INNOVAZIONI TERAPEUTICHE IN ONCOLOGIA MEDICA CAGLIARI 23-24 GIUGNO 2005 Policlinico Universitario - Cagliari MULTI TARGETED ANTIFOLATE Elena Massa CATTEDRA DI ONCOLOGIA MEDICA UNIVERSITA DEGLI STUDI DI CAGLIARI 1
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: 4450-4454, 1992 2
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
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
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;6:363-373
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
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
Vitamin Supplementation Intervention Folic Acid: Vitamin B 12 : 350-1000 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) 2001 8
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
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 10-40 40 neuts 2MR q 3 Wkly Daily x 5 q 3 wks 50-700 700 neuts 4PR, 6MR 0.2-4.0 4.0 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 13:2842-2850, 1995 Rinaldi D et al. Cancer Chemother Pharmacol 44(5):372-380, 1999 McDonald AC et al.clin Cancer Res 4(3):605-610, 1998 10
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
ALIMTA ACTIVITY IN PLEURAL MESOTHELIOMA
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
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; 21:2636 44 14
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
Final Study Design R A N D O M IZ 58 pts No FA/B 12 ALIMTA + Cisplatin 168 pts FA/B 12 226 pts E 59 pts 163 pts 222 pts Cisplatin Final Analysis Primary endpoint: survival 16 Nicholas Vogelzang, et al. J Clin Oncol 2003; 21:2636 44
Survival: All Eligible Patients 100 ALIMTA + Cisplatin (n=226) Cisplatin (n=222) % Alive 75 50 MST = 9.3 mos HR 0.77 Logrank p-value 0.020 MST = 12.1 mos 25 0 0 5 10 15 20 25 30 Months 17 Method: Kaplan-Meier
Survival: Fully Supplemented Patients 100 ALIMTA + Cisplatin (n=168) Cisplatin (n=163) % Alive 75 50 MST = 10.0 mos HR 0.75 Logrank p-value 0.051 MST = 13.3 mos 25 0 0 5 10 15 20 25 30 Months 18
TTPD: All Eligible Patients 100 ALIMTA + Cisplatin (n=226) Cisplatin (n=222) % Progression 75 50 25 HR 0.68 Logrank p-value 0.001 MTPD = 5.7 mos 0 MTPD = 3.9 mos 0 5 10 15 20 25 30 Months 19 Method: Kaplan-Meier
TTPD: Fully Supplemented Patients 100 ALIMTA + Cisplatin (n=168) Cisplatin (n=163) % Progression 75 50 25 MTPD = 6.1 mos HR 0.64 Logrank p-value 0.008 0 MTPD = 3.9 mos 0 5 10 15 20 25 Months 20
Patient Treated with ALIMTA + Cisplatin Baseline Visit 4 21
Tumor Response Rates % 50 40 p <0.001 41 (CI 35-48) p <0.001 46 (CI 38-53) ALIMTA/Cis Cis p =0.005 30 29 (CI 18-43) 20 17 (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
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 28 2 41 0 23 3 Platelets 6 0 7 0 5 0 Febr. Neut. 2 1 5 0 1 1 Vomiting 13 4 21 2 11 4 Stomatitis 4 0 7 0 3 0 Diarrhea 4 0 7 0 4 0 23
Lung Function (Vital Capacity) by Treatment Arm 2.70 2.65 ALIMTA/Cis Cis p =0.324 p =0.034 p =0.002 2.60 VC (L) 2.55 2.50 2.45 2.40 0 2 4 6 Cycle 24
Lung Cancer Symptom Scale: Dyspnea Worse 40 ALIMTA/Cis Cis p =0.004 35 p =0.476 p =0.344 mm 30 Better 25 0 2 4 6 Cycle 25
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
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
Conclusions (3) ALIMTA and cisplatin with FA/B 12 should now be considered standard front-line therapy for patients with malignant pleural mesothelioma 28
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
ALIMTA Single Agent in NSCLC Response Rusthoven Clarke Postmus CDDP n/cddp Evaluable 30 51 44 35 CR 0 0 0 1 PR 7 9 2 4 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, 1999 30
Phase II ALIMTA in NSCLC Combination Studies with Cisplatin Two Phase II combination trials in untreated NSCLC Shepherd et al, Cancer, 92(3):595-600, 2001 Manegold et al, Ann Oncol, 11(4):435, 2000 No vitamin supplementation administered in these studies 31
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, 2000. Shepherd, et al. Cancer, 92(3):595-600, 2001. 32
Phase II ALIMTA + Cisplatin in NSCLC Results Shepherd Manegold N Evaluable 29 36 PR 13 14 SD 11 17 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):595-600, 2001. Manegold, et al. Ann Oncol 11(4):435-40, 2000. 33
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 22:1589-1597, 1597, 2004
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):2354-2362, 2000 2 Shepherd et al., JCO 18(10):2095-2103, 2000 35
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 22:1589-1597, 1597, 2004 36
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
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
Patient Characteristics (n=571) ALIMTA (n=283) Docetaxel (n=288) Median Age (range) 59 (22-81) 57 (28-87) ECOG PS 0 or 1 (%) 88.3 87.0 Stage IV (%) 74.9 74.7 Homocysteine levels < 12 (%) 71.4 68.9 Histology (%) Adenocarcinoma 54.4 49.3 Squamous 27.6 32.3 Best response to prior chemo CR/PR (%) 35.6 36.5 Time since last chemo < 3 mos 50.4 48.1 > 3 mos 49.6 51.9 Prior taxane (%) 25.8 27.8 Prior platinum (%) 92.6 89.9 39
Response Rates 50 45 Pemetrexed (n=264) % 40 35 30 25 20 45,8 46,4 Docetaxel (n=274) 15 10 [CI=5.9,13.2] [CI=5.7,12.8] 5 9,1 8,8 0 CR and PR Stable Disease 40
Progression-Free Survival (ITT) % Progression 1.00 0.75 0.50 0.25 0.00 MPFS = 2.9 mos MPFS = 2.9 mos ALIMTA (n=283) Docetaxel (n=288) HR 0.97 95% CI of HR (0.82, 1.16) ITT = intent to treat HR = hazard ratio CI = confidence interval MPFS = median progression-free survival 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Months 41
Survival (ITT) Survival Distribution Function 1.00 0.75 0.50 0.25 0.00 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 0.99 95% CI of HR (0.82, 1.20) MST 8.3 mos 1-yr OS: 29.7% 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 42
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 6.4 7.9 4.9 34.0 30.9 16.2 14.7 12.8 0.8 15.9 1.1 4.5 6.4 1.9 0 5.3 2.6 1.5 1.1 0.4 0 0.8 0 0 37.7 1.4 15.9 35.9 16.7 12.0 17.4 24.3 2.1 8.0 1.8 8.3 37.7 0 1.1 5.4 1.8 1.1 1.1 2.5 1.4 0.7 0 0 <.001.028 NS NS NS NS NS NS NS NS NS NS 1 = applies to grade 3/4 toxicity only 43
Hematological Toxicities (Grade 3/4 % Patient) ALIMTA Docetaxel (n=265) (n=276) p value Neutropenia 5.3 40.2 <.001 Febrile Neutropenia 1.9 12.7 <.001 Infection w/ gr 3/4 Neutropenia 0 3.3.004 Anemia 4.2 4.3 1.00 Thrombocytopenia 2 <1.116 Hanna N et al JCO 22:1589-1597, 1597, 2004 44
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
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
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
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
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
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