New Oncology Drugs 2004: A Year in Review. Susannah E. Koontz, Pharm.D., BCOP Clinical Practice Specialist Pediatrics M.D. Anderson Cancer Center

Transcription

1 New Oncology Drugs 2004: A Year in Review Susannah E. Koontz, Pharm.D., BCOP Clinical Practice Specialist Pediatrics M.D. Anderson Cancer Center The following material was presented to members of the Department of Pediatrics at the Children s Cancer Hospital at M. D. Anderson Cancer Center as part of their Oncology Grand Rounds Series, November 29,

2 Objectives 1. Identify drugs that earned FDA approval for oncology indications in With respect to each drug mentioned, be able to describe their respective mechanism(s) of action, approved use(s), dosing strategies and common side effects. Drugs Alimta (Pemetrexed) Erbitux TM (Cetuximab) Avastin TM (Bevacizumab) Vidaza TM (Azacitadine) Tarceva TM (Erlotinib) 2

3 Alimta (Pemetrexed) February 2, 2004 Eli Lily and Company Alimta (Pemetrexed) 1st drug approved in the United States for the treatment of malignant pleural mesothelioma (in combination with cisplatin) whose disease is not resectable or when patients are not candidates for curative surgery 3

4 Alimta (Pemetrexed) Alimta (Pemetrexed) Antifolate/Folic acid antagonist Somewhat similar to methotrexate Disrupts folate-dependent metabolic processes necessary for cellular replication by enzyme inhibition: Thymidylate synthetase (TS) Dihydrofolate reductase (DHFR) Glycinamide ribonucleotide formyltransferase (GARFT) 4

5 Alimta (Pemetrexed) Alimta (Pemetrexed) Pivotal trial Multicenter, randomized, single-blind Phase III study 448 chemotherapy-naïve patients Pemetrexed + cisplatin vs. cisplatin alone Pemetrexed 500 mg/m 2 IV on Day 1 Cisplatin 75 mg/m 2 IV on Day 1 Regimen repeated every 21 days 5

6 Alimta (Pemetrexed) Trial modified to include vitamin supplementation Folic acid mcg PO Daily Vitamin B mcg IM 1-3 weeks before chemo and then Q 9 weeks during chemo) Increased toxicity seen in patients with reduced stores Alimta (Pemetrexed) Pemetrexed + Cisplatin Pemetrexed + Cis + Vit Suppl* Cisplatin alone Cisplatin alone + Vit Suppl* Response rate (%) (all PR) 41 a 45 a Median survival time (months) (primary study endpoint) 12.1 b 13.3 c year survival rate (%) 50.3 d 56.5 e Median time to progression (months) 5.7 f 6.1 g Vit Suppl = Vitamin Supplementation *Among 331 patients receiving vitamin supplementation (folic acid 350 to 1000 mcg orally daily and vitamin B mcg intramuscularly every 9 weeks) a p<0.001 vs cisplatin alone groups b Hazard ratio 0.77, p=0.020 vs. cisplatin alone c Hazard ratio 0.75, p=0.51 vs. cisplatin alone + vit suppl d p=0.012 vs. cisplatin alone e p=0.011 vs. cisplatin + vit suppl f Hazard ratio 0.68, p=0.001 vs. cisplatin alone ghazard ratio 0.64, p=

7 Alimta (Pemetrexed) Alimta (Pemetrexed) Myelosuppression Fatigue Fever Rash Stomatitis Pharyngitis Nausea Anorexia Vomiting Infection Increase in liver function tests 7

8 Alimta (Pemetrexed) Not extensively metabolized Cleared by the kidneys Interaction with NSAIDs Teratogencity (Category D) Alimta (Pemetrexed) Non-Small Cell Lung Cancer (NSCLC) As a single-agent for the treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy Effectiveness based on the surrogate endpoints and response rate No controlled trials demonstrating a clinical benefit (e.g., favorable survival effect or improvement of disease-related symptoms) 8

