsPreliminary Efficacy Results Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. ChemoChemo →→ CetuximabCetuximab (n = 119)*(n = 119)* Chemo +Chemo + CetuximabCetuximab (n = 106)*(n = 106)* Complete responseComplete response 00 00 Partial response, % (95% CI)Partial response, % (95% CI) 25 (17–36)25 (17–36) 37 (26–49)37 (26–49) Stable disease, % (95% CI)Stable disease, % (95% CI) 44 (33–55)44 (33–55) 38 (27–50)38 (27–50) Disease stabilization, %Disease stabilization, % (95% CI)(95% CI) 69 (58–78)69 (58–78) 75 (63–84)75 (63–84) Progression-free survival, moProgression-free survival, mo 44 44 Median overall survival, moMedian overall survival, mo 99 1010 1-year overall survival, %1-year overall survival, % 4343 4949 *Patients evaluable for response: 71 in the chemo + cetuximab arm and 87 in the chemo-only arm.
    17. 17. 17 SWOG 0342—Phase II Trial ofSWOG 0342—Phase II Trial of Paclitaxel/Carboplatin + CetuximabPaclitaxel/Carboplatin + Cetuximab Preliminary Safety ResultsPreliminary Safety Results Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly. %ofEvaluablePatients Chemo +/- C 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - Adverse Events (grade 3/4)Adverse Events (grade 3/4) Post-Chemo C 55 67 20 27 N=101 N=94 N=20 N=22 Sequential Concurrent %ofEvaluablePatients Chemo +/- C 14 - 12 - 10 - 8 - 6 - 4 - 2 - 0 - Rash (grade 3/4)Rash (grade 3/4) Post-Chemo C 1 12 10 N=94 N=20 N=22 No new cases concurrent ann Sequential Concurrent Grade 3/4 AE (>5%) on Chemo (+/-C)Grade 3/4 AE (>5%) on Chemo (+/-C) AdverseAdverse EventEvent Chemo + CChemo + C N = 94N = 94 Chemo CChemo C N = 94N = 94 P-P-ValueValue DyspneaDyspnea 6.46.4 44 NSNS FatigueFatigue 8.58.5 99 NSNS LeukocytesLeukocytes 1616 18.818.8 NSNS Joint painJoint pain 6.46.4 33 NSNS NauseaNausea 6.46.4 22 NSNS NeuropathyNeuropathy 1515 5.95.9 .04.04 NeutrophilsNeutrophils 41.441.4 36.636.6 NSNS Chemo = paclitaxel/carboplatin; C = cetuximab. N=101
    18. 18. 18 Phase II Trial ofPhase II Trial of Paclitaxel/Carboplatin + CetuximabPaclitaxel/Carboplatin + Cetuximab Preliminary ConclusionsPreliminary Conclusions  Concurrent cetuximab + chemotherapy arm metConcurrent cetuximab + chemotherapy arm met predetermined 10-month minimal median survivalpredetermined 10-month minimal median survival requirementrequirement  Trend toward higher response rate in concurrent armTrend toward higher response rate in concurrent arm  Rash only significant additional toxicity seen withRash only significant additional toxicity seen with concurrent administration of cetuximab + chemotherapyconcurrent administration of cetuximab + chemotherapy  Biomarker correlative studies ongoingBiomarker correlative studies ongoing  New trials with this concurrent regimen + bevacizumabNew trials with this concurrent regimen + bevacizumab plannedplanned Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.
    19. 19. 19 Phase III Trial ofPhase III Trial of Cisplatin/Vinorelbine ± CetuximabCisplatin/Vinorelbine ± Cetuximab Preliminary Safety ReportPreliminary Safety Report  Stage IIIB with documented malignant pleural effusion or stageStage IIIB with documented malignant pleural effusion or stage IV previously untreated NSCLCIV previously untreated NSCLC  Epidermal growth factor receptor expression byEpidermal growth factor receptor expression by immunohistochemistryimmunohistochemistry  Patients recruited from 166 centers in 29 countries in Europe,Patients recruited from 166 centers in 29 countries in Europe, Asia, Australia, and South AmericaAsia, Australia, and South America  Primary objective: overall survivalPrimary objective: overall survival  Preplanned analysis by Data Safety Monitoring Board (DSMB) ofPreplanned analysis by Data Safety Monitoring Board (DSMB) of baseline and safety data from 365 patientsbaseline and safety data from 365 patients  ResultsResults – Recruitment completed in February 2006Recruitment completed in February 2006 – 1125 patients randomized1125 patients randomized – Trial continuesTrial continues Von Pawl J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.
    20. 20. 20 SWOG S0339—Phase II Trial of Bortezomib +SWOG S0339—Phase II Trial of Bortezomib + Gemcitabine/CarboplatinGemcitabine/Carboplatin  DesignDesign – Primary endpoint: OS (goal 10 month median OS to rulePrimary endpoint: OS (goal 10 month median OS to rule out null hypothesis)out null hypothesis) – Stage IIIB (with pleural effusion) or IV NSCLC,Stage IIIB (with pleural effusion) or IV NSCLC, chemotherapy-naivechemotherapy-naive – PS = 0 or 1PS = 0 or 1  ResultsResults – N = 121 accrued (116 eligible)N = 121 accrued (116 eligible) – Median age: 64 years (range, 28–78)Median age: 64 years (range, 28–78) – 11% stage IIIB, 86% stage IV11% stage IIIB, 86% stage IV – Median follow-up: >15 monthsMedian follow-up: >15 months – Median number of cycles: 3.6Median number of cycles: 3.6 Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017. SWOG = Southwest Oncology Group; OS = overall survival; PS = performance status.
    21. 21. 21 Phase II Trial of BortezomibPhase II Trial of Bortezomib + Gemcitabine/ Carboplatin+ Gemcitabine/ Carboplatin Efficacy and Safety ResultsEfficacy and Safety Results ResponseResponse No. (%)No. (%) (n = 114)(n = 114) ORRORR 24 (21)24 (21) CRCR 2 (2)2 (2) PRPR 22 (19)22 (19) SDSD 51 (45)51 (45) PDPD 21 (18)21 (18) Not evaluableNot evaluable 18 (16)18 (16) Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.  Overall survival 11 months (95% CI 8.2–13 months)Overall survival 11 months (95% CI 8.2–13 months)  1-year survival 47%; 2-year survival 14%1-year survival 47%; 2-year survival 14%  Results above predetermined statistical endpoint to proceed to a phase III trialResults above predetermined statistical endpoint to proceed to a phase III trial Grade 3/4 Toxicity inGrade 3/4 Toxicity in > 10% of Patients> 10% of Patients No. (%)No. (%) (n = 114)(n = 114) NeutropeniaNeutropenia 59 (52)59 (52) ThrombocytopeniaThrombocytopenia 72 (63)72 (63) AnemiaAnemia 15 (13)15 (13) FatigueFatigue 15 (13)15 (13) AST/ALTAST/ALT 14 (12)14 (12) ORR = overall response rate; CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; AST = aspartate aminotransferase; ALT = alanine aminotransferase.
