INNOVAZIONI TERAPEUTICHE IN ONCOLOGIA MEDICA CAGLIARI 23-24 GIUGNO 2005 Policlinico Universitario - Cagliari LAPATINIB Elena Massa CATTEDRA DI ONCOLOGIA MEDICA UNIVERSITA DEGLI STUDI DI CAGLIARI
ErbB Inhibition as a Therapeutic Strategy ErbB receptors play key roles in cell growth and survival. Overexpression and/or mutation of ErbB receptors is commonly seen in human tumors and is associated with poorer patient outcome and decreased survival. Overexpressed and mutant receptors can still respond to regulation. ErbB receptor inhibition is associated with decreased proliferation and increased apoptosis of tumor cells as well as regression of metastases.
Human ErbB receptor Family consists of 4 closely related receptor tyrosine kinase: ErbB-1 (EGFR/HER1) ErbB-2 (HER2) ErbB-3 (HER3) ErbB-4 (HER4)
Bence AK et al Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects. Invest New Drugs. 2005 Jan;23(1):39-49. Phase I Studies of Lapatinib Oral Lapatinib was administered to 135 healthy volunteers in four studies at doses of 10-250 mg and was found to be: -Safe - Well tolerated
Study EGF10003 A PHASE I STUDY OF GW572016 IN PATIENTS WITH SOLID TUMORS Toxicity data by grade in 43 solid tumor patients receiving lapatinib Lapatinib dose (mg) n of patients n with AE (%) Common toxicity criteria grade n adverse events (% at dose level) 1 2 3 4 175 2 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 375 4 4 (100) 11 (79) 3 (21) 0 (0) 0 (0) 675 4 4 (100) 15 (100) 0 (0) 0 (0) 0 (0) 900 5 4 (80) 2 (40) 6 (60) 0 (0) 0 (0) 1200 6 3 (50) 11 (79) 3 (21) 0 (0) 0 (0) 1600 10 8 (80) 4 (57) 3 (43) 0 (0) 0 (0) 1800 9 9 (100) 14 (78) 4 (22) 0 (0) 0 (0) 900 bid 3 2 (67) 0 (0) 0 (0) 2 (100) 0 (0) total 43 34 (71) 57 (76) 16 (21) 2 (3) 0 (0) Burris HA et al, Proc Am Soc Clin Oncol 2003; 22: 258
Study EGF10003 A PHASE I STUDY OF GW572016 IN PATIENTS WITH SOLID TUMORS Adverse events in 43 solid tumor patients Adeverse event Grade n of patients Rash 1 7 2 1 Diarrhea 1 6 2 6 3 2 Nausea 1 7 2 2 Vomiting 1 2 2 1 Constipation 1 4 2 1 Fatigue 1 8 2 1 Anorexia 1 5 Burris HA et al, Proc Am Soc Clin Oncol 2003; 22: 258
Study EGF10003: A PHASE I STUDY OF GW572016 IN PATIENTS WITH SOLID TUMORS Patients on study EGF10003 for 4 months: Diagnosis (N.o patient) Lapatinib dose Disease Status Duration on study months Adenocarcinoma, lung (4) 675/900/1200/1600 SD 12 Adenocystic/salivary (2) 1200/1600 SD 9+ Breast cancer (1) 1600 SD 7 Nasopharyngeal cancer (1) 1800 SD 13 Unknown primary site (3) 1200/1250/1600/1800 SD 6 Colorectal cancer (4) 675/900/1200/1600 SD 4 Head Neck cancer(1) 1250 CR 19+ Burris HA et al, Proc Am Soc Clin Oncol 2003; 22: 258
Phase I Safety,Pharmacokinetics, and Clinical Activity Study of Lapatinib (GW572016), a Reversible, Dual Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinases in Heavily Pretreated Patients With Metastatic Carcinomas Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KI, O Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector N J Clin Oncol Jun 2005 online
Phase I Study in Heavily Pretreated Patients With Metastatic Carcinomas Entry criteria - EGRF or ErbB2 overexpression (IHC), gene amplification (ErbB2), or evidence of activated EGFR/ErbB2 receptors (IHC) Study Design - Randomized to 500, 650, 900, 1200, 1600 mg/qd - PK, safety and tolerability - PD samples (tumor and skin) obtained ad Day 0 and Day 21 - Identification of a biologically active dose range - Clinical activity J Clin Oncol Jun 2005 online
Patient Characteristics by Lapatinib Cohort No of patients (No 67) Disease site 500 650 900 1000 1200 1600 Breast 6 6 5 3 6 4 AUP 1 1 2 0 0 1 CRC 2 2 1 0 1 1 H&N 0 1 0 0 2 2 Ovarian 1 1 1 0 0 1 Lung 1 2 2 0 2 3 Other 2 0 0 0 1 1 J Clin Oncol Jun 2005 online
Overall Toxicity Summary Drug was well tolerated with no grade 4 events reported Common adverse events (grades 1 and 2) Rash (31%) Diarrhea (42%) Nausea and vomiting (13%) Fatigue (10%) No treatment-related cardiac or pulmonary toxicity J Clin Oncol Jun 2005 online
Overall Toxicity Summary Five grade 3 AEs Experienced by four patients were considered to be drug-related: 1 patient had grade 3 abdominal pain at 650 mg dose level 1 patient had grade 3 rash and grade 3 diarrhea at the 1000 mg dose level 1 patient had grade 3 diarrhea at the 1200 mg dose level 1 patient had grade 3 gastroesophageal reflux J Clin Oncol Jun 2005 online
Clinical Response Data Response Total (N=59) CR 0 (0%) PR 4 (6.8%) SD* PD 31 (52.5%) 24 (40.7%) *10 patients received lapatinib for 6 m Partial response (PR) occurred at the following doses: 1200 mg (2), 900 mg (1) (600 mg). Stable disease (SD) occurred at the following doses: 500 m (5), 650 mg (4), 900 mg (4), 1000 mg (3), 1200 mg (2) and 1600 mg (2) Tumor types responding to treatment: breast (14), CRC (3), ovarian (1), NSCLC (5), AUP (1), Granular cell CA (1), H&N (3) J Clin Oncol Jun 2005 online
Frequency of achieving (>75%) inhibition of either p- ErbB1, p-erbb2, p-erk1/2 or p-akt expression in tumors at day 21 compared to baseline frequenza (%) 100 80 60 40 20 25 66,67 60 75 80 0 500 650 900 1200 1600 J Clin Oncol Jun 2005 online
Summary of GW572016 administered on a Daily Oral Schedule GW572016 was well-tolerated at all doses tested Clinical responses were observed at a variety of doses in heavily pre-treated subjects with metastatic disease Responses were observed in ErbB2 expressing breast cancer that had progressed on previous Herceptin TMbased regimens Disease stabilization also observed in 12 subjects with a variety of tumor types J Clin Oncol Jun 2005 online
Summary of GW572016 administered on a Daily Oral Schedule GW572016 inhibited signaling pathways implicated in tumor growth and survival Inhibition of p-erk1/2, p-akt, or Cyclin D, may be necessary, but is not sufficient to induce clinically detectable anti-tumor effects Induction of tumor cell apoptosis, as measured by TUNEL assay, appeared to correlate with clinical response J Clin Oncol Jun 2005 online
Clinical Trials of Lapatinib in Advanced/Metastatic Breast Cancers
Blackwell KL, Proc Am Soc Clin Oncol 2004
Blackwell KL, Proc Am Soc Clin Oncol 2004
Blackwell KL, Proc Am Soc Clin Oncol 2004
Blackwell KL, Proc Am Soc Clin Oncol 2004
Blackwell KL, Proc Am Soc Clin Oncol 2004
Blackwell KL, Proc Am Soc Clin Oncol 2004
Blackwell KL, Proc Am Soc Clin Oncol 2004
Blackwell KL, Proc Am Soc Clin Oncol 2004
Clinical Trials of Lapatinib in Advanced/Metastatic Breast Cancers
*EGF100151 A phase III, Randomized, Open-label, multicenter study comparing GW572016 and Capecitabine (Xeloda) versus Capecitabine in women with Refractory Advanced or Metastatic Breast Cancer Primary Endpoint= TTP
Clinical Trials of Lapatinib in Advanced/Metastatic Breast Cancers
*EGF30001 A randomized, multicenter, double-blind, placebo-controlled, 2- arm,phase III Study of Oral GW572016 in combination with Paclitaxel (Taxol) in Subjects previously untreated for Advanced or Metastatic Breast Cancer Primary Endpoint= TTP