MULTI TARGETED ANTIFOLATE

Transcription

1 INNOVAZIONI TERAPEUTICHE IN ONCOLOGIA MEDICA CAGLIARI GIUGNO 2005 Policlinico Universitario - Cagliari MULTI TARGETED ANTIFOLATE Elena Massa CATTEDRA DI ONCOLOGIA MEDICA UNIVERSITA DEGLI STUDI DI CAGLIARI 1

2 Chemical Structure of ALIMTA (pemetrexed disodium, LY231514) H 2 N HN O N N H N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7Hpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-Lglutamic acid ALIMTA O O N H OH OH O O OH O N H O O OH HN Lometrexol H 2 N N N H O O N H NH N O HO 2 N OH N H N N N 2 Methotrexate OH H O N O N S O HN O OH N Raltitrexed COOH O HN NH NH NH O NH 2 N NH COOH TH-FA Taylor et al., J Med Chem 35: ,

3 ALIMTA: Key Intracellular Enzyme Targets ALIMTA dump TS dtmp 5-FU, Raltitrexed DNA PRPP 10-CHO CHO-THF GARFT 5,10-CH2 CH2-THF DHFR DHF NADPH Methotrexate GAR THF NADP+ fgar AMP, GMP DNA, RNA TS: thymidylate synthase DHFR: dihydrofolate reductase GARFT: glycinamide ribonucleotide formyltransferase

4 ALIMTA vs Other Antimetabolites like 5- FU/Leucovorin like Raltitrexed ALIMTA inhibits TS ALIMTA inhibits like Methotrexate ALIMTA inhibits DHFR unlike any other marketed drug ALIMTA inhibits GARFT ALIMTA inhibits PYRIMYDINE SYNTHESIS ALIMTA inhibits DNA PURINE SYNTHESIS ALIMTA inhibits DNA, RNA biosynthesis 4

5 ALIMTA: Preclinical activity Additive Synergistic additive Synergistic Vinorelbine Doxorubicin Cyclophosphamide RT (sequential) Gemcitabine Cisplatin Carboplatin Oxaliplatin Taxotere 5-FU Paclitaxel RT (concurrent) 5 Hanauske et al. The Oncologist 2001;6:

6 Toxicity Before and After Addition of FA and B 12 ALIMTA Studies Follow-up safety data from studies... to 12 to Before FA restoration After FA restoration Death rate 8.3% 1.4% (n=36) (n=148) Any grade 4 hem toxicity grade 3/4 Nonhem tox 4.2% (all studies; n=1169) 22% (n=394) 1.4% (all studies; n=504) 11% (n=196) 6

7 Folic Acid/Vitamin B 12 Supplementation Rationale Folic acid is a supplement in cereal products in the US to reduce the incidence of neural tube defects. Plasma homocysteine concentration is a sensitive marker of folate and vitamin B 12 status. Plasma homocysteine concentrations are associated with an increased risk of coronary artery disease and cerebral vascular mortality. Folic acid supplementation reduces toxicity without affecting efficacy in patients receiving low-dose methotrexate for rheumatoid arthritis and with B 12 /B 6, reduces the rate of coronary restenosis. 7

8 Vitamin Supplementation Intervention Folic Acid: Vitamin B 12 : µg orally daily beginning 1-2 weeks prior to first dose of ALIMTA and continuing while the patient remains on study 1000 µg im prior to the first dose of ALIMTA and repeated every 3 cycles while the patient remains on study Bunn, et al. Proc Amer Soc Clin Oncol 76a: (abstr 300)

9 ALIMTA SAFETY SUMMARY Folic acid and vitamin B 12 supplementation results in a dramatic reduction in drug-related death. Folic acid and vitamin B 12 supplementation significantly reduces the number of episodes of grade 4 hematologic or grade 3/4 nonhematologic toxicity associated with ALIMTA. The improved safety profile of ALIMTA may be attributed to the decrease in Hcys levels achieved through folic acid and vitamin B 12 supplementation. While folic acid and vitamin B 12 supplementation has significantly reduced Hcy levels in all patients, the effect appears to be more pronounced in patients whose baseline Hcys 12 µmol. Patients with baseline Hcys 12 µmol benefit more from the FA and vitamin B 12 supplementation. Bunn P, et al. Proceedings of ASCO 2001: 76a:A300 9

10 Phase I Trials of ALIMTA Single-Agent Schedule Dose MTD DL Effects Responses (mg/m 2 ) (mg/m 2 ) Wkly x 4 q 6 wks neuts 2MR q 3 Wkly Daily x 5 q 3 wks neuts 4PR, 6MR neuts 2MR 600/500 mg/m 2 administered as a 10-minute IV infusion once every 21 days schedule taken into Phase II trials Rinaldi D et al. JCO 13: , 1995 Rinaldi D et al. Cancer Chemother Pharmacol 44(5): , 1999 McDonald AC et al.clin Cancer Res 4(3): ,

11 Phase I ALIMTA Combination Studies Completed Ongoing ALIMTA + Cisplatin* ALIMTA + Carboplatin* ALIMTA + Oxaliplatin* ALIMTA + GEMZAR* ALIMTA + Vinorelbine ALIMTA + Paclitaxel ALIMTA + Docetaxel ALIMTA + Irinotecan ALIMTA + Cyclophosphamide ALIMTA + Radiation ALIMTA + Epirubicin *Studies completed prior to folic acid/b 12 supplementation 11

12 ALIMTA ACTIVITY IN PLEURAL MESOTHELIOMA

13 ALIMTA in Mesothelioma Phase I Phase II No of trials 2 1 Regimen ALIMTA- Cisplatin ALIMTA -Carboplatin ALIMTA Sigle agent Status Thödtmann, JCO Huges, JCO Shin ASCO Phase III 2 ALIMTA Cisplatin vs Cisplatin ALIMTA vs BSC Vogelzang JCO ongoing 13

14 Phase III, Single-Blinded Trial of ALIMTA (pemetrexed)) and Cisplatin versus Cisplatin Alone in Chemonaive Patients with Malignant Pleural Mesothelioma Nicholas Vogelzang, et al. J Clin Oncol 2003; 21:

15 Initial Study Design Stratified by: PS, histology, gender, WBC, disease measurability baseline homocysteine,, R A N D O M IZ E ALIMTA 500 mg/m 2 + Cisplatin 75 mg/m 2 (n=140) Cisplatin 75 mg/m2 (n=140) Statistical Plan Phase III single-blinded trial Primary endpoint: survival 80% power to detect hazard ratio of.67 (based on α = 0.05 level, two-sided logrank test) 15

16 Final Study Design R A N D O M IZ 58 pts No FA/B 12 ALIMTA + Cisplatin 168 pts FA/B pts E 59 pts 163 pts 222 pts Cisplatin Final Analysis Primary endpoint: survival 16 Nicholas Vogelzang, et al. J Clin Oncol 2003; 21:

17 Survival: All Eligible Patients 100 ALIMTA + Cisplatin (n=226) Cisplatin (n=222) % Alive MST = 9.3 mos HR 0.77 Logrank p-value MST = 12.1 mos Months 17 Method: Kaplan-Meier

18 Survival: Fully Supplemented Patients 100 ALIMTA + Cisplatin (n=168) Cisplatin (n=163) % Alive MST = 10.0 mos HR 0.75 Logrank p-value MST = 13.3 mos Months 18

19 TTPD: All Eligible Patients 100 ALIMTA + Cisplatin (n=226) Cisplatin (n=222) % Progression HR 0.68 Logrank p-value MTPD = 5.7 mos 0 MTPD = 3.9 mos Months 19 Method: Kaplan-Meier

20 TTPD: Fully Supplemented Patients 100 ALIMTA + Cisplatin (n=168) Cisplatin (n=163) % Progression MTPD = 6.1 mos HR 0.64 Logrank p-value MTPD = 3.9 mos Months 20

21 Patient Treated with ALIMTA + Cisplatin Baseline Visit 4 21

22 Tumor Response Rates % p < (CI 35-48) p < (CI 38-53) ALIMTA/Cis Cis p = (CI 18-43) (CI 12-22) 20 (CI 14-27) 10 8 (CI 3-19) 0 n=225 n=222 n=167 n=163 n=58 n=59 All Eligible FA/B 12 Partially and no FA/B 12 22

23 Selected Grade 3/4 Toxicity (%) All Patients NO FA/B 12 FA/B 12 Possible DRD Alimta/Cis No=226 4 Cis No=222 2 Alimta/Cis No=58 7 Cis No=59 3 Alimta/Cis No=58 3 Cis No=59 2 Neutropenia Platelets Febr. Neut Vomiting Stomatitis Diarrhea

24 Lung Function (Vital Capacity) by Treatment Arm ALIMTA/Cis Cis p =0.324 p =0.034 p = VC (L) Cycle 24

25 Lung Cancer Symptom Scale: Dyspnea Worse 40 ALIMTA/Cis Cis p = p =0.476 p =0.344 mm 30 Better Cycle 25

26 Conclusions (1) ALIMTA and cisplatin significantly improved survival compared to cisplatin alone ALIMTA and cisplatin also significantly improved: Time to progressive disease Tumor response rate Lung function Subjective indicators of quality of life 26

27 Conclusions (2) Following the sequential, non-random addition of folic acid and B 12 : The improved efficacy of ALIMTA and cisplatin over cisplatin was maintained There was strong evidence of reduction in toxicity (including drug related deaths) Improved efficacy in FA/B 12 supplemented patients may be due to the higher median number of cycles delivered 27

28 Conclusions (3) ALIMTA and cisplatin with FA/B 12 should now be considered standard front-line therapy for patients with malignant pleural mesothelioma 28

29 ALIMTA in NSCLC Single Agent Studies Two trials in previously untreated patients Rusthoven et al, (NCIC), J Clin Oncol, 1999 Clarke et al, (S.Africa/Australia), Ann Oncol 9:86, 1998 One trial in patients with one previous CT regimen Postmus et al, Eur J Cancer, 35:249, 1999 No vitamin supplementation administered in these studies 29

30 ALIMTA Single Agent in NSCLC Response Rusthoven Clarke Postmus CDDP n/cddp Evaluable CR PR Overall RR 23.3% 14% 5% 14% Med Surv 9.2m 7.2m 6.4m 4m No vitamin supplementation administered in these studies Rusthoven et al, (NCIC), J Clin Oncol,1999 Clarke et al, (S.Africa/Australia),Ann Oncol,1998; Data on file, 2001 Postmus et al, Eur J Cancer, 35:249,

31 Phase II ALIMTA in NSCLC Combination Studies with Cisplatin Two Phase II combination trials in untreated NSCLC Shepherd et al, Cancer, 92(3): , 2001 Manegold et al, Ann Oncol, 11(4):435, 2000 No vitamin supplementation administered in these studies 31

32 Phase II ALIMTA + Cisplatin in NSCLC Study Design Treatment and Eligibility (both trials) ALIMTA 500 mg/m2 Cisplatin 75mg/m2 D1 Q21 days No prior Chemotherapy Stage IIIB/IV PS 0,1 and 2 Measurable disease Manegold, et al. Ann Oncol 11(4):435-40, Shepherd, et al. Cancer, 92(3): ,

33 Phase II ALIMTA + Cisplatin in NSCLC Results Shepherd Manegold N Evaluable PR SD RR 44.8% 38.9% Med Surv 8.9 mo 10.9 mo 1-year Surv 49% 50% No vitamin supplementation administered in these studies Shepherd, et al. Cancer, 92(3): , Manegold, et al. Ann Oncol 11(4):435-40,

34 Randomized Phase III Trial of ALIMTA (Pemetrexed( Pemetrexed) ) vs. Docetaxel in Patients with Locally Advanced or Metastatic NSCLC Previously Treated with Chemotherapy Nasser Hanna, Frances Shepherd, Rafael Rosell, Jose Pereira, Filippo DeMarinis, Frank Fossella, Louis Kayitalire, Sofia Paul, Lawrence Einhorn, Paul Bunn Hanna N et al JCO 22: , 1597, 2004

35 Background Lung cancer is the leading cause of cancer-related death worldwide 1 st -line chemotherapy offers a modest survival advantage over best supportive care (BSC) Phase III studies have demonstrated docetaxel improves 1 year survival by ~10-15% compared to BSC, ifosfamide or vinorelbine in the 2 nd- line setting 1,2 ALIMTA, a novel multi-targeted antifolate, shows activity as a single-agent in 1 st -line and 2 nd- line NSCLC 1 Fossella et. al., JCO 18(12): , Shepherd et al., JCO 18(10): ,

36 A Phase III Study of ALIMTA vs. Docetaxel in 2 nd -line NSCLC Primary Endpoint Survival Secondary Endpoints Tumor Response Rate Progression-free Survival Toxicity Hanna N et al JCO 22: , 1597,

37 Inclusion Inclusion/Exclusion Criteria Histological/cytological NSCLC Stage III or IV NSCLC Previously treated with only 1 regimen for metastatic disease ECOG PS 0-2 Adequate end organ function Exclusion Symptomatic brain metastasis Grade 3 or 4 peripheral neuropathy Weight loss > 10% over previous 6 weeks Uncontrolled pleural effusions 37

38 ALIMTA vs. Docetaxel in 2 nd -line NSCLC Stratified by: ECOG PS 0/1 vs. 2 Stage III vs. IV # of prior chemo Best response to prior chemo Time since last chemo Prior platinum Prior taxane Homocysteine level Center R A N D O M IZ E D ALIMTA 500 mg/m 2 i.v. q3wks (n=283) (folic acid 350-1,000 µg daily + vitamin B 12 1,000 µg q 9wks; dexamethasone 4mg bid on d-1,d0,d+1) Docetaxel 75 mg/m 2 i.v. q3wks (n=288) (dexamethasone 8 mg bid on d-1,d0,d+1) 38

39 Patient Characteristics (n=571) ALIMTA (n=283) Docetaxel (n=288) Median Age (range) 59 (22-81) 57 (28-87) ECOG PS 0 or 1 (%) Stage IV (%) Homocysteine levels < 12 (%) Histology (%) Adenocarcinoma Squamous Best response to prior chemo CR/PR (%) Time since last chemo < 3 mos > 3 mos Prior taxane (%) Prior platinum (%)

40 Response Rates Pemetrexed (n=264) % ,8 46,4 Docetaxel (n=274) [CI=5.9,13.2] [CI=5.7,12.8] 5 9,1 8,8 0 CR and PR Stable Disease 40

41 Progression-Free Survival (ITT) % Progression MPFS = 2.9 mos MPFS = 2.9 mos ALIMTA (n=283) Docetaxel (n=288) HR % CI of HR (0.82, 1.16) ITT = intent to treat HR = hazard ratio CI = confidence interval MPFS = median progression-free survival Months 41

42 Survival (ITT) Survival Distribution Function ITT = intent to treat HR = hazard ratio CI = confidence interval MST = median survival time MST 7.9 mos 1-yr OS: 29.7% Months ALIMTA (n=283) Docetaxel (n=288) HR % CI of HR (0.82, 1.20) MST 8.3 mos 1-yr OS: 29.7%

43 Nonhematological Toxicities (% Patient) Any grade ALIMTA (n=265) Grade 3/4 Docetaxel (n=276) Any grade Grade 3/4 P value 1 Alopecia ALT Neurosensory Fatigue Nausea Vomiting Stomatitis Diarrhea Pulmonary Tox Rash Weight Loss Edema < NS NS NS NS NS NS NS NS NS NS 1 = applies to grade 3/4 toxicity only 43

44 Hematological Toxicities (Grade 3/4 % Patient) ALIMTA Docetaxel (n=265) (n=276) p value Neutropenia <.001 Febrile Neutropenia <.001 Infection w/ gr 3/4 Neutropenia Anemia Thrombocytopenia 2 <1.116 Hanna N et al JCO 22: , 1597,

45 Hospitalizations, Transfusions & Growth Factors ALIMTA Docetaxel (n=265) (n=276) p-value Patients with > 1 hosp 31.7% 40.6%.032 due to an adverse event Total hospitalizations 1.5% 13.4% <.001 due to febrile neutropenia G-CSF/GM-CSF 2.6% 19.2% <.001 Erythropoietin 6.8% 10.1%.169 Red blood cell 16.6% 11.6%.085 Transfusions 45

46 Summary This is the largest phase III study ever reported for treatment in 2 nd -line NSCLC ALIMTA and docetaxel have similar efficacy: - response rates - progression-free survival - overall survival 46

47 Summary ALIMTA had a more favorable hematological toxicity profile when compared with docetaxel: less severe neutropenia w/without fever and infections fewer hospitalizations less need for G-CSF/GM-CSF support ALIMTA is an effective 2 nd -line chemotherapy agent in NSCLC 47

48 Phase III ALIMTA Clinical Trials ALIMTA + Cisplatin vs. Cisplatin in mesothelioma: Completed; ALIMTA + Cisplatin showed survival advantage ALIMTA vs. Docetaxel for 2 nd Line NSCLC Completed; ALIMTA showed equal efficacy but more favorable hematological toxicity profile ALIMTA + GEMZAR vs. GEMZAR in Pancreatic Cancer Completed accrual; awaiting data analysis 48

49 Conclusions I ALIMTA is an unique antifolate that inhibits several different enzymes in the DNA and RNA biosynthesis pathway ALIMTA has activity in a number of solid tumors: NSCLC, pancreas, breast, colorectal, bladder and mesothelioma In malignant pleural mesothelioma, a hard to-treat cancer, ALIMTA became the first agent that demonstrated superior survival and this represents a significant advance In addition to survival benefits, ALIMTA also reduces disease-related symptoms and produces significantly higher objective response rates than the control arm in a phase III study 49

50 Conclusions II ALIMTA is an effective 2 nd -line chemotherapy agent in NSCLC ALIMTA had a more favorable hematological toxicity profile when compared with control arm in a phase III study on 2 nd line NSCLC ALIMTA has an easy-to-control toxicity profile; physicians can deliver the planned course of therapy with simple folic acid and vitamin B 12 supplementation The antitumor activity of ALIMTA is retained or enhanced by folic acid and vitamin B 12 supplementation ALIMTA has a simple, brief outpatient administration and can easily be combined with other cytotoxic drugs 50