    22. 22. 22 SummarySummary  Clarification with regards to carboplatin/paclitaxel ± bevacizumabClarification with regards to carboplatin/paclitaxel ± bevacizumab phase III trial ECOG 4599phase III trial ECOG 4599 –Bevacizumab does have some differential gender effectBevacizumab does have some differential gender effect on overall survival, but not clinically meaningfulon overall survival, but not clinically meaningful –Potential predictive or prognostic biomarkersPotential predictive or prognostic biomarkers –Risk factors for bevacizumab-associated pulmonaryRisk factors for bevacizumab-associated pulmonary hemorrhagehemorrhage  Promising results from phase II trialsPromising results from phase II trials –Cetuximab + carboplatin/paclitaxelCetuximab + carboplatin/paclitaxel –Cetuximab + cisplatin/vinorelbineCetuximab + cisplatin/vinorelbine –Bortezomib + gemcitabine/carboplatinBortezomib + gemcitabine/carboplatin  Data from phase III trials needed for cetuximab and bortezomibData from phase III trials needed for cetuximab and bortezomib
    23. 23. 23 Focus on Small Molecules andFocus on Small Molecules and Investigational AgentsInvestigational Agents Roy S. Herbst, MD, PhDRoy S. Herbst, MD, PhD Professor of MedicineProfessor of Medicine Department of Thoracic/HeadDepartment of Thoracic/Head and Neck Medical Oncologyand Neck Medical Oncology University of TexasUniversity of Texas M.D. Anderson Cancer CenterM.D. Anderson Cancer Center Houston, TexasHouston, Texas
    24. 24. 24 Update on Small MoleculeUpdate on Small Molecule and Investigational Agentsand Investigational Agents  Tyrosine kinase inhibitorsTyrosine kinase inhibitors with FDA approvalswith FDA approvals – SunitinibSunitinib – SorafenibSorafenib – ErlotinibErlotinib – GefitinibGefitinib  Investigational agentsInvestigational agents – VatalanibVatalanib – ZD6474ZD6474 – ABI-007ABI-007 – AMG706/panitumumabAMG706/panitumumab  BiomarkersBiomarkers – OsteopontinOsteopontin – EGF, Her2, p-AktEGF, Her2, p-Akt – RXR-beta, pPARyRXR-beta, pPARy
    25. 25. 25 Tyrosine Kinase Inhibitors Target Both the Tumor and Endothelial CellsTyrosine Kinase Inhibitors Target Both the Tumor and Endothelial Cells Endothelial Cell VEGFR 1,2,3 PDGFR EGFR RAS-RAF VEGFR NRP1 Tumor Cell PDGF VEGF Endothelial Cell Pericytes Nucleus Nucleus VEGFR/PDGFR Growth Factor Receptor
    26. 26. 26 Similarities and Differences in Targets for TKIsSimilarities and Differences in Targets for TKIs and Monoclonalsand Monoclonals Tumor Endothelial cells bFGF VEGF TGF-α Mechanism Inhibits tumor cell growth and blocks synthesis of angiogenetic proteins (eg, bFGF, VEGF, TGF- α) by tumor cells Inhibits endothelial cells from responding to the angiogenic protein VEGF Inhibitor Erlotinib Bevacizumab Herbst RS, et al. J Clin Oncol. 2005;23:2544. Reprinted with permission from the American Society of Clinical Oncology.
    27. 27. 27 Sunitinib Phase II Trial in Previously TreatedSunitinib Phase II Trial in Previously Treated Advanced NSCLCAdvanced NSCLC  Open-label, single-arm, 2-stage multicenter trialOpen-label, single-arm, 2-stage multicenter trial  Patients had recurrent stage IIIB/IV NSCLC that had failed 1 or morePatients had recurrent stage IIIB/IV NSCLC that had failed 1 or more chemotherapy regimens (with/out EGFR inhibitor)chemotherapy regimens (with/out EGFR inhibitor)  Sunitinib given at 50 mg/d for 4 wk followed by 2 wk off treatmentSunitinib given at 50 mg/d for 4 wk followed by 2 wk off treatment before next 6-week cyclebefore next 6-week cycle  Primary endpoint: overall confirmed objective response rate (ORR)Primary endpoint: overall confirmed objective response rate (ORR)  EnrollmentEnrollment – 63 patients63 patients – 64% had adenocarcinoma, 90% had stage IV disease64% had adenocarcinoma, 90% had stage IV disease – 43% had 1 prior regimen, 44% had 2 prior regimens, 13% had 343% had 1 prior regimen, 44% had 2 prior regimens, 13% had 3 or more prior regimensor more prior regimens – 33% had received prior EGFR inhibitor33% had received prior EGFR inhibitor Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.
    28. 28. 28 Sunitinib Phase II Trial inSunitinib Phase II Trial in Previously Treated Advanced NSCLCPreviously Treated Advanced NSCLC Safety ResultsSafety Results  Most toxicities were grade 1 or 2Most toxicities were grade 1 or 2  3 hemorrhage-related deaths on study: 2 (a pulmonary hemorrhage and3 hemorrhage-related deaths on study: 2 (a pulmonary hemorrhage and a cerebral hemorrhage) were considered study-drug relateda cerebral hemorrhage) were considered study-drug related Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001. Severe Events Occurring inSevere Events Occurring in ≥≥ 10% of Patients10% of Patients % of Patients% of Patients Adverse EventAdverse Event Grade 3Grade 3 Grade 4Grade 4 Fatigue/astheniaFatigue/asthenia 2222 55 Pain/myalgiaPain/myalgia 1414 33 Nausea/vomitingNausea/vomiting 1010 00 DyspneaDyspnea 1313 00
    29. 29. 29 Sunitinib Phase II Trial inSunitinib Phase II Trial in Previously Treated Advanced NSCLCPreviously Treated Advanced NSCLC Efficacy ResultsEfficacy Results ResponseResponse No. (%)No. (%) (n = 63)(n = 63) ORRORR 6 (9.5)6 (9.5) 95% CI (3.6–19.6)95% CI (3.6–19.6) PRPR 6 (9.5)6 (9.5) SDSD 27 (42.9)27 (42.9) PDPD 14 (22.2)14 (22.2) Not evaluableNot evaluable 16 (25.4)16 (25.4) Best Response forBest Response for Target Lesions by PatientTarget Lesions by Patient 100 80 60 40 20 0 -20 -40 -60 -80 -100 ChangefromBaseline(%) Partial Responses by RECIST Stable Disease/Progressive Disease Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001. Reprinted with permission from Dr. Socinski. ORR = overall response rate; PR = partial response; SD = stable disease; PD = progressive disease; RECIST = response evaluation criteria in solid tumors.  Median duration of response: 12.2 weeks (range, 4.3–30.1+ weeks)Median duration of response: 12.2 weeks (range, 4.3–30.1+ weeks)  Median PFS: 11.3 weeks (95% CI 10.0–15.7)Median PFS: 11.3 weeks (95% CI 10.0–15.7)  Median OS: 23.9 weeks (95% CI 17.0–28.3)Median OS: 23.9 weeks (95% CI 17.0–28.3)
    30. 30. 30 Phase II Trial of Sorafenib in Advanced NSCLCPhase II Trial of Sorafenib in Advanced NSCLC  Primary objective: tumor response by RECIST of sorafenib 400 mg BID inPrimary objective: tumor response by RECIST of sorafenib 400 mg BID in previously treated ptspreviously treated pts  EligibilityEligibility – 1–2 prior treatments1–2 prior treatments – No prior gefitinibNo prior gefitinib – Asymptomatic brain metastases permittedAsymptomatic brain metastases permitted  EnrollmentEnrollment – 52 patients52 patients – Median age 62 years (range, 26–85)Median age 62 years (range, 26–85) – 85% ECOG PS = 185% ECOG PS = 1 – 54% adenocarcinoma, 31% squamous cell carcinoma54% adenocarcinoma, 31% squamous cell carcinoma – 94% stage IV94% stage IV – 67% 1 prior chemotherapy; 29% 2 prior chemotherapy67% 1 prior chemotherapy; 29% 2 prior chemotherapy Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. RECIST = response evaluation criteria in solid tumors; ECOG = eastern cooperative oncology group; PS = performance status.
    31. 31. 31 Phase II Trial of Sorafenib in Advanced NSCLCPhase II Trial of Sorafenib in Advanced NSCLC Efficacy ResultsEfficacy Results ResponseResponse No. (%)No. (%) (n = 51)(n = 51) SDSD 30 (59)30 (59) PDPD 18 (35)18 (35) Not evaluated*Not evaluated* 3 (6)3 (6) 60 40 20 0 -20 -40 -60 SD Patients PD Patients Maximum Percentage Reduction ofMaximum Percentage Reduction of Target Lesion by Patient (N = 48)Target Lesion by Patient (N = 48)†† *Patients died prior to tumor assessment. † 48 patients with postbaseline tumor measurements available. Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier. SD = stable disease; PD = progressive disease; PFS = progression-free survival; OS = overall survival.  Tumor cavitation in 4 patientsTumor cavitation in 4 patients  Median PFS: 2.7 mo; median OS: 6.7 moMedian PFS: 2.7 mo; median OS: 6.7 mo  SD patients: median PFS 5.5 moSD patients: median PFS 5.5 mo  2 patients treated for > 2 years with ongoing treatment2 patients treated for > 2 years with ongoing treatment
    32. 32. 32 Phase II Trial of Sorafenib in Advanced NSCLCPhase II Trial of Sorafenib in Advanced NSCLC Safety and Biomarker Analysis ResultsSafety and Biomarker Analysis Results  SafetySafety – No grade 4 eventsNo grade 4 events – Grade 3 events: hand-foot skinGrade 3 events: hand-foot skin reactions (20%), hypertensionreactions (20%), hypertension (4%), diarrhea (2%), fatigue (2%),(4%), diarrhea (2%), fatigue (2%), headache (2%)headache (2%) – 4 patients had sorafenib-related4 patients had sorafenib-related bleeding events (3 epistaxis, 1 fatalbleeding events (3 epistaxis, 1 fatal pulmonary hemorrhage 30 dayspulmonary hemorrhage 30 days after stopping sorafenib)after stopping sorafenib)  Biomarker analysisBiomarker analysis – Plasma biomarkers evaluated byPlasma biomarkers evaluated by ELISAELISA – High VEGF at baselineHigh VEGF at baseline correlated with shorter survivalcorrelated with shorter survival ((PP < .05)< .05) SurvivalFraction Time to Death (Days) 1.0 0.5 0.0 Low VEGF High VEGF 0 100 200 300 400 500 600 700 Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier. ELISA = enzyme-linked immunosorbent assay; VEGF = vascular endothelial growth factor.
    33. 33. 33 Phase II Trial of Sorafenib in Advanced NSCLCPhase II Trial of Sorafenib in Advanced NSCLC ConclusionsConclusions  Sorafenib has some activity in NSCLCSorafenib has some activity in NSCLC  Historical comparisons show that 59% stable disease is inHistorical comparisons show that 59% stable disease is in same range as other targeted agents in NSCLCsame range as other targeted agents in NSCLC  Agent generally well tolerated, with low incidence of bleedingAgent generally well tolerated, with low incidence of bleeding  Deterioration of quality of life not seenDeterioration of quality of life not seen  Shorter median overall survival correlated with high baselineShorter median overall survival correlated with high baseline VEGF and greater decreases in plasma VEGF during sorafenibVEGF and greater decreases in plasma VEGF during sorafenib treatmenttreatment  Phase III study of carboplatin/paclitaxel ± sorafenib is currentlyPhase III study of carboplatin/paclitaxel ± sorafenib is currently accruing patientsaccruing patients Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.
    34. 34. 34 Randomized Phase II Trial of Chemotherapy ±Randomized Phase II Trial of Chemotherapy ± Bevacizumab vs Erlotinib + BevacizumabBevacizumab vs Erlotinib + Bevacizumab  Phase II, multicenter 3-arm randomized trialPhase II, multicenter 3-arm randomized trial – Arm 1: chemotherapy (docetaxel or pemetrexed) + placeboArm 1: chemotherapy (docetaxel or pemetrexed) + placebo – Arm 2: chemotherapy (docetaxel or pemetrexed) + bevacizumabArm 2: chemotherapy (docetaxel or pemetrexed) + bevacizumab – Arm 3: erlotinib + bevacizumabArm 3: erlotinib + bevacizumab  Arms 1 and 2 were double-blindedArms 1 and 2 were double-blinded  Patients stratified by ECOG performance status and smoking historyPatients stratified by ECOG performance status and smoking history  Eligibility: recurrent unresectable NSCLCEligibility: recurrent unresectable NSCLC  Primary endpoint: safety and preliminary efficacyPrimary endpoint: safety and preliminary efficacy Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062.
    35. 35. 35 Phase II Chemotherapy ± Bevacizumab vsPhase II Chemotherapy ± Bevacizumab vs Erlotinib + BevacizumabErlotinib + Bevacizumab EfficacyEfficacy ChemotherapyChemotherapy (n = 41)(n = 41) Chemotherapy +Chemotherapy + BevacizumabBevacizumab (n = 40)(n = 40) Erlotinib +Erlotinib + BevacizumabBevacizumab (n = 39)(n = 39) Progression-free survivalProgression-free survival Median, moMedian, mo 3.03.0 4.84.8 4.44.4 6-mo rate6-mo rate 21.5%21.5% 30.5%30.5% 33.6%33.6% Adjusted HR* (95% CI)Adjusted HR* (95% CI) NANA 0.66 (0.38, 1.16)0.66 (0.38, 1.16) 0.72 (0.42,1.23)0.72 (0.42,1.23) Unadjusted HR (95% CI)Unadjusted HR (95% CI) NANA 0.78 (0.47, 1.30)0.78 (0.47, 1.30) 0.76 (0.45, 1.28)0.76 (0.45, 1.28) Overall survivalOverall survival 6-mo rate6-mo rate 62.4%62.4% 72.1%72.1% 78.3%78.3% Response rateResponse rate CR/PRCR/PR 12.2%12.2% 12.5%12.5% 17.9%17.9% CR/PR/SDCR/PR/SD 39.0%39.0% 52.5%52.5% 51.3%51.3% *Adjusted by randomization stratification factors (ECOG PS, smoking history). Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher. HR = hazard ratio; NA = not applicable; CR = complete response; PR = partial response; SD = stable disease.
    36. 36. 36 Phase II Chemotherapy ± Bevacizumab vsPhase II Chemotherapy ± Bevacizumab vs Erlotinib + BevacizumabErlotinib + Bevacizumab SafetySafety ToxicitiesToxicities ChemotherapyChemotherapy (n = 41)(n = 41) Chemotherapy +Chemotherapy + BevacizumabBevacizumab (n = 40)(n = 40) Erlotinib +Erlotinib + BevacizumabBevacizumab (n = 39)(n = 39) Most common overallMost common overall FatigueFatigue 6666 7070 5656 NauseaNausea 4848 4242 4141 DiarrheaDiarrhea 1717 4040 6969 Rash/dermatitis/acneformRash/dermatitis/acneform 2929 2020 8282 AnemiaAnemia 2222 3232 1010 NeutropeniaNeutropenia 2424 3030 1010 Most common grade 3/4Most common grade 3/4 FatigueFatigue 1212 1212 77 NeutropeniaNeutropenia 1717 2020 55 Drug-related deathsDrug-related deaths 22 33 11 Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher. Percent of PatientsPercent of Patients
    37. 37. 37 Phase II Trial of Erlotinib vsPhase II Trial of Erlotinib vs Carboplatin/Paclitaxel in NSCLCCarboplatin/Paclitaxel in NSCLC  Primary endpoint: PFS (treatment worthy of further evaluation if PFSPrimary endpoint: PFS (treatment worthy of further evaluation if PFS ≥≥ 3.53.5 months)months)  Study designStudy design – Eligibility: stage IIIB or IV no prior chemotherapyEligibility: stage IIIB or IV no prior chemotherapy – Performance status 2Performance status 2 – No prior treatment with any EGFR inhibitor; no uncontrolled brainNo prior treatment with any EGFR inhibitor; no uncontrolled brain metastasesmetastases – Optional cross-over to erlotinibOptional cross-over to erlotinib  Enrollment: 103 patientsEnrollment: 103 patients  Arms well balanced in demographics and baseline characteristicsArms well balanced in demographics and baseline characteristics Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022. PFS = progression-free survival; EGFR = epidermal growth factor receptor.
    38. 38. 38 Phase II Trial of Erlotinib vs Carboplatin/Phase II Trial of Erlotinib vs Carboplatin/ Paclitaxel (CP) in NSCLCPaclitaxel (CP) in NSCLC Efficacy ResultsEfficacy Results No. of Pts (%)No. of Pts (%) ResponseResponse ErlotinibErlotinib (n = 52)(n = 52) CPCP (n = 51)(n = 51) PRPR 1 (2)1 (2) 6 (12)6 (12) SDSD 19 (37)19 (37) 21 (41)21 (41) PDPD 23 (44)23 (44) 10 (20)10 (20) Unable toUnable to determine/notdetermine/not evaluatedevaluated 8 (15)8 (15) 13 (25)13 (25) Still on activeStill on active therapytherapy 1 (2)1 (2) 1 (2)1 (2) PFSProbability PFS (Months) 1.0 - 0.9 - 0.8 - 0.7 - 0.6 - 0.5 - 0.4 - 0.3 - 0.2 - 0.1 - 0.0 - Progression-Free Survival (PFS)Progression-Free Survival (PFS) 0 6 12 18 24 36 Group N Median(M) 95% Cl Erlotinib 52 1.91 (1.28, 2.69) PC 51 3.52 (1.48, 4.87) Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022. Reprinted with permission from Dr. Lilenbaum.
    39. 39. 39 Phase II Trial of Erlotinib vsPhase II Trial of Erlotinib vs Carboplatin/Paclitaxel in NSCLCCarboplatin/Paclitaxel in NSCLC ConclusionsConclusions  Single-agent erlotinib treatment did not meet progression-freeSingle-agent erlotinib treatment did not meet progression-free survival endpoint to warrant further evaluationsurvival endpoint to warrant further evaluation  Results in erlotinib-treated patients who developed grade 2+Results in erlotinib-treated patients who developed grade 2+ rash were “in closer range to chemotherapy”rash were “in closer range to chemotherapy”  Sample size too small to make significant correlation betweenSample size too small to make significant correlation between biomarkers analyzed and outcomebiomarkers analyzed and outcome  Quality of life parameters similar between 2 treatment armsQuality of life parameters similar between 2 treatment arms  Development of erlotinib in 1st-line NSCLC centers onDevelopment of erlotinib in 1st-line NSCLC centers on – Molecular selection of patientsMolecular selection of patients – Combination with other targeted agentsCombination with other targeted agents – Dosing optimizationDosing optimization Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.
    40. 40. 40 Molecular Predictors of Outcome with Erlotinib inMolecular Predictors of Outcome with Erlotinib in Bronchioloalveolar Cell Carcinoma (BAC)Bronchioloalveolar Cell Carcinoma (BAC)  Results of a prospective phase II trialResults of a prospective phase II trial  Objective: compare clinical, pathologic, and molecular characteristics of tumorObjective: compare clinical, pathologic, and molecular characteristics of tumor specimens associated with response, PFS, and OSspecimens associated with response, PFS, and OS  Marker analysis: EGFR (mutations, amplification, polysomy, chromogenic in situMarker analysis: EGFR (mutations, amplification, polysomy, chromogenic in situ hybridization [CISH]), KRAS (mutations)hybridization [CISH]), KRAS (mutations) Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003. Adapted with permission from Dr. Miller. Outcome of Patients Treated with ErlotinibOutcome of Patients Treated with Erlotinib n Median PFS Median OS (mo) (mo) All 102 4 17 CR+PR 22 15 24 Stable disease 38 6 29 Progression 36 1 8 Not evaluable 6 1 1 P < .01 Molecular Characteristics and OutcomeMolecular Characteristics and Outcome Median PFS Median OS n RR(%) P (mo) P (mo) P EGFR mut + 18 83 <.01 13 <.01 23 .65 EGFR wt 64 7 2 17 CISH ≥ 4 24 43 <.01 9 <.01 25 .38 CISH < 4 53 13 2 16 IHC ≥ 1 25 20 .99 4 .76 19 .60 IHC 0 39 21 4 16 KRAS mut + 19 0 <.01 4 .25 13 .24 KRAS wt 62 32 5 21
    41. 41. 41 Molecular Predictors of OutcomeMolecular Predictors of Outcome with Erlotinib in BACwith Erlotinib in BAC ConclusionsConclusions  Erlotinib resulted in 23% overall response rate (ORR) and 17 moErlotinib resulted in 23% overall response rate (ORR) and 17 mo median overall survival (OS) in BACmedian overall survival (OS) in BAC  Presence of EGFR mutation associated with an 83% ORR,Presence of EGFR mutation associated with an 83% ORR, 13 mo progression-free survival (PFS) and 22 mo OS13 mo progression-free survival (PFS) and 22 mo OS  EGFR amplification in BAC rareEGFR amplification in BAC rare  EGFR polysomy predictive of improvement in PFSEGFR polysomy predictive of improvement in PFS  KRAS exon 2 mutation associated with no responses and poorer OSKRAS exon 2 mutation associated with no responses and poorer OS  Patients with EGFR mutation + CISHPatients with EGFR mutation + CISH ≥≥ 4 had ORR 90%,4 had ORR 90%, PFS 15 mo, OS 35 moPFS 15 mo, OS 35 mo  Patients with wild type EGFR + CISH < 4 had ORR 4%, PFS 2 mo,Patients with wild type EGFR + CISH < 4 had ORR 4%, PFS 2 mo, OS 15 moOS 15 mo Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003.
    42. 42. 42 Phase II Trial 1st-Line Erlotinib in PatientsPhase II Trial 1st-Line Erlotinib in Patients with NSCLC and EGFR Mutationswith NSCLC and EGFR Mutations  Primary endpoint: time to progressionPrimary endpoint: time to progression  EligibilityEligibility – Stage IIIB/IV NSCLC + mutated EGFRStage IIIB/IV NSCLC + mutated EGFR – No prior chemotherapyNo prior chemotherapy – No prior EGFR targeted agentsNo prior EGFR targeted agents Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020. Response, % (95% CI)Response, % (95% CI) All (n = 38)All (n = 38) Exon 19 (n = 20)Exon 19 (n = 20) Exon 21 (n = 18)Exon 21 (n = 18) ORRORR 8282 (66–92)(66–92) 9595 (75–100)(75–100) 6767 (41–87)(41–87) CRCR 13.213.2 2020 5.55.5 PRPR 68.468.4 7575 61.161.1 SDSD 13.213.2 55 22.222.2 PDPD 5.35.3 00 11.111.1
    43. 43. 43 Phase II Trial 1st-Line Erlotinib in NSCLCPhase II Trial 1st-Line Erlotinib in NSCLC with EGFR Mutationswith EGFR Mutations ResultsResults ConclusionsConclusions  Most benefit: Exon 19 deletions, patients who neverMost benefit: Exon 19 deletions, patients who never smoked, visceral site other than lungsmoked, visceral site other than lung  Phase III trial planned (erlotinib vs platinum-basedPhase III trial planned (erlotinib vs platinum-based chemotherapy in EGFR-mutated NSCLC)chemotherapy in EGFR-mutated NSCLC) ORR P-value EGFR Mutation .038 Exon 19 19 (95%) Exon 21 12 (67%) Smoking .038 Never 24 (90%) Former 7 (70%) Current 0 (0%) Gender .203 Female 22 (88%) Male 9 (69%) ORR P-value PS .662 0 8 (73%) 1 18 (86%) 2 5 (83%) Histology .754 Adeno 23 (79%) BAC 4 (100%) Other 4 (80%) Stage 1.0 IIIB 4 (100%) IV 27 (79%) Response PredictorsResponse Predictors Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020. Reprinted with permission from Dr. Paz-Ares. TTP According to Smoking HabitsTTP According to Smoking Habits TTP According to Mutational StatusTTP According to Mutational Status Log Rank P =.06 Breslow P =.06 Log Rank P =.12 Breslow P =.02
    44. 44. 44 Randomized Phase II Trial of ZD6474 vsRandomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLCGefitinib in Advanced NSCLC Part A ResultsPart A Results Secondary Efficacy Endpoint in Part ASecondary Efficacy Endpoint in Part A No. of Patients (%)No. of Patients (%) ZD6474 (n = 83)ZD6474 (n = 83) Gefitinib (n = 85)Gefitinib (n = 85) Objective responseObjective response 7 (8)7 (8) 1 (1)1 (1) Disease control > 8 wkDisease control > 8 wk 37 (45)37 (45) 29 (34)29 (34) Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale. Primary Endpoint in Part A:Primary Endpoint in Part A: Progression-Free SurvivalProgression-Free Survival Individual Changes in Size of TargetIndividual Changes in Size of Target Lesions from Baseline: Part ALesions from Baseline: Part A ProbabilityofRemaining Progression-Free Progression-free survival in Part A (months) Hazard ratio = 0.69 95% Cl = 0.50 to 0.96 Two-sided P-value = .025 Median PFS ZD6474 = 11.0 Gefitinib = 8.1 weeks BestConfirmedChangefromBaseline inTargetLesionSize(%) ZD6474 Gefitinib Final data cut-off, July 2005
    45. 45. 45 Randomized Phase II Trial of ZD6474 vsRandomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLCGefitinib in Advanced NSCLC Part B ResultsPart B Results Secondary Endpoint:Secondary Endpoint: Overall SurvivalOverall Survival Median PFS ZD6474 then gefitinib = 6.1 months Gefitinib then ZD6474 = 7.4 months Hazard ratio = 1.19 (95% Cl = 0.84 to 1.68) Two-sided P-value = .34 ProbabilityofRemainingAlive Time to Death (months) Final data cut-off, July 2005 Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.
    46. 46. 46 Randomized Phase II Trial of ZD6474 vs Gefitinib inRandomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLC: Adverse EventsAdvanced NSCLC: Adverse Events Event*Event* ZD6474 (n = 83)ZD6474 (n = 83) Gefitinib (n = 85)Gefitinib (n = 85) DiarrheaDiarrhea 58%58% 41%41% Grade 3/4, no.Grade 3/4, no. 4/24/2 1/01/0 RashRash 46%46% 49%49% Grade 3, no.Grade 3, no. 44 11 Nausea/vomitingNausea/vomiting 28%28% 34%34% Grade 3, no.Grade 3, no. 11 11 HeadacheHeadache 18%18% 13%13% Grade 3, no.Grade 3, no. 22 00 DizzinessDizziness 14%14% 9%9% HypertensionHypertension 12%12% 1%1% Grade 3, no.Grade 3, no. 33 00 QT-related eventsQT-related events 21%21% 5%5% *AEs are all CTC grade 1 or 2 except where noted. Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.
    47. 47. 47 Randomized Phase II Trial of ZD6474 vsRandomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLCGefitinib in Advanced NSCLC ConclusionsConclusions  Part A met primary endpoint of prolonging progression-freePart A met primary endpoint of prolonging progression-free survival (PFS)survival (PFS) – ZD6474 prolonged PFS by 45% compared with gefitinibZD6474 prolonged PFS by 45% compared with gefitinib  PFS prolongation did not result in overall survivalPFS prolongation did not result in overall survival advantage in Part Badvantage in Part B – Why? Not clear, maybe optional switchover confoundedWhy? Not clear, maybe optional switchover confounded survival assessmentsurvival assessment  Adverse events (AEs) for both agents mostly mildAdverse events (AEs) for both agents mostly mild  Slight differences in AE profilesSlight differences in AE profiles Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000.
    48. 48. 48 Novel Targeted Agents UnderNovel Targeted Agents Under Investigation for Lung Cancer TreatmentInvestigation for Lung Cancer Treatment Highlights of ASCO 2006Highlights of ASCO 2006 AgentAgent StudyStudy ResultsResults AMG706AMG706 BlumenscheinBlumenschein Abstract 7119Abstract 7119 Ongoing phase Ib trial in advanced NSCLC of AMG706 + CP, AMG706 +Ongoing phase Ib trial in advanced NSCLC of AMG706 + CP, AMG706 + panitumumab ± CPpanitumumab ± CP TGFTGFββASAS VaccineVaccine NemunaitisNemunaitis Abstract 7018Abstract 7018 75 patients, safety of optimal dose determined, results suggest greater75 patients, safety of optimal dose determined, results suggest greater survival compared with historical controlssurvival compared with historical controls VatalanibVatalanib JahanJahan Abstract 7081Abstract 7081 Tolerated in mesotheliomaTolerated in mesothelioma Activity: 8.5% PR, 68.1% SDActivity: 8.5% PR, 68.1% SD But 3-mo PFS (53.3%) did not met protocol-specified level of 75%But 3-mo PFS (53.3%) did not met protocol-specified level of 75% ZD6474ZD6474 NataleNatale Abstract 7000Abstract 7000 As shown in previous slides, ZD6474 produced longer PFS compared withAs shown in previous slides, ZD6474 produced longer PFS compared with gefitinib in refractory NSCLCgefitinib in refractory NSCLC HeymachHeymach Abstract 7016Abstract 7016 ZD6474 + docetaxel is being tested in ongoing double-blind, randomizedZD6474 + docetaxel is being tested in ongoing double-blind, randomized phase II trial in 2nd-line NSCLCphase II trial in 2nd-line NSCLC ABI-007ABI-007 RizviRizvi Abstract 7105Abstract 7105 Phase I/II trial, 1st-line in advanced NSCLC, MTD reached; ORR 30% andPhase I/II trial, 1st-line in advanced NSCLC, MTD reached; ORR 30% and 10.9 mo OS; grade 3 sensory neuropathy and fatigue, minimal10.9 mo OS; grade 3 sensory neuropathy and fatigue, minimal myelosuppresionmyelosuppresion AZD2171AZD2171 LaurieLaurie Abstract 3054Abstract 3054 Phase I trial in advanced NSCLC of AZD2171 + CP; manageable toxicitiesPhase I trial in advanced NSCLC of AZD2171 + CP; manageable toxicities including hypertension; evidence of activityincluding hypertension; evidence of activity CP = carboplatin/paclitaxel.
    49. 49. 49 Other Searches for UsefulOther Searches for Useful Biomarkers in NSCLC—ASCO 2006Biomarkers in NSCLC—ASCO 2006 Mack PC, et alMack PC, et al11  Elevated osteopontin plasmaElevated osteopontin plasma levels may have prognosticlevels may have prognostic value in advanced NSCLCvalue in advanced NSCLC  Osteopontin is a secretedOsteopontin is a secreted glycoprotein involved inglycoprotein involved in induction of urokinase (uPA)induction of urokinase (uPA) and increased cell migrationand increased cell migration Toschi L, et alToschi L, et al22  FISH or IHC analysis of samplesFISH or IHC analysis of samples from 190 consecutive patientsfrom 190 consecutive patients treated for advanced NSCLCtreated for advanced NSCLC  EGFR, HEr2, and p-Akt statusEGFR, HEr2, and p-Akt status are not predictors of sensitivityare not predictors of sensitivity to chemotherapyto chemotherapy  EGFR FISH + and/or HER2EGFR FISH + and/or HER2 FISH+ patients seemed toFISH+ patients seemed to benefit more from nonplatinumbenefit more from nonplatinum vs platinum-based combinationsvs platinum-based combinations (but N small)(but N small)  In EGFR FISH+ patients, RRIn EGFR FISH+ patients, RR and TTP after EGFR-TKI usedand TTP after EGFR-TKI used as 2nd-line treatment were atas 2nd-line treatment were at least equal to 1st-lineleast equal to 1st-line chemotherapychemotherapy 1. Mack PC, et al. 42nd ASCO, June 2-6, 2006. Abstract 7198. 2. Toschi L, et al. 42nd ASCO, June 2-6, 2006. Abstract 7111.
    50. 50. 50 SummarySummary  First-generation TKIs (gefitinib, erlotinib) the search continues forFirst-generation TKIs (gefitinib, erlotinib) the search continues for – Molecular markers for patient selectionMolecular markers for patient selection – Optimal combinationsOptimal combinations – Improved dosingImproved dosing  Multitargeted TKIs currently on the market (sorafenib, sunitinib)Multitargeted TKIs currently on the market (sorafenib, sunitinib) – Some promising, but not yet conclusive resultsSome promising, but not yet conclusive results  Investigational multitargeted TKIs (vatalanib, ZD6474, AMG706, AZ2171)Investigational multitargeted TKIs (vatalanib, ZD6474, AMG706, AZ2171) – Need data from randomized trialsNeed data from randomized trials – Some differences in adverse event profilesSome differences in adverse event profiles  General areas of needGeneral areas of need – Surrogate markers for evaluation of agentsSurrogate markers for evaluation of agents – Biomarkers for patient selectionBiomarkers for patient selection – Optimization of clinical trial designOptimization of clinical trial design
    51. 51. 51 Toxicity Management of TargetedToxicity Management of Targeted Therapies: Implications forTherapies: Implications for Nursing and Managed CareNursing and Managed Care Michelle Purdom, RN, BSNMichelle Purdom, RN, BSN Manager, Clinical Trials OperationsManager, Clinical Trials Operations Phase I ProgramPhase I Program University of TexasUniversity of Texas M.D. Anderson Cancer CenterM.D. Anderson Cancer Center Houston, TexasHouston, Texas
    52. 52. 52 OverviewOverview  Management of side effects associated withManagement of side effects associated with targeted therapiestargeted therapies  Pharmacoeconomics of cancer managementPharmacoeconomics of cancer management and role/implications of targeted therapies inand role/implications of targeted therapies in managed care settingmanaged care setting
    53. 53. 53 * Iressa was approved with contingencies on May 2, 2003. Targeted Therapies and Approval DatesTargeted Therapies and Approval Dates February 26, 2004 2003 May 2, 2003* May 13, 2003 2004 February 12, 2004 November 19, 2004 2005 December 20, 2005 2006 January 26, 2006 QuickTime™ and aTIFF (LZW) decompreare needed to see this pic
    54. 54. 54 Most Common Side Effects AssociatedMost Common Side Effects Associated with FDA-Approved Targeted Therapieswith FDA-Approved Targeted Therapies Includes: *+IFL, +5-FU/LV, +FOLFOX4, and monotherapy; **+radiation, +irinotecan, and monotherapy; † +gemcitabine and monotherapy; ‡ 250 mg/d and 500 mg/d. Side Effect Bevacizumab* Sunitinib Bortezomib Sorafenib Cetuximab** Erlotinib† Gefitinib‡ Abdominal pain     Acne and/or rash       Alopecia    Altered taste  Anemia   Anorexia and/or weight loss     Appetite decrease/ taste disorder  Arthralgia/myalgia    Asthenia    Bleeding  Constipation      Cough   Dehydration  Diarrhea       Dizziness   Dry and/or discolored skin   Dysesthesia and/or paresthesia  Dyspepsia   Dyspnea     
    55. 55. 55 Most Common Side Effects AssociatedMost Common Side Effects Associated with FDA-Approved Targeted Therapieswith FDA-Approved Targeted Therapies (cont’d)(cont’d) Includes: *+IFL, +5-FU/LV, +FOLFOX4, and monotherapy; **+radiation, +irinotecan, and monotherapy; † +gemcitabine and monotherapy; ‡ 250 mg/d and 500 mg/d. Side Effect Bevacizumab* Sunitinib Bortezomib Sorafenib Cetuximab** Erlotinib† Gefitinib‡ Edema   Epistaxis  Fatigue    Fever     GI hemorrhage  Hand-foot skin reaction  Headache     Hypertension   Insomnia  Leukopenia and/or neutropenia and/or thrombocytopenia   Mucositis/stomatits     Nausea and/or vomiting       Pain     Peripheral neuropathy  Pharyngitis  Proteinuria  Pruritis  Upper respiratory infection  Xerostomia 
    56. 56. 56 Management of Bevacizumab-AssociatedManagement of Bevacizumab-Associated Side EffectsSide Effects Side EffectSide Effect ScopeScope Symptoms and ManagementSymptoms and Management HypertensionHypertension Incidence Gr 3/4: B + C 12% vs C 2%Incidence Gr 3/4: B + C 12% vs C 2% Not infusion related; usually observedNot infusion related; usually observed during course of treatmentduring course of treatment Standard oral antihypertensivesStandard oral antihypertensives If severe, temporarily suspend treatmentIf severe, temporarily suspend treatment If hypertensive crisis, discontinue treatmentIf hypertensive crisis, discontinue treatment Monitor BP at least every 2–3 weeksMonitor BP at least every 2–3 weeks AT eventsAT events Incidence B + C 4.4% vs C 1.9%Incidence B + C 4.4% vs C 1.9% Permanently discontinue treatmentPermanently discontinue treatment GI perforationGI perforation Incidence: B + C 2–4% vs C 0.3%Incidence: B + C 2–4% vs C 0.3% Symptoms: abdominal pain, constipation, vomitingSymptoms: abdominal pain, constipation, vomiting Wound healing orWound healing or bleedingbleeding complicationscomplications Incidence: among patients requiring surgeryIncidence: among patients requiring surgery within 60 d of B + C 15% vs C 4%within 60 d of B + C 15% vs C 4% Wait for complete healing of surgical incision andWait for complete healing of surgical incision and at least 28 d after surgery before startingat least 28 d after surgery before starting B therapyB therapy HemorrhageHemorrhage Incidence Gr 3–5 bleeding: B + C 5.2% vsIncidence Gr 3–5 bleeding: B + C 5.2% vs B 3.8% vs C 0.7%B 3.8% vs C 0.7% Incidence epistaxis (nosebleeds): B + CIncidence epistaxis (nosebleeds): B + C 35% vs C 10%35% vs C 10% Epistaxis usually mild, use standard first aidEpistaxis usually mild, use standard first aid techniquestechniques Patients with recent hemoptysis should notPatients with recent hemoptysis should not receive B therapyreceive B therapy Sources: www.avastin.com/avastin/nurseFaqPro4.m Avastin (bevacizumab) prescribing information. Available at: http//www.gene.com/gene/products/information/oncology/avastin/insert.jsp AT = arterial thromboembolic; B = bevacizumab; C = chemotherapy.
    57. 57. 57 Blood Pressure DiaryBlood Pressure Diary Courtesy of Michelle Purdom, RN, BSN
    58. 58. 58 Management of Bortezomib-AssociatedManagement of Bortezomib-Associated Side EffectsSide Effects Side EffectSide Effect ScopeScope Symptoms and ManagementSymptoms and Management PeripheralPeripheral neuropathyneuropathy Incidence of new cases: 36%Incidence of new cases: 36% Gr 3, 7%Gr 3, 7% Monitor patients for symptoms: burning sensation, hyperesthesia,Monitor patients for symptoms: burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic painhypoesthesia, paresthesia, discomfort, neuropathic pain New and worsening neuropathy: depending on severity considerNew and worsening neuropathy: depending on severity consider recommended changes in dose and schedulerecommended changes in dose and schedule Before initiating therapy, carefully consider risk/benefits ofBefore initiating therapy, carefully consider risk/benefits of bortezomib treatment for patients with pre-existing neuropathybortezomib treatment for patients with pre-existing neuropathy AstheniaAsthenia (fatigue,(fatigue, malaise,malaise, weakness)weakness) Incidence: bortezomib 61% (GrIncidence: bortezomib 61% (Gr 3/4, 12%) vs dexamethasone3/4, 12%) vs dexamethasone 45% (Gr 3/4, 6%)45% (Gr 3/4, 6%) Educate patients about caution in operating cars and otherEducate patients about caution in operating cars and other machinery because of potential for fatigue, dizziness, syncope,machinery because of potential for fatigue, dizziness, syncope, hypotension, diplopia, blurred visionhypotension, diplopia, blurred vision Educate patients about avoiding dehydration and seeking medicalEducate patients about avoiding dehydration and seeking medical advice if experience dizziness, light-headedness, or fainting spellsadvice if experience dizziness, light-headedness, or fainting spells GI toxicitiesGI toxicities Incidence Gr 3 bortezomib 18%Incidence Gr 3 bortezomib 18% vs dexamethasone 6% (Gr 4vs dexamethasone 6% (Gr 4 rare in both groups)rare in both groups) Most common GI toxicities: nausea, diarrhea, constipation,Most common GI toxicities: nausea, diarrhea, constipation, vomiting, and anorexiavomiting, and anorexia HypotensionHypotension Incidence: bortezomib 11% vsIncidence: bortezomib 11% vs dexamethasone 2%dexamethasone 2% May need to adjust doses of antihypertensive medicationsMay need to adjust doses of antihypertensive medications Velcade (bortezomib) prescribing information.
    59. 59. 59 Management of Cetuximab-AssociatedManagement of Cetuximab-Associated Side EffectsSide Effects Side EffectSide Effect ScopeScope Symptoms and ManagementSymptoms and Management Infusion reactionsInfusion reactions Incidence of severeIncidence of severe reactions: 2%–4%reactions: 2%–4% Incidence of Gr 1–2Incidence of Gr 1–2 reactions: 16%–19%reactions: 16%–19% Symptoms of severe (potentially fatal) reactions: rapid onset of airwaySymptoms of severe (potentially fatal) reactions: rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria,obstruction (bronchospasm, stridor, hoarseness), urticaria, hypertension, and/or cardiac arresthypertension, and/or cardiac arrest Symptoms of Gr 1–2 reactions: chills, fever, dyspnea on 1Symptoms of Gr 1–2 reactions: chills, fever, dyspnea on 1stst day ofday of initial dosinginitial dosing Severe reactions: immediate and permanent cetuximab treatmentSevere reactions: immediate and permanent cetuximab treatment discontinuationdiscontinuation Mild/moderate reactions: slow infusion rate, use antihistamines (eg,Mild/moderate reactions: slow infusion rate, use antihistamines (eg, diphenhydramine) in subsequent dosesdiphenhydramine) in subsequent doses CardiopulmonaryCardiopulmonary arrestarrest Incidence of arrestIncidence of arrest and/or sudden death:and/or sudden death: cetuximab + radiationcetuximab + radiation therapy 2% vs 0% fortherapy 2% vs 0% for radiation therapyradiation therapy Use with caution in patients with coronary heart disease, congestiveUse with caution in patients with coronary heart disease, congestive heart failure, and arrhythmiasheart failure, and arrhythmias Closely monitor serum electrolytes (including magnesium, potassium,Closely monitor serum electrolytes (including magnesium, potassium, calcium) during and after cetuximab therapycalcium) during and after cetuximab therapy DermatologicDermatologic toxicitytoxicity Incidence in CRC: 89%Incidence in CRC: 89% of all treated patients,of all treated patients, severe in 11%severe in 11% Signs: acneform rash, skin drying and fissuringSigns: acneform rash, skin drying and fissuring Monitor for development of inflammatory and infectious sequelae;Monitor for development of inflammatory and infectious sequelae; consider topical and/or oral antibioticsconsider topical and/or oral antibiotics Severe acneform rash: institute dose modificationsSevere acneform rash: institute dose modifications Topical corticosteroids not recommendedTopical corticosteroids not recommended www.erbitux.com
    60. 60. 60 Management of Erlotinib-AssociatedManagement of Erlotinib-Associated Side EffectsSide Effects Side EffectSide Effect ScopeScope Symptoms and ManagementSymptoms and Management RashRash Overall incidence of rash: erlotinibOverall incidence of rash: erlotinib 75% vs placebo 17%75% vs placebo 17% Incidence of Gr 3 rash with erlotinib:Incidence of Gr 3 rash with erlotinib: 8%8% Take erlotinib at the same time each day betweenTake erlotinib at the same time each day between meals (one hour before or two hours after eating).meals (one hour before or two hours after eating). Pts with severe skin reactions may need dosePts with severe skin reactions may need dose reductions or interruptionsreductions or interruptions DiarrheaDiarrhea Incidence of severe diarrhea: 6%Incidence of severe diarrhea: 6% Educate patients to seek prompt medical attentionEducate patients to seek prompt medical attention for severe or persistent diarrheafor severe or persistent diarrhea Usually managed with loperamideUsually managed with loperamide Use dose reductions or interruptions in patientsUse dose reductions or interruptions in patients who are dehydrated or have unresponsive severewho are dehydrated or have unresponsive severe diarrheadiarrhea InterstitialInterstitial lung diseaselung disease (ILD)(ILD) Overall incidence of ILD-like events:Overall incidence of ILD-like events: 0.7%0.7% Most cases in lung cancer patientsMost cases in lung cancer patients associated with confounding factorsassociated with confounding factors Interrupt treatment for acute onset or progressionInterrupt treatment for acute onset or progression of unexplained pulmonary symptomsof unexplained pulmonary symptoms If ILD confirmed, discontinue treatmentIf ILD confirmed, discontinue treatment Educate patients to seek prompt medical attentionEducate patients to seek prompt medical attention for onset or worsening of unexplained shortness offor onset or worsening of unexplained shortness of breath or coughbreath or cough www.tarceva.com.
    61. 61. 61 Management of Gefitinib-AssociatedManagement of Gefitinib-Associated Side EffectsSide Effects Side EffectSide Effect ScopeScope Symptoms and ManagementSymptoms and Management Interstitial lungInterstitial lung disease (ILD)disease (ILD) Overall incidence: 1% ofOverall incidence: 1% of gefitinib-treated patients (1/3gefitinib-treated patients (1/3 of these cases were fatal)of these cases were fatal) Symptoms: acute onset of dyspnea, sometimesSymptoms: acute onset of dyspnea, sometimes with cough or low-grade fever, often quicklywith cough or low-grade fever, often quickly worsening and requiring hospitalizationworsening and requiring hospitalization Interrupt treatment in patients with acute onset orInterrupt treatment in patients with acute onset or worsening of pulmonary symptoms (dyspnea,worsening of pulmonary symptoms (dyspnea, cough, fever)cough, fever) Discontinue gefitinib treatment if ILD confirmedDiscontinue gefitinib treatment if ILD confirmed Eye toxicityEye toxicity Low incidence of eye pain andLow incidence of eye pain and corneal erosion/ulcer,corneal erosion/ulcer, sometimes with aberrantsometimes with aberrant eyelash growtheyelash growth Consider therapy interruption until symptomsConsider therapy interruption until symptoms resolved and removal of aberrant eyelash (ifresolved and removal of aberrant eyelash (if present)present) www.iressa.com Most common gefitinib-associated adverse events: diarrhea, rash, acne, dry skin, nausea, vomitingMost common gefitinib-associated adverse events: diarrhea, rash, acne, dry skin, nausea, vomiting
    62. 62. 62 Example ofExample of TypicalTypical Rash Induced byRash Induced by EGFR InhibitorsEGFR Inhibitors Courtesy of Michelle Purdom, RN, BSN
    63. 63. 63 EGFR RashEGFR Rash Courtesy of Michelle Purdom, RN, BSN
    64. 64. 64 Management of Sunitinib-AssociatedManagement of Sunitinib-Associated Side EffectsSide Effects Side EffectSide Effect ScopeScope Symptoms and ManagementSymptoms and Management GI eventsGI events Most common: diarrhea, nausea,Most common: diarrhea, nausea, stomatitis, dyspepsia, vomitingstomatitis, dyspepsia, vomiting Supportive care with antiemetic or antidiarrhea medicationsSupportive care with antiemetic or antidiarrhea medications Left ventricularLeft ventricular dysfunctiondysfunction Incidence: sunitinib 11% vs placebo 3%Incidence: sunitinib 11% vs placebo 3% Some patients recovered without interventionSome patients recovered without intervention Possible interventions: dose reduction, use of antihypertensive orPossible interventions: dose reduction, use of antihypertensive or diureticdiuretic Carefully monitor patients for signs and symptoms of congestiveCarefully monitor patients for signs and symptoms of congestive heart failureheart failure HemorrhageHemorrhage Incidence of bleeding: sunitinib 18% vsIncidence of bleeding: sunitinib 18% vs placebo 17%placebo 17% Fatal pulmonary hemorrhage occurred in 2Fatal pulmonary hemorrhage occurred in 2 patients in a sunitinib NSCLC clinical trialpatients in a sunitinib NSCLC clinical trial Epistaxis most common hemorrhagic adverse eventEpistaxis most common hemorrhagic adverse event HypertensionHypertension Incidence: sunitinib 15% (Gr 3, 4%) vsIncidence: sunitinib 15% (Gr 3, 4%) vs placebo 11% (Gr 3, 0)placebo 11% (Gr 3, 0) No Gr 4No Gr 4 Monitor and treat with standard hypertensiveMonitor and treat with standard hypertensive If severe, suspend sunitinib treatment until hypertension isIf severe, suspend sunitinib treatment until hypertension is controlledcontrolled Skin toxicitySkin toxicity Skin discoloration: occurs in 1/3 of ptsSkin discoloration: occurs in 1/3 of pts Attributed to yellow drug colorAttributed to yellow drug color Advise patients of potential occurrenceAdvise patients of potential occurrence Other possible dermatologic effects: dryness, thickness or crackingOther possible dermatologic effects: dryness, thickness or cracking of skin, blister or rash on palms of hand and soles of feetof skin, blister or rash on palms of hand and soles of feet www.sutent.com
    65. 65. 65 Management of Sorafenib-AssociatedManagement of Sorafenib-Associated Side EffectsSide Effects Side EffectSide Effect ScopeScope Symptoms and ManagementSymptoms and Management DermatologicDermatologic Hand-foot skin reaction (35%)Hand-foot skin reaction (35%) and rash (38%) most commonand rash (38%) most common adverse eventadverse event Usually Gr 1-2, appear duringUsually Gr 1-2, appear during 11stst 6 weeks of treatment6 weeks of treatment Topical therapies for symptomatic reliefTopical therapies for symptomatic relief Temporary treatment interruption or doseTemporary treatment interruption or dose modificationsmodifications Severe or persistent cases may require treatmentSevere or persistent cases may require treatment discontinuationdiscontinuation HypertensionHypertension Incidence: sorafenib 16.9% vsIncidence: sorafenib 16.9% vs placebo 1.8%placebo 1.8% Usually mild to moderate andUsually mild to moderate and occurs early in treatmentoccurs early in treatment BP should be monitored weekly for 1BP should be monitored weekly for 1stst 6 weeks of6 weeks of sorafenib therapysorafenib therapy Manage with standard antihypertensive therapyManage with standard antihypertensive therapy Temporary treatment interruption or doseTemporary treatment interruption or dose modificationsmodifications Treatment discontinuation rareTreatment discontinuation rare HemorrhageHemorrhage Incidence: sorafenib 15.3%Incidence: sorafenib 15.3% (Gr 3, 2%; no Gr 4) vs placebo(Gr 3, 2%; no Gr 4) vs placebo 8.2% (Gr 3, 1.3%; Gr 4 0.2%)8.2% (Gr 3, 1.3%; Gr 4 0.2%) If bleeding necessitates medical intervention,If bleeding necessitates medical intervention, consider permanently discontinuing sorafenibconsider permanently discontinuing sorafenib Cardiac ischemiaCardiac ischemia and/or infarctionand/or infarction Incidence: sorafenib 2.9% vsIncidence: sorafenib 2.9% vs placebo 0.4%placebo 0.4% Consider temporary or permanent treatmentConsider temporary or permanent treatment discontinuationdiscontinuation www. nexavar.com
    66. 66. 66 Pharmacoeconomics of CancerPharmacoeconomics of Cancer Management and Role/Implications ofManagement and Role/Implications of Targeted Therapies inTargeted Therapies in Managed Care SettingManaged Care Setting Cohen M, et al. Am J Manag Care. 2006;12:524.
    67. 67. 67 Targeted Therapies and Managed CareTargeted Therapies and Managed Care  New therapies need evidence of effectivenessNew therapies need evidence of effectiveness and safetyand safety  Impact on quality of lifeImpact on quality of life  Net impact on total cost of careNet impact on total cost of care  Concept of value differs among patients,Concept of value differs among patients, providers, health plans, and employersproviders, health plans, and employers Cohen M, et al. Am J Manag Care. 2006;12:524.
    68. 68. 68 Biotechnology PipelineBiotechnology Pipeline AIDS/HIV infections/related conditions Autoimmune disorders Blood disorders Cancer/related conditions Cardiovascular disease Eye conditions Diabetes/related conditions Digestive disorders Genetic disorders Growth disorder Infectious disease Neurologic disorders Other conditions not specified here Respiratory disorders Skin disorders Transplantation 2004 Survey. Medicines in Development: Biotechnology. Available at: http://www.phrma.org/files/Biotech%20survey.pdf. Accessed February 15, 2006. 17 26 2 154 19 5 10 11 9 3 43 16 17 14 7 3 Condition Number of Agents
    69. 69. 69 Growth Drivers for BiologicsGrowth Drivers for Biologics Key contributors from managed care perspective includeKey contributors from managed care perspective include Increased availability of targets for biologic agentsIncreased availability of targets for biologic agents Increased use of approved drugsIncreased use of approved drugs Increased approval of biotechnology drugs for moreIncreased approval of biotechnology drugs for more common conditionscommon conditions Expanded indications for approved drugsExpanded indications for approved drugs Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.
    70. 70. 70 Reasons for Off-Label Use of BiologicsReasons for Off-Label Use of Biologics  Small population size and/or assessed cost of clinical trials maySmall population size and/or assessed cost of clinical trials may discourage marketers from seeking formal FDA approvaldiscourage marketers from seeking formal FDA approval  Potential of newer therapies for better efficacy and outcomesPotential of newer therapies for better efficacy and outcomes  Proven safety and efficacy in other disease statesProven safety and efficacy in other disease states  Potential for increased quality of lifePotential for increased quality of life  Thought leader advocacy/patient demandThought leader advocacy/patient demand  Better understanding of disease pathways, particularly immune-Better understanding of disease pathways, particularly immune- modulating diseasesmodulating diseases Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.
    71. 71. 71 Managed Care’s Concerns RegardingManaged Care’s Concerns Regarding Off-Label Use of BiologicsOff-Label Use of Biologics  Safety/efficacy questionsSafety/efficacy questions  Differing dosing and administrationDiffering dosing and administration  Potential for inappropriate carePotential for inappropriate care  Potential for cost increasePotential for cost increase  Paucity of dataPaucity of data  Lack of uniform guidelines/bestLack of uniform guidelines/best practicespractices  Legal/ethical issuesLegal/ethical issues Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.
    72. 72. 72 Recommendations for ManagingRecommendations for Managing Expanded IndicationsExpanded Indications  Scan the pipeline to become aware of impending drugScan the pipeline to become aware of impending drug launcheslaunches  Increase education for P&T committeesIncrease education for P&T committees  Define a process and clear criteriaDefine a process and clear criteria  Develop and/or augment treatment guidelines forDevelop and/or augment treatment guidelines for expanded indicationsexpanded indications  Increase case management/disease managementIncrease case management/disease management  Strive for innovative management strategies thatStrive for innovative management strategies that contain cost and maintain accesscontain cost and maintain access Cohen M, et al. Am J Manag Care. 2006;12:524.
    73. 73. 73 Continued Challenges forContinued Challenges for Managed Care OrganizationsManaged Care Organizations  Expanding indications for FDA-approved drugs present uniqueExpanding indications for FDA-approved drugs present unique challenges for MCOs.challenges for MCOs. – This translates into added expenditures for MCOs because of increasedThis translates into added expenditures for MCOs because of increased frequency of administration and/or longer duration of therapyfrequency of administration and/or longer duration of therapy – For patients, may result in higher copays and more restrictive accessFor patients, may result in higher copays and more restrictive access management strategies, particularly the use of prior authorizationmanagement strategies, particularly the use of prior authorization  Maintain focus on potential of agents for reduction in disease progression andMaintain focus on potential of agents for reduction in disease progression and disability rather than solely on patient copays and aggressive managementdisability rather than solely on patient copays and aggressive management strategiesstrategies – Shift focus on cost to clinical decision making through evidence-basedShift focus on cost to clinical decision making through evidence-based medicinemedicine  Adequately plan for agents with multiple indicationsAdequately plan for agents with multiple indications – Need more definitive criteria for evaluating expanded indications andNeed more definitive criteria for evaluating expanded indications and potential for cost savingspotential for cost savings Cohen M, et al. Am J Manag Care. 2006;12:524.
    74. 74. 74 Nursing ImplicationsNursing Implications  The nurse should help the patient understandThe nurse should help the patient understand importance of prior insurance authorization dueimportance of prior insurance authorization due to the high cost of biopharmaceuticalsto the high cost of biopharmaceuticals  The nurse should assist the patient as a liaisonThe nurse should assist the patient as a liaison with the hospital business office/MCO bywith the hospital business office/MCO by initiating the process early and ofteninitiating the process early and often  Emotional supportEmotional support
    75. 75. 75 SummarySummary  Expanding indications and off-label applications of FDA-approvedExpanding indications and off-label applications of FDA-approved targeted therapies present unique challengestargeted therapies present unique challenges – MCOs face added expensesMCOs face added expenses – Patients face higher co-pays and more restrictive accessPatients face higher co-pays and more restrictive access – Clinicians need to expand their knowledge base and skill setsClinicians need to expand their knowledge base and skill sets  Nurses have an important role in providingNurses have an important role in providing – Professional careProfessional care – Toxicity management and side effect educationToxicity management and side effect education – Assistance in navigating the preauthorization processAssistance in navigating the preauthorization process – Emotional supportEmotional support
    76. 76. 76 Keeping Pace with Targeted Therapies in Lung CancerKeeping Pace with Targeted Therapies in Lung Cancer Highlights from the ASCO 2006 Annual MeetingHighlights from the ASCO 2006 Annual Meeting

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