9 Alimta (Pemetrexed) MPM (in combination with cisplatin) 500 mg/m 2 IV over 10 minutes on Day 1 given every 21 days Vitamin supplementation NSCLC (single agent) 500 mg/m 2 IV over 10 minutes on Day 1 given every 21 days 500 mg vials Alimta (Pemetrexed) Hanauske A-R, Chen V, Paoletti P, Niyikiza C. Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors. The Oncologist. 2001;6: Gralla RJ, Hollen PJ, Liepa AM, et al. Improving quality of life in patients with malignant pleural mesothelioma: results of the randomized pemetrexed + cisplatin vs cisplatin trial using the LCSS-meso instrument. Proc Am Soc Clin Oncol. 2003;22:621. Abstract Khalil MY, Mapa M, Shin HJ, Shin DM. Advances in the management of malignant mesothelioma. Curr Oncol Rep. 2003;5: Manegold C, Symanowski J, Gatzemeier U, et al. Secondary (post-study) chemotherapy in the phase III study of pemetrexed + cisplatin vs. cisplatin in malignant pleural mesothelioma is associated with longer survival. Proc Am Soc Clin Oncol. 2003;22:667. Abstract Vogelzang NJ, Rusthoven J, Paoletti P, et al. Phase III single-blinded study of pemetrexed + cisplatin vs. cisplatin alone in chemonaive patients with malignant pleural mesothelioma. Proc Am Soc Clin Oncol. 2002;21:6a. Abstract 5. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetazel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:

10 Erbitux TM (Cetuximab) February 12, 2004 Imclone Systems, Inc. Erbitux TM (Cetuximab) Indicated in use with irinotecan for metastatic colorectal cancer that expresses epidermal growth factor receptor (EGFR) and that is resistant to irinotecan As a single agent in patients with metastatic colorectal cancer that are intolerant to irinotecan-based chemotherapy and who express EGFR 10

11 Erbitux TM (Cetuximab) Anti-Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody Erbitux TM (Cetuximab) 11

12 Erbitux TM (Cetuximab) Erbitux TM (Cetuximab) 12

13 Erbitux TM (Cetuximab) 3 clinical trials Biologic License Application Randomized, controlled trial with 329 patients 2:1 ratio of Erbitux + irinotecan (66% male; median 71 yrs) Erbitux alone (59% male; median 70 yrs) Erbitux 400 mg/m 2 IV followed by 250 mg/m 2 IV weekly; Irinotecan at same dose Erbitux TM (Cetuximab) Licensure Trial Median duration of response in the overall population was 5.7 months with Erbitux + irinotecan versus 4.2 months with Erbitux alone. Paitents randomized to Erbitux + irinotecan demonstrated a significantly longer median time to disease progression compared with Erbitux alone. 13

14 Erbitux TM (Cetuximab) Infusion related reactions Skin toxicity (rash, acne, dry skin, etc.) GI toxicity (diarrhea, nausea, vomiting) Malaise Fever Erbitux TM (Cetuximab) No known contraindications No known drug interactions 14

15 Erbitux TM (Cetuximab) Metastatic colorectal cancer (+/- irinotecan) Load: 400 mg/m 2 IV over 2 hours week 1 Maint: 250 mg/m 2 IV over 1 hour weekly Premedication with diphenhydramine 100 mg vials Erbitux TM (Cetuximab) Herbst RS, Hong WK. IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody for treatment of head and neck cancer. Semin Oncol 2002 Oct;29(5 Suppl 14):18-30 Herbst RS, Kim ES, Harari PM. IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody, for treatment of head and neck cancer. Expert Opin Biol Ther 2001 Jul;1(4): Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMC- C225). Curr Opin Oncol 2001 Nov;13(6): Sclabas GM, Fujioka S, Schmidt C, Fan Z, Evans DB, Chiao PJ. Restoring Apoptosis in Pancreatic Cancer Cells by Targeting the Nuclear Factor-kappaB Signaling Pathway With the Anti-Epidermal Growth Factor Antibody IMC-C225. J Gastrointest Surg 2003 Jan;7(1):

16 Avastin TM (Bevacizumab) February 26, 2004 Genentech, Inc. Avastin TM (Bevacizumab) Approved in combination with IV 5- fluorouracil-based chemotherapy for the treatment of previously untreated metastatic colorectal cancer Angiogenesis inhibitor Binds vascular endothelial growth factor (VEGF) Inhibits binding of VGEF to its receptors (Flt-1 and KDR) on the surface of endothelial cells 16

