- Email: [email protected]
O-186 Mutations in EGFR, HER2, KRAS and BRAF in NSCLC: Prevalences and correlations with clinical outcomes in patients treated with carboplatin and paclitaxel with or without erlotinib
Oral Sessions / Targeted therapies
$62
outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). One explanation is antagonism due to TKI-induced G1 arrest, reducing cell cycle phase-dependent activity of chemotherapy (Gumedock: ASCO, 2003). We hypothesized that pharmacodynamic separation by intermittent delivery of EGFR-TKI with chemotherapy would increase efficacy and overcome the hypothesized antagonism of concurrent administration. Based on our pre-clinical studies and pharmacologic considerations, we proposed two schedules for testing intermittent erlotinib in combination with D e c . Methods: Two dose escalating phase I trials (Arm A and Arm B) were conducted simultaneously. D e c every 21 days in both arms (70-75 mg/m 2 IV). Arm A: erlotinib given weekly days 2, 9, 16 (600 800 mg). Arm B: erlotinib given days 2-16 (150-300 mg). Dose limiting toxicity (DLT) was defined as: grade 4 platelets, grade 3 platelets with bleeding, febrile neutropenia, grade 4 ANC />7 days, or any ~>grade 3 non-heme toxicity. Results: 42 pts with advanced solid tumors were treated, including 22 NSCLC. Characteristics: Age range 34-83; Gender: 22 M; KPS />90/<90: 19123; Median cycles: 4. Treatment was generally well tolerated. DLTs included febrile neutropenia, mucositis, and diarrhea. Grade 1/2 acneform rash' 88% Arm A MTD: D e c 70 mg/m 2 and weekly erlotinib 600 mg. Arm B MTD: D e c 70 mg/m 2 and erlotinib 200 mg day 2-16. Arm A was associated with more febrile neutropenia. Of 22 NSCLC patients there were 4 partial responses, 4 minor responses, and 5 stable disease. 4 NSCLC patients remain on therapy at 24, 23, 16 and 11 months. Further clinical updates and correlative science studies will be available at the time of presentation. Conclusions: 1. We report the first clinical trial testing intermittent EGFR inhibition plus chemotherapy to overcome hypothesized antagonism of concurrent administration. 2. Intermittent dosing of erlotinib plus D e c is feasible and has promising activity in advanced NSCLC. 3. Due to a more tolerable toxicity profile Arm B regimen was chosen to examine efficacy in a phase II trial for second-line NSCLC.
[ O ~ 6 ] Mutations in EGFR, HER2, KRAS and BRAF in NSCLC: Prevalences and correlations with clinical outcomes in patients treated With carboplatin and paclitaxel with or without erlotinib D. Eberhard 1, B. Johnson 2, A. Goddard 1, R. Herbst 3, P. Janne 2, D. Johnson 4, Iq Klein 1, M. Ostland 1, S. Seshagiri 1, K. Hillan 1. lGenentech, Inc., South
San Francisco, California, USA; 2Dana Farber Cancer Institute, Boston, USA; 3M.D. Anderson Cancer Center, Houston, USA, 4Vanderbilt Medical Center, Nashville, USA Background: Recent studies have suggested that mutations in the EGFR tyrosine kinase domain (TKD) may be closely linked to NSCLC responses to the EGFR inhibitors erlotinib and gefitinib as single agents in 2nd /3 rd line after chemotherapy failure. EGFR mutations have been detected in 2% to 40% of unselected NSCLC series. Recently, TKD mutations in the EGFR]Her family co-receptor Her2 were described in 5 of 120 (4.2%) of an unselected NSCLC series. The relationship of Her2 mutations to response to Her inhibitors is not known. Activating mutations in downstream signaling molecules may also affect responses to Her inhibitors. K-ras mutations occur in 10-30% of NSCLC. B-raf mutations are less common, occurring in 1.5-3% of NSCLC. In the present study, we investigated the frequency of EGFR, HER2, KRAS and BRAF mutations and their relationships to clinical outcome in a randomized phase III study (TRIBUTE) of advanced NSCLC patients treated with first-line carboplatin and paclitaxel (CP) in combination with either edotinib (Tarceva TM) or placebo. Methods: Patients enrolled in TRIBUTE were assessed for survival, response, and time to progression (TTP). Archival tumor samples were collected with informed consent and EGFR exons 18-21, HER2 exon 20, KRAS exon 2 and BRAF exerts 11 and 15 were sequenced. Outcomes were correlated with mutation status in retrospective subset analyses.
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Efficacy and safety of single agent pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in Non-Small Cell Lung Cancer (NSCLC) patients after prior chemotherapy
R. Herbst 1, A. Davies 2, B. Johnson 3, R. Natale 4, T. Dang s, J. Murren 6, J. Schiller 7, L. Gadand 8, V. Miller£, D. Mendelson 1°, Y. Melenevsky11, D. Devries 11, A. Van Den Abbeele 11, D. Eberhard 12, B. Lyons 12, S. /utzker 12.
1MD Anderson Cancer Group Houston, USA; 2UC Davis Cancer Center, Sacramento, USA; 3Dana Farber Cancer/nstitute/Lowe Center for Thoracic Once/ogy, Boston, USA; 4Cedars-Sinai Cancer Center, Los Angeles, USA; 5 Vanderbi/t-/ngram Cancer Center, Knoxville, USA; 6Yale University School of Medicine, Section of Medica/ Onco/ogy, New Haven, USA; 7University of Wisconsin, Madison, USA; 8Arizona Cancer Center, Tucscon, USA; 9Memeria/-S/oan Kettering Cancer Center, New York, USA; 1°Arizona Cancer Center, Scettsda/e, USA Background: Partuzumab (rhuMAb 2C4), a humanized HER2 antibody, represents a new class of targeted therapeutics (HER Dimerization Inhibitor or HDI) that inhibits dimerization of HER2 with ligand-activated EGFR, HER3 and HER4. Preclinical xenograft studies have demonstrated efficacy of pertuzumab in treating NSCLC. Interim data from a phase II multi-center tdal of single agent pertuzumab in NSCLC is presented. Methods: Patients with advanced or recurrent NSC/C that progressed on or after at least one chemotherapy regimen were eligible. There was no upper limit on the number of prior chemotherapy regimens. Pertuzumab was administered with an 840 mg IV loading dese with repeat doses of 420 mg IV every 3 weeks until progressive disease, death or toxicity Mandatory fresh tumor biopsies were obtained prior to pertuzumab treatment for biomarker analysis. CT scans were obtained after 2, 4, 8, 12 and 16 cycles. Tumor overall response (OR) rate by RECIST was the primary endpoint. Left ventricular ejