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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 Keeping Pace with Targeted Therapies in Lung Cancer Presentation Transcript

  • Keeping Pace with Targeted Therapies in Lung Cancer Highlights from the ASCO 2006 Annual Meeting
  • Introduction
  • Overview of Targeted Therapies and Focus on Monoclonals Karen Kelly, MD Professor of Medicine Department of Medical Oncology University of Colorado at Denver Aurora, Colorado
  • FDA-Approved Agents Being Investigated for Lung Cancer Treatment 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. Bexarotene (Targretin ® ; Ligand) Bortezomib (Velcade ® , Millennium) Sorafenib (Nexavar ® ; Bayer) Sunitinib (Sutent ® ; Pfizer) Gefitinib (Iressa ® ; AstraZeneca) Erlotinib (Tarceva ® ; Genentech) Cetuximab (Erbitux ® ; ImClone) Bevacizumab (Avastin ® ; Genentech) Agent Cutaneous T-cell lymphoma RXR α , RXR β , RXR γ Retinoid (oral) NSCLC HER1/EGFR Reversible TKI (oral) Multiple myeloma Proteasome Proteasome inhibitor (IV) RCC VEGFR-2, -3; cRAF; bRAF; PDGFR- β ; FLT3; KIT RCC, GIST VEGFR-1, -2, -3; PDGFR- α , - β ; KIT; RET; FLT3 NSCLC HER1/EGFR Head & neck cancer, CRC EGFR CRC VEGF Monoclonal (IV) Indications Targets Class
  • Examples of Novel Targeted Agents Being Investigated for Lung Cancer Treatment EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor; PDGFR = platelet-derived growth factor receptor; TGF = transforming growth factor. TGF β AS Vaccine (Lucanix; NovaRx) TGF- β antisense gene modified allogeneic tumor cell vaccine Vaccine (intradermal) Tumor AMG706 (Amgen) VEGFR-1, -2, -3; PDGFR; RET AZD2171 (AstraZeneca) VEGFR-2 Angiogenesis + tumorigenesis Angiogenesis Tumorigenesis Biologic Target Dual reversible TKI (oral) Reversible TKI (oral) Monoclonal (IV) Class VEGFR-2, -3; RET; EGFR VEGFR-1, -2, -3; PDGFR- β EGFR Molecular Targets ZD6474 (Zactima; AstraZeneca) Vatalanib (Novartis/Schering AG) Panitumumab (Amgen) Agent
  • ASCO 2006 Update Bevacizumab in NSCLC
    • Paclitaxel + carboplatin ± bevacizumab (updated results from randomized phase III trial E4599)
      • Sandler AB, et al. 1
      • Brahmer JR, et al. 2
      • Dowlati A, et al. 3
    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.
  • Paclitaxel/Carboplatin ± Bevacizumab Previously Reported ECOG 4599 Results Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4. *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. 22.1 16.9 24-mo OS, % 51.9 43.7 12-mo OS, % .007 12.5 10.2 Median OS, mo 14.6 6.4 1-y PFS, % 55.0 32.6 6-mo PFS, % < .0001 6.4 4.5 Median PFS, mo < .0001 27.2 10 Response rate, %* P -Value PCB (n = 420) PC (n = 427)
  • Paclitaxel/Carboplatin ± Bevacizumab Possible Gender Differences in Overall Survival
    • Unplanned subgroup analysis of ECOG 4599
    • Key finding: compared with males, females did not appear to gain same overall survival benefit from addition of bevacizumab
    Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036. ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab. .87 13.3 13.1 Overall survival females, mo .001 11.7 8.7 Overall survival males, mo .003 12.3 10.3 Overall survival, mo P -Value PCB PC
  • Paclitaxel/Carboplatin ± Bevacizumab No Gender Differences in Overall Survival
    • Females on PCB arm had higher response rate and progression-free survival compared with females in the PC arm
    Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036. P = paclitaxel; C = carboplatin; B = bevacizumab; CR = complete response; PR = partial response. Females Males 5.3 14.2 PC (n = 162) 6.2 41.1 PCB (n = 190) < .0001 .001 P -Value .002 6.3 4.3 Progression-free survival, mo < .0001 28.8 15.7 Overall response rate (CR + PR), % P -Value PCB (n = 191) PC (n = 230)
  • Paclitaxel/Carboplatin ± Bevacizumab Perspective on Unplanned Analysis by Gender
    • Treatments at time of disease progression were not different, except that in the PCB arm, females were slightly less likely than males to get chemotherapy as 2 nd -line therapy
    • Reasons for observed differences in overall survival are unclear, possibilities include
      • Random chance
      • Pitfalls of unplanned subgroup analysis
    • These results contrast with results in CRC trials where no gender differences reported in overall survival
    • PCB 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. N Engl J Med . 2004;350:2335. Genentech data on file PCB = paclitaxel/carboplatin/bevacizumab; CRC = colorectal cancer; ECOG = Eastern Cooperative Oncology Group; NSCLC = non–small-cell lung cancer.
  • Prospective Correlative Assessment of Biomarkers from ECOG 4599
    • Biomarkers studied
    • Endothelial leukocyte adhesion molecule-1 (E-selectin)
      • Expressed only on endothelial cell after activation by inflammatory cytokines
      • Elevated E-selectin seen in disorders characterized by endothelial cell apoptosis and malignancies
    • Intercellular adhesion molecule-1 (ICAM-1; CD54)
      • Expressed on endothelial, epithelial, lymphocytes, monocytes, hepatocytes, and hemapoietic cells
      • Elevated levels seen in many malignancies and alterations seen with vascular targeting and antiangiogenic agents
    • Vascular endothelial growth factor (VEGF) and basic-fibroblast growth factor (b-FGF)
      • Well-known angiogenic factors
    Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.
  • Prospective Correlative Assessment of Biomarkers 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 be prognostic for response and survival in advanced NSCLC
      • This might be useful stratification factor in future trials
      • Low levels indicate a 2-fold increase in likelihood of response to chemotherapy (unclear if this is prognostic or predictive)
    • Future trials are needed to determine if these will be better markers for clinical outcome than conventional radiographic response assessment
    Probability Months 1.0 - 0.8 - 0.6 - 0.4 - 0.2 - 0.0 - Survival 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%
  • Risk Factors for Pulmonary Hemorrhage (PH) in Bevacizumab-Treated Patients
    • Retrospective study of ECOG 4599 data examining association between baseline clinical factors and incidence of early onset (< 150 d from initial treatment) PH
    • Grade  3 PH occurred in 2.3% of patients
    • Of 10 cases identified, 6 met criteria for early onset PH related to bevacizumab
    • Pretreatment cavitation may be associated with increased risk of PH
    • Hemoptysis was predicative of possible future PH
    Sandler AB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7068.
  • ASCO 2006 Update on Cetuximab in NSCLC
    • SWOG 0342 phase II trial of chemotherapy + cetuximab vs chemotherapy followed by cetuximab 1
    • FLEX phase III trial of cisplatin/vinorelbine ± cetuximab 2
    1. Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. 2. Von Pawl, J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.
  • Preliminary Results of SWOG 0342 Phase II Trial of Paclitaxel/Carboplatin + Cetuximab
    • Primary objectives
    • Compare response rate and toxicity of concurrent vs sequential platinum-based chemotherapy + cetuximab regimens as 1 st -line treatment for advanced NSCLC
    • Select 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
  • Phase II Trial of Paclitaxel/Carboplatin + Cetuximab Preliminary Efficacy Results Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. *Patients evaluable for response: 71 in the chemo + cetuximab arm and 87 in the chemo-only arm. 49 43 1-year overall survival, % 10 9 Median overall survival, mo 4 4 Progression-free survival, mo 75 (63–84) 69 (58–78) Disease stabilization, % (95% CI) 38 (27–50) 44 (33–55) Stable disease, % (95% CI) Chemo + Cetuximab (n = 106)* Chemo  Cetuximab (n = 119)* 37 (26–49) 0 25 (17–36) Partial response, % (95% CI) 0 Complete response
  • SWOG 0342—Phase II Trial of Paclitaxel/Carboplatin + Cetuximab Preliminary Safety Results Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly. % of Evaluable Patients Chemo +/- C 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - Adverse Events (grade 3/4) Post-Chemo C 55 67 20 27 N=101 N=94 N=20 N=22 Sequential Concurrent % of Evaluable Patients Chemo +/- C 14 - 12 - 10 - 8 - 6 - 4 - 2 - 0 - 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) Chemo = paclitaxel/carboplatin; C = cetuximab. N=101 NS 36.6 41.4 Neutrophils .04 5.9 15 Neuropathy NS 2 6.4 Nausea NS 3 6.4 Joint pain NS 18.8 16 Leukocytes NS 9 8.5 Fatigue NS 4 6.4 Dyspnea P- Value Chemo C N = 94 Chemo + C N = 94 Adverse Event
  • Phase II Trial of Paclitaxel/Carboplatin + Cetuximab Preliminary Conclusions
    • Concurrent cetuximab + chemotherapy arm met predetermined 10-month minimal median survival requirement
    • Trend toward higher response rate in concurrent arm
    • Rash only significant additional toxicity seen with concurrent administration of cetuximab + chemotherapy
    • Biomarker correlative studies ongoing
    • New trials with this concurrent regimen + bevacizumab planned
    Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.
  • Phase III Trial of Cisplatin/Vinorelbine ± Cetuximab Preliminary Safety Report
    • Stage IIIB with documented malignant pleural effusion or stage IV previously untreated NSCLC
    • Epidermal growth factor receptor expression by immunohistochemistry
    • Patients recruited from 166 centers in 29 countries in Europe, Asia, Australia, and South America
    • Primary objective: overall survival
    • Preplanned analysis by Data Safety Monitoring Board (DSMB) of baseline and safety data from 365 patients
    • Results
      • Recruitment completed in February 2006
      • 1125 patients randomized
      • Trial continues
    Von Pawl J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.
  • SWOG S0339—Phase II Trial of Bortezomib + Gemcitabine/Carboplatin
    • Design
      • Primary endpoint: OS (goal 10 month median OS to rule out null hypothesis)
      • Stage IIIB (with pleural effusion) or IV NSCLC, chemotherapy-naive
      • PS = 0 or 1
    • Results
      • N = 121 accrued (116 eligible)
      • Median age: 64 years (range, 28–78)
      • 11% stage IIIB, 86% stage IV
      • Median follow-up: >15 months
      • Median 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.
  • Phase II Trial of Bortezomib + Gemcitabine/ Carboplatin Efficacy and Safety Results Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.
    • Overall survival 11 months (95% CI 8.2–13 months)
    • 1-year survival 47%; 2-year survival 14%
    • Results above predetermined statistical endpoint to proceed to a phase III trial
    ORR = overall response rate; CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; AST = aspartate aminotransferase; ALT = alanine aminotransferase. 2 (2) CR 18 (16) Not evaluable 21 (18) PD 51 (45) SD 22 (19) PR 24 (21) ORR No. (%) (n = 114) Response 14 (12) AST/ALT 15 (13) Fatigue 15 (13) Anemia 72 (63) Thrombocytopenia 59 (52) Neutropenia No. (%) (n = 114) Grade 3/4 Toxicity in > 10% of Patients
  • Summary
    • Clarification with regards to carboplatin/paclitaxel ± bevacizumab phase III trial ECOG 4599
      • Bevacizumab does have some differential gender effect on overall survival, but not clinically meaningful
      • Potential predictive or prognostic biomarkers
      • Risk factors for bevacizumab-associated pulmonary hemorrhage
    • Promising results from phase II trials
      • Cetuximab + carboplatin/paclitaxel
      • Cetuximab + cisplatin/vinorelbine
      • Bortezomib + gemcitabine/carboplatin
    • Data from phase III trials needed for cetuximab and bortezomib
  • Focus on Small Molecules and Investigational Agents Roy S. Herbst, MD, PhD Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology University of Texas M.D. Anderson Cancer Center Houston, Texas
  • Update on Small Molecule and Investigational Agents
    • Tyrosine kinase inhibitors with FDA approvals
      • Sunitinib
      • Sorafenib
      • Erlotinib
      • Gefitinib
    • Investigational agents
      • Vatalanib
      • ZD6474
      • ABI-007
      • AMG706/panitumumab
    • Biomarkers
      • Osteopontin
      • EGF, Her2, p-Akt
      • RXR-beta, pPARy
  • Tyrosine 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
  • Similarities and Differences in Targets for TKIs and Monoclonals Tumor Endothelial cells bFGF VEGF TGF-  Mechanism Inhibits tumor cell growth and blocks synthesis of angiogenetic proteins (eg, bFGF, VEGF, TGF-  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.
  • Sunitinib Phase II Trial in Previously Treated Advanced NSCLC
    • Open-label, single-arm, 2-stage multicenter trial
    • Patients had recurrent stage IIIB/IV NSCLC that had failed 1 or more chemotherapy regimens (with/out EGFR inhibitor)
    • Sunitinib given at 50 mg/d for 4 wk followed by 2 wk off treatment before next 6-week cycle
    • Primary endpoint: overall confirmed objective response rate (ORR)
    • Enrollment
      • 63 patients
      • 64% had adenocarcinoma, 90% had stage IV disease
      • 43% had 1 prior regimen, 44% had 2 prior regimens, 13% had 3 or more prior regimens
      • 33% had received prior EGFR inhibitor
    Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.
  • Sunitinib Phase II Trial in Previously Treated Advanced NSCLC Safety Results
    • Most toxicities were grade 1 or 2
    • 3 hemorrhage-related deaths on study: 2 (a pulmonary hemorrhage and a cerebral hemorrhage) were considered study-drug related
    Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001. % of Patients Severe Events Occurring in  10% of Patients 13 10 14 22 Grade 3 0 Dyspnea 0 Nausea/vomiting 3 Pain/myalgia 5 Fatigue/asthenia Grade 4 Adverse Event
  • Sunitinib Phase II Trial in Previously Treated Advanced NSCLC Efficacy Results Best Response for Target Lesions by Patient 100 80 60 40 20 0 -20 -40 -60 -80 -100 Change from Baseline (%) 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 PFS: 11.3 weeks (95% CI 10.0–15.7)
    • Median OS: 23.9 weeks (95% CI 17.0–28.3)
    16 (25.4) Not evaluable 14 (22.2) PD 27 (42.9) SD 6 (9.5) PR 6 (9.5) 95% CI (3.6–19.6) ORR No. (%) (n = 63) Response
  • Phase II Trial of Sorafenib in Advanced NSCLC
    • Primary objective: tumor response by RECIST of sorafenib 400 mg BID in previously treated pts
    • Eligibility
      • 1–2 prior treatments
      • No prior gefitinib
      • Asymptomatic brain metastases permitted
    • Enrollment
      • 52 patients
      • Median age 62 years (range, 26–85)
      • 85% ECOG PS = 1
      • 54% adenocarcinoma, 31% squamous cell carcinoma
      • 94% stage IV
      • 67% 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.
  • Phase II Trial of Sorafenib in Advanced NSCLC Efficacy Results 60 40 20 0 -20 -40 -60 SD Patients PD Patients Maximum Percentage Reduction of 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 patients
    • Median PFS: 2.7 mo; median OS: 6.7 mo
    • SD patients: median PFS 5.5 mo
    • 2 patients treated for > 2 years with ongoing treatment
    3 (6) Not evaluated* 18 (35) PD 30 (59) SD No. (%) (n = 51) Response
  • Phase II Trial of Sorafenib in Advanced NSCLC Safety and Biomarker Analysis Results
    • Safety
      • No grade 4 events
      • Grade 3 events: hand-foot skin reactions (20%), hypertension (4%), diarrhea (2%), fatigue (2%), headache (2%)
      • 4 patients had sorafenib-related bleeding events (3 epistaxis, 1 fatal pulmonary hemorrhage 30 days after stopping sorafenib)
    • Biomarker analysis
      • Plasma biomarkers evaluated by ELISA
      • High VEGF at baseline correlated with shorter survival ( P < .05)
    Survival Fraction 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.
  • Phase II Trial of Sorafenib in Advanced NSCLC Conclusions
    • Sorafenib has some activity in NSCLC
    • Historical comparisons show that 59% stable disease is in same range as other targeted agents in NSCLC
    • Agent generally well tolerated, with low incidence of bleeding
    • Deterioration of quality of life not seen
    • Shorter median overall survival correlated with high baseline VEGF and greater decreases in plasma VEGF during sorafenib treatment
    • Phase III study of carboplatin/paclitaxel ± sorafenib is currently accruing patients
    Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.
  • Randomized Phase II Trial of Chemotherapy ± Bevacizumab vs Erlotinib + Bevacizumab
    • Phase II, multicenter 3-arm randomized trial
      • Arm 1: chemotherapy (docetaxel or pemetrexed) + placebo
      • Arm 2: chemotherapy (docetaxel or pemetrexed) + bevacizumab
      • Arm 3: erlotinib + bevacizumab
    • Arms 1 and 2 were double-blinded
    • Patients stratified by ECOG performance status and smoking history
    • Eligibility: recurrent unresectable NSCLC
    • Primary endpoint: safety and preliminary efficacy
    Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062.
  • Phase II Chemotherapy ± Bevacizumab vs Erlotinib + Bevacizumab Efficacy *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. 51.3% 52.5% 39.0% CR/PR/SD 17.9% 12.5% 12.2% CR/PR Response rate 78.3% 72.1% 62.4% 6-mo rate Overall survival 0.76 (0.45, 1.28) 0.78 (0.47, 1.30) NA Unadjusted HR (95% CI) 0.72 (0.42,1.23) 0.66 (0.38, 1.16) NA Adjusted HR* (95% CI) 33.6% 30.5% 21.5% 6-mo rate 4.4 4.8 3.0 Median, mo Progression-free survival Erlotinib + Bevacizumab (n = 39) Chemotherapy + Bevacizumab (n = 40) Chemotherapy (n = 41)
  • Phase II Chemotherapy ± Bevacizumab vs Erlotinib + Bevacizumab Safety Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher. Percent of Patients 10 32 22 Anemia 1 3 2 Drug-related deaths 5 20 17 Neutropenia 7 12 12 Fatigue Most common grade 3/4 10 30 24 Neutropenia 82 20 29 Rash/dermatitis/acneform 69 40 17 Diarrhea 41 42 48 Nausea 56 70 66 Fatigue Most common overall Erlotinib + Bevacizumab (n = 39) Chemotherapy + Bevacizumab (n = 40) Chemotherapy (n = 41) Toxicities
  • Phase II Trial of Erlotinib vs Carboplatin/Paclitaxel in NSCLC
    • Primary endpoint: PFS (treatment worthy of further evaluation if PFS  3.5 months)
    • Study design
      • Eligibility: stage IIIB or IV no prior chemotherapy
      • Performance status 2
      • No prior treatment with any EGFR inhibitor; no uncontrolled brain metastases
      • Optional cross-over to erlotinib
    • Enrollment: 103 patients
    • Arms 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.
  • Phase II Trial of Erlotinib vs Carboplatin/ Paclitaxel (CP) in NSCLC Efficacy Results PFS Probability 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) 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. 1 (2) 1 (2) Still on active therapy No. of Pts (%) 6 (12) 1 (2) PR 8 (15) 23 (44) 19 (37) Erlotinib (n = 52) 13 (25) Unable to determine/not evaluated 10 (20) PD 21 (41) SD CP (n = 51) Response
  • Phase II Trial of Erlotinib vs Carboplatin/Paclitaxel in NSCLC Conclusions
    • Single-agent erlotinib treatment did not meet progression-free survival endpoint to warrant further evaluation
    • Results in erlotinib-treated patients who developed grade 2+ rash were “in closer range to chemotherapy”
    • Sample size too small to make significant correlation between biomarkers analyzed and outcome
    • Quality of life parameters similar between 2 treatment arms
    • Development of erlotinib in 1st-line NSCLC centers on
      • Molecular selection of patients
      • Combination with other targeted agents
      • Dosing optimization
    Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.
  • Molecular Predictors of Outcome with Erlotinib in Bronchioloalveolar Cell Carcinoma (BAC)
    • Results of a prospective phase II trial
    • Objective: compare clinical, pathologic, and molecular characteristics of tumor specimens associated with response, PFS, and OS
    • Marker analysis: EGFR (mutations, amplification, polysomy, chromogenic in situ 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 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 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
  • Molecular Predictors of Outcome with Erlotinib in BAC Conclusions
    • Erlotinib resulted in 23% overall response rate (ORR) and 17 mo median overall survival (OS) in BAC
    • Presence of EGFR mutation associated with an 83% ORR, 13 mo progression-free survival (PFS) and 22 mo OS
    • EGFR amplification in BAC rare
    • EGFR polysomy predictive of improvement in PFS
    • KRAS exon 2 mutation associated with no responses and poorer OS
    • Patients with EGFR mutation + CISH  4 had ORR 90%, PFS 15 mo, OS 35 mo
    • Patients with wild type EGFR + CISH < 4 had ORR 4%, PFS 2 mo, OS 15 mo
    Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003.
  • Phase II Trial 1st-Line Erlotinib in Patients with NSCLC and EGFR Mutations
    • Primary endpoint: time to progression
    • Eligibility
      • Stage IIIB/IV NSCLC + mutated EGFR
      • No prior chemotherapy
      • No prior EGFR targeted agents
    Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020. 5.5 20 13.2 CR 67 (41–87) 95 (75–100) 82 (66–92) ORR 0 5 75 Exon 19 (n = 20) 61.1 68.4 PR 5.3 13.2 All (n = 38) 11.1 PD 22.2 SD Exon 21 (n = 18) Response, % (95% CI)
  • Phase II Trial 1st-Line Erlotinib in NSCLC with EGFR Mutations Results
    • Conclusions
    • Most benefit: Exon 19 deletions, patients who never smoked, visceral site other than lung
    • Phase III trial planned (erlotinib vs platinum-based chemotherapy in EGFR-mutated NSCLC)
    Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020. Reprinted with permission from Dr. Paz-Ares. TTP According to Smoking Habits TTP According to Mutational Status Log Rank P =.06 Breslow P =.06 Log Rank P =.12 Breslow P =.02 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 Predictors
  • Randomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLC Part A Results Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale. Primary Endpoint in Part A: Progression-Free Survival Individual Changes in Size of Target Lesions from Baseline: Part A Probability of Remaining 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 Best Confirmed Change from Baseline in Target Lesion Size (%) ZD6474 Gefitinib Final data cut-off, July 2005 No. of Patients (%) Secondary Efficacy Endpoint in Part A 1 (1) 7 (8) Objective response 37 (45) ZD6474 (n = 83) 29 (34) Disease control > 8 wk Gefitinib (n = 85)
  • Randomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLC Part B Results Secondary Endpoint: Overall 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 Probability of Remaining Alive 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.
  • Randomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLC: Adverse Events *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. 0 3 Grade 3, no. 0 2 Grade 3, no. 1 1 Grade 3, no. 1 4 Grade 3, no. 1/0 4/2 Grade 3/4, no. 5% 21% QT-related events 1% 12% Hypertension 9% 14% Dizziness 13% 18% Headache 34% 28% Nausea/vomiting 41% 58% Diarrhea 46% ZD6474 (n = 83) 49% Rash Gefitinib (n = 85) Event*
  • Randomized Phase II Trial of ZD6474 vs Gefitinib in Advanced NSCLC Conclusions
    • Part A met primary endpoint of prolonging progression-free survival (PFS)
      • ZD6474 prolonged PFS by 45% compared with gefitinib
    • PFS prolongation did not result in overall survival advantage in Part B
      • Why? Not clear, maybe optional switchover confounded survival assessment
    • Adverse events (AEs) for both agents mostly mild
    • Slight differences in AE profiles
    Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000.
  • Novel Targeted Agents Under Investigation for Lung Cancer Treatment Highlights of ASCO 2006 CP = carboplatin/paclitaxel. Phase I trial in advanced NSCLC of AZD2171 + CP; manageable toxicities including hypertension; evidence of activity Laurie Abstract 3054 AZD2171 As shown in previous slides, ZD6474 produced longer PFS compared with gefitinib in refractory NSCLC Natale Abstract 7000 ZD6474 ZD6474 + docetaxel is being tested in ongoing double-blind, randomized phase II trial in 2nd-line NSCLC Heymach Abstract 7016 Rizvi Abstract 7105 Jahan Abstract 7081 Nemunaitis Abstract 7018 Blumenschein Abstract 7119 Study Tolerated in mesothelioma Activity: 8.5% PR, 68.1% SD But 3-mo PFS (53.3%) did not met protocol-specified level of 75% Vatalanib Phase I/II trial, 1st-line in advanced NSCLC, MTD reached; ORR 30% and 10.9 mo OS; grade 3 sensory neuropathy and fatigue, minimal myelosuppresion ABI-007 75 patients, safety of optimal dose determined, results suggest greater survival compared with historical controls TGF β AS Vaccine Ongoing phase Ib trial in advanced NSCLC of AMG706 + CP, AMG706 + panitumumab ± CP AMG706 Results Agent
  • Other Searches for Useful Biomarkers in NSCLC—ASCO 2006
    • Mack PC, et al 1
    • Elevated osteopontin plasma levels may have prognostic value in advanced NSCLC
    • Osteopontin is a secreted glycoprotein involved in induction of urokinase (uPA) and increased cell migration
    • Toschi L, et al 2
    • FISH or IHC analysis of samples from 190 consecutive patients treated for advanced NSCLC
    • EGFR, HEr2, and p-Akt status are not predictors of sensitivity to chemotherapy
    • EGFR FISH + and/or HER2 FISH+ patients seemed to benefit more from nonplatinum vs platinum-based combinations (but N small)
    • In EGFR FISH+ patients, RR and TTP after EGFR-TKI used as 2nd-line treatment were at least equal to 1st-line chemotherapy
    • Mack PC, et al. 42nd ASCO, June 2-6, 2006. Abstract 7198.
    • Toschi L, et al. 42nd ASCO, June 2-6, 2006. Abstract 7111.
  • Summary
    • First-generation TKIs (gefitinib, erlotinib) the search continues for
      • Molecular markers for patient selection
      • Optimal combinations
      • Improved dosing
    • Multitargeted TKIs currently on the market (sorafenib, sunitinib)
      • Some promising, but not yet conclusive results
    • Investigational multitargeted TKIs (vatalanib, ZD6474, AMG706, AZ2171)
      • Need data from randomized trials
      • Some differences in adverse event profiles
    • General areas of need
      • Surrogate markers for evaluation of agents
      • Biomarkers for patient selection
      • Optimization of clinical trial design
  • Toxicity Management of Targeted Therapies: Implications for Nursing and Managed Care Michelle Purdom, RN, BSN Manager, Clinical Trials Operations Phase I Program University of Texas M.D. Anderson Cancer Center Houston, Texas
  • Overview
    • Management of side effects associated with targeted therapies
    • Pharmacoeconomics of cancer management and role/implications of targeted therapies in managed care setting
  • Targeted Therapies and Approval Dates * Iressa was approved with contingencies on May 2, 2003. 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
  • Most Common Side Effects Associated with 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     
  • Most Common Side Effects Associated with FDA-Approved Targeted Therapies (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 
  • Management of Bevacizumab-Associated Side Effects 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. Epistaxis usually mild, use standard first aid techniques Patients with recent hemoptysis should not receive B therapy Incidence Gr 3–5 bleeding: B + C 5.2% vs B 3.8% vs C 0.7% Incidence epistaxis (nosebleeds): B + C 35% vs C 10% Hemorrhage Wait for complete healing of surgical incision and at least 28 d after surgery before starting B therapy Incidence: among patients requiring surgery within 60 d of B + C 15% vs C 4% Wound healing or bleeding complications GI perforation AT events Hypertension Side Effect Symptoms: abdominal pain, constipation, vomiting Incidence: B + C 2–4% vs C 0.3% Permanently discontinue treatment Incidence B + C 4.4% vs C 1.9% Standard oral antihypertensives If severe, temporarily suspend treatment If hypertensive crisis, discontinue treatment Monitor BP at least every 2–3 weeks Incidence Gr 3/4: B + C 12% vs C 2% Not infusion related; usually observed during course of treatment Symptoms and Management Scope
  • Blood Pressure Diary Courtesy of Michelle Purdom, RN, BSN
  • Management of Bortezomib-Associated Side Effects Velcade (bortezomib) prescribing information. Most common GI toxicities: nausea, diarrhea, constipation, vomiting, and anorexia Incidence Gr 3 bortezomib 18% vs dexamethasone 6% (Gr 4 rare in both groups) GI toxicities May need to adjust doses of antihypertensive medications Incidence: bortezomib 11% vs dexamethasone 2% Hypotension Asthenia (fatigue, malaise, weakness) Peripheral neuropathy Side Effect Educate patients about caution in operating cars and other machinery because of potential for fatigue, dizziness, syncope, hypotension, diplopia, blurred vision Educate patients about avoiding dehydration and seeking medical advice if experience dizziness, light-headedness, or fainting spells Incidence: bortezomib 61% (Gr 3/4, 12%) vs dexamethasone 45% (Gr 3/4, 6%) Monitor patients for symptoms: burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain New and worsening neuropathy: depending on severity consider recommended changes in dose and schedule Before initiating therapy, carefully consider risk/benefits of bortezomib treatment for patients with pre-existing neuropathy Incidence of new cases: 36% Gr 3, 7% Symptoms and Management Scope
  • Management of Cetuximab-Associated Side Effects www.erbitux.com Dermatologic toxicity Cardiopulmonary arrest Infusion reactions Side Effect Signs: acneform rash, skin drying and fissuring Monitor for development of inflammatory and infectious sequelae; consider topical and/or oral antibiotics Severe acneform rash: institute dose modifications Topical corticosteroids not recommended Incidence in CRC: 89% of all treated patients, severe in 11% Use with caution in patients with coronary heart disease, congestive heart failure, and arrhythmias Closely monitor serum electrolytes (including magnesium, potassium, calcium) during and after cetuximab therapy Incidence of arrest and/or sudden death: cetuximab + radiation therapy 2% vs 0% for radiation therapy Symptoms of severe (potentially fatal) reactions: rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, hypertension, and/or cardiac arrest Symptoms of Gr 1–2 reactions: chills, fever, dyspnea on 1 st day of initial dosing Severe reactions: immediate and permanent cetuximab treatment discontinuation Mild/moderate reactions: slow infusion rate, use antihistamines (eg, diphenhydramine) in subsequent doses Incidence of severe reactions: 2%–4% Incidence of Gr 1–2 reactions: 16%–19% Symptoms and Management Scope
  • Management of Erlotinib-Associated Side Effects www.tarceva.com. Interstitial lung disease (ILD) Diarrhea Rash Side Effect Interrupt treatment for acute onset or progression of unexplained pulmonary symptoms If ILD confirmed, discontinue treatment Educate patients to seek prompt medical attention for onset or worsening of unexplained shortness of breath or cough Overall incidence of ILD-like events: 0.7% Most cases in lung cancer patients associated with confounding factors Educate patients to seek prompt medical attention for severe or persistent diarrhea Usually managed with loperamide Use dose reductions or interruptions in patients who are dehydrated or have unresponsive severe diarrhea Incidence of severe diarrhea: 6% Take erlotinib at the same time each day between meals (one hour before or two hours after eating). Pts with severe skin reactions may need dose reductions or interruptions Overall incidence of rash: erlotinib 75% vs placebo 17% Incidence of Gr 3 rash with erlotinib: 8% Symptoms and Management Scope
  • Management of Gefitinib-Associated Side Effects www.iressa.com Most common gefitinib-associated adverse events: diarrhea, rash, acne, dry skin, nausea, vomiting Eye toxicity Interstitial lung disease (ILD) Side Effect Consider therapy interruption until symptoms resolved and removal of aberrant eyelash (if present) Low incidence of eye pain and corneal erosion/ulcer, sometimes with aberrant eyelash growth Symptoms: acute onset of dyspnea, sometimes with cough or low-grade fever, often quickly worsening and requiring hospitalization Interrupt treatment in patients with acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) Discontinue gefitinib treatment if ILD confirmed Overall incidence: 1% of gefitinib-treated patients (1/3 of these cases were fatal) Symptoms and Management Scope
  • Example of Typical Rash Induced by EGFR Inhibitors Courtesy of Michelle Purdom, RN, BSN
  • EGFR Rash Courtesy of Michelle Purdom, RN, BSN
  • Management of Sunitinib-Associated Side Effects www.sutent.com Supportive care with antiemetic or antidiarrhea medications Most common: diarrhea, nausea, stomatitis, dyspepsia, vomiting GI events Advise patients of potential occurrence Other possible dermatologic effects: dryness, thickness or cracking of skin, blister or rash on palms of hand and soles of feet Skin discoloration: occurs in 1/3 of pts Attributed to yellow drug color Skin toxicity Hypertension Hemorrhage Left ventricular dysfunction Side Effect Monitor and treat with standard hypertensive If severe, suspend sunitinib treatment until hypertension is controlled Incidence: sunitinib 15% (Gr 3, 4%) vs placebo 11% (Gr 3, 0) No Gr 4 Epistaxis most common hemorrhagic adverse event Incidence of bleeding: sunitinib 18% vs placebo 17% Fatal pulmonary hemorrhage occurred in 2 patients in a sunitinib NSCLC clinical trial Some patients recovered without intervention Possible interventions: dose reduction, use of antihypertensive or diuretic Carefully monitor patients for signs and symptoms of congestive heart failure Incidence: sunitinib 11% vs placebo 3% Symptoms and Management Scope
  • Management of Sorafenib-Associated Side Effects www. nexavar.com Consider temporary or permanent treatment discontinuation Incidence: sorafenib 2.9% vs placebo 0.4% Cardiac ischemia and/or infarction Hemorrhage Hypertension Dermatologic Side Effect If bleeding necessitates medical intervention, consider permanently discontinuing sorafenib Incidence: sorafenib 15.3% (Gr 3, 2%; no Gr 4) vs placebo 8.2% (Gr 3, 1.3%; Gr 4 0.2%) BP should be monitored weekly for 1 st 6 weeks of sorafenib therapy Manage with standard antihypertensive therapy Temporary treatment interruption or dose modifications Treatment discontinuation rare Incidence: sorafenib 16.9% vs placebo 1.8% Usually mild to moderate and occurs early in treatment Topical therapies for symptomatic relief Temporary treatment interruption or dose modifications Severe or persistent cases may require treatment discontinuation Hand-foot skin reaction (35%) and rash (38%) most common adverse event Usually Gr 1-2, appear during 1 st 6 weeks of treatment Symptoms and Management Scope
  • Pharmacoeconomics of Cancer Management and Role/Implications of Targeted Therapies in Managed Care Setting Cohen M, et al. Am J Manag Care . 2006;12:524.
  • Targeted Therapies and Managed Care
    • New therapies need evidence of effectiveness and safety
    • Impact on quality of life
    • Net impact on total cost of care
    • Concept of value differs among patients, providers, health plans, and employers
    Cohen M, et al. Am J Manag Care . 2006;12:524.
  • Biotechnology 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
  • Growth Drivers for Biologics
    • Key contributors from managed care perspective include
    • Increased availability of targets for biologic agents
    • Increased use of approved drugs
    • Increased approval of biotechnology drugs for more common conditions
    • Expanded indications for approved drugs
    Cohen M, et al. Am J Manag Care . 2006;12:524-537. Reprinted with permission.
  • Reasons for Off-Label Use of Biologics
    • Small population size and/or assessed cost of clinical trials may discourage marketers from seeking formal FDA approval
    • Potential of newer therapies for better efficacy and outcomes
    • Proven safety and efficacy in other disease states
    • Potential for increased quality of life
    • Thought leader advocacy/patient demand
    • Better understanding of disease pathways, particularly immune-modulating diseases
    Cohen M, et al. Am J Manag Care . 2006;12:524-537. Reprinted with permission.
  • Managed Care’s Concerns Regarding Off-Label Use of Biologics
    • Safety/efficacy questions
    • Differing dosing and administration
    • Potential for inappropriate care
    • Potential for cost increase
    • Paucity of data
    • Lack of uniform guidelines/best practices
    • Legal/ethical issues
    Cohen M, et al. Am J Manag Care . 2006;12:524-537. Reprinted with permission.
  • Recommendations for Managing Expanded Indications
    • Scan the pipeline to become aware of impending drug launches
    • Increase education for P&T committees
    • Define a process and clear criteria
    • Develop and/or augment treatment guidelines for expanded indications
    • Increase case management/disease management
    • Strive for innovative management strategies that contain cost and maintain access
    Cohen M, et al. Am J Manag Care . 2006;12:524.
  • Continued Challenges for Managed Care Organizations
    • Expanding indications for FDA-approved drugs present unique challenges for MCOs.
      • This translates into added expenditures for MCOs because of increased frequency of administration and/or longer duration of therapy
      • For patients, may result in higher copays and more restrictive access management strategies, particularly the use of prior authorization
    • Maintain focus on potential of agents for reduction in disease progression and disability rather than solely on patient copays and aggressive management strategies
      • Shift focus on cost to clinical decision making through evidence-based medicine
    • Adequately plan for agents with multiple indications
      • Need more definitive criteria for evaluating expanded indications and potential for cost savings
    Cohen M, et al. Am J Manag Care . 2006;12:524.
  • Nursing Implications
    • The nurse should help the patient understand importance of prior insurance authorization due to the high cost of biopharmaceuticals
    • The nurse should assist the patient as a liaison with the hospital business office/MCO by initiating the process early and often
    • Emotional support
  • Summary
    • Expanding indications and off-label applications of FDA-approved targeted therapies present unique challenges
      • MCOs face added expenses
      • Patients face higher co-pays and more restrictive access
      • Clinicians need to expand their knowledge base and skill sets
    • Nurses have an important role in providing
      • Professional care
      • Toxicity management and side effect education
      • Assistance in navigating the preauthorization process
      • Emotional support
  • Keeping Pace with Targeted Therapies in Lung Cancer Highlights from the ASCO 2006 Annual Meeting