17 Avastin TM (Bevacizumab) Avastin TM (Bevacizumab) Pivotal Trial (Phase III) Randomized, controlled, double-blind 923 patients with previously untreated metastatic colorectal cancer 17

18 Avastin TM (Bevacizumab) Avastin TM (Bevacizumab) 18

19 Avastin TM (Bevacizumab) Avastin TM (Bevacizumab) 19

20 Avastin TM (Bevacizumab) Avastin TM (Bevacizumab) Serious toxicities GI perforation Wound healing complication Hemorrhage Hypertensive crisis Nephrotic syndrome Congestive heart failure 20

21 Avastin TM (Bevacizumab) Other side effects Nausea Vomiting Diarrhea Constipation Pain Headache Abdominal Pain Hypertension Anorexia Stomatitis URI Epistaxis Dyspnea Asthenia Exfoliative dermatitis Leukopenia Avastin TM (Bevacizumab) Metastaic Colorectal Cancer 5 mg/kg IV every 14 days over 90 minutes (2 nd dose over 60 minutes and subsequent doses over 30 minutes if well tolerated) 100 mg and 400 mg vials 21

22 Avastin TM (Bevacizumab) Hurwitz H, Novotny W, Cartwright T et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350: Folprecht G, Kohne CH.The role of new agents in the treatment of colorectal cancer. Oncology. 2004;66(1):1-17 Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57: Salgaller ML Technology evaluation: bevacizumab, Genentech/Roche. Curr Opin Mol Ther Dec;5(6): Vidaza TM (Azacitadine) May 19, 2004 Pharmion Corporation 22

23 Vidaza TM (Azacitadine) 1 st drug approved in the US for the treatment of myelodysplastic syndrome (MDS) Antimetabolite Pyrimidine nucleoside analog (Cytosine) Vidaza TM (Azacitadine) 23

24 Vidaza TM (Azacitadine) Dual mechanism of action Hypomethylation of DNA restores normal gene function to those genes responsible for cellular division and differentiation (DNA methyltransferase can not work adequately) Apoptosis to rapidly dividing cells Vidaza TM (Azacitadine) Pivotal trial was CALGB 9221 Randomized, open-label, controlled 191 patients were enrolled; 172 evaluable patients All FAB MDS Subtypes were included Vidaza + supportive care (99 patients) vs. supportive care alone (92 patients) 55% crossover 24

25 Vidaza TM (Azacitadine) 132 males (69%) and 59 females Median age 68 years (Range 31-92) 75 mg/m 2 SQ daily for 7 days every 4 weeks Dosed increased to 100 mg/m 2 if no response seen after 2 cycles Vidaza TM (Azacitadine) Gender (n%) Male Female Race (n%) White Black Hispanic Asian/Oriental Age (years) N Mean ± SD Range Adjudicated MDS diagnosis at study entry (n%) RA RARS RAEB RAEB-T CMMoL AML Transfusion product used in 3 months before study entry (n%) Any transfusion product Blood cells, packed human Platelets, human blood Hetastarch Plasma protein fraction Other VIDAZA (N=99) 72 (72.7) 27 (27.3) 93 (93.9) 1 (1.0) 3 (3.0) 2 (2.0) ± (21.2) 6 (6.1) 38 (38.4) 16 (16.2) 8 (8.1) 10 (10.1) 70 (70.7) 66 (66.7) 15 (15.2) 0 (0.0) 1 (1.0) 2 (2.0) Observation (N=92) 60 (65.2) 32 (34.8) 85 (92.4) 1 (1.1) 5 (5.4) 1 (1.1) ± (19.6) 5 (5.4) 39 (42.4) 14 (15.2) 7 (7.6) 9 (9.8) 59 (64.1) 55 (59.8) 12 (13.0) 1 (1.1) 0 (0.0) 2 (2.2) 25

26 Vidaza TM (Azacitadine) RA RARS RAEB RAEB-T CMMoL Complete Response (CR), duration 4 weeks Marrow Peripheral Blood < 5% blasts Normal CBC if abnormal at baseline Absence of blasts in the peripheral circulation Partial Response (PR), duration 4 weeks Marrow No marrow requirements 50% decrease in blasts Improvement of marrow dyspoiesis Peripheral Blood 50% restoration in the deficit from normal levels of baseline white cells, hemoglobin and platelets if abnormal at baseline No blasts in the peripheral circulation For CMMoL, if WBC is elevated at baseline, a 75% reduction in the excess count over the upper limit of normal Vidaza TM (Azacitadine) VIDAZA (N=89) Observation Before Crossover (N=83) Response Overall (CR+PR) Complete (CR) Partial (PR) n (%) 14 (15.7) 5 (5.6) 9 (10.1) n (%) 0 (0.0) 0 (0.0) 0 (0.0) P value (<0.0001) (0.06) -- 26

27 Vidaza TM (Azacitadine) Decrease in BM blast percentage Increase in platelets, Hgb or WBC >90% of responders showed a change in parameters by the 5 th cycle Transfusion dependent transfusion independent during CR or PR Vidaza TM (Azacitadine) Thrombocytopenia Neutropenia Anemia Leukopenia Nausea Anorexia Vomiting Diarrhea Arthalgia Fatigue Fever Ecchymosis Injection site reactions (pain, erythema) 27

28 Vidaza TM (Azacitadine) Potentially hepatotoxic Excreted by the kidneys Teratogencity (Category D) Vidaza TM (Azacitadine) All forms of MDS 75 mg/m 2 SQ daily for 7 days every 4 weeks Increase dose to 100 mg/m 2 if no response after 2 cycles Treatment for minimum of 4 cycles 100 mg vials 28

29 Vidaza TM (Azacitadine) Suwanawiboon B, Sumida KN. 5-azacitidine: An alternative treatment of myelodysplastic syndromes in patient with refractory response to hematopoietic growth factor, a case report and review of literatures. Hawaii Medical Journal Jan;63(1):14-6, 25. Leone G, Voso MT, Teofili L, Lubbert M. Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clinical Immunologly Oct;109(1): Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. Journal of Clinical Oncology May 15;20(10): Tarceva TM (Erlotinib) November 18, 2004 OSI Pharmaceuticals, Inc. 29

30 Tarceva TM (Erlotinib) Approved for treatment of patients with locally advanced or metastatic Non- Small Cell Lung Cancer (NSCLC) after having failed at least one chemotherapy regimen Tarceva TM (Erlotinib) 30

31 Tarceva TM (Erlotinib) Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) which inhibits ligand-induced phosphorylation Inhibition of tumor cell growth Induction of apoptosis Decreased EGFR production Tarceva TM (Erlotinib) 31

32 Tarceva TM (Erlotinib) Pivotal trial Randomized, Double-Blind, Placebo- Controlled 731 patients 2/3 male 50% had only 1 prior course of chemo 2:1 ratio: Erlotinib 150 mg PO daily Placebo Tarceva TM (Erlotinib) 32

33 Tarceva TM (Erlotinib) Tarceva TM (Erlotinib) Results from 2 multi-center, placebocontrolled trials in more than 1000 patients conducted in first line therapies showed no clinical benefit when erlotinib was combined with a platinumbased regimen (carboplatin and paclitaxel OR cisplatin and gemcitabine) 33

34 Tarceva TM (Erlotinib) Side effects: rash and diarrhea Metabolism is mediated by P450 CYP3A4 and excreted in bile Inhibitors: azoles, erythromycins, verapamil, diltiazem, grapefruit juice Inducers: rifampin, phenytaoin, carbamazepine, phenobarbital Pregnancy category D Tarceva TM (Erlotinib) NSCLC 150 mg PO Daily 1 hour prior to or 2 hours following ingestion of food 25 mg, 100 mg and 150 mg tablets 34

35 Tarceva TM (Erlotinib) Shepherd FA, Pereira J, Ciuleanu TE, et al. A randomized placebocontrolled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial [abstract]. Proc Am Soc Clin Oncol. 2004;23:abstract 7022 Herbst RS, Prager D, Hermann R, et al. TRIBUTE a phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC) [abstract]. Proc Am Soc Clin Oncol. 2004;23:abstract Gatzemeier U, Pluzanska A, Szczesna A, et al. Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC) [abstract]. Proc Am Soc Clin Oncol. 2004;23:abstract Bonomi P. Erlotinib: a new therapeutic approach for non-small cell lung cancer. Expert Opin Investig Drugs. 2003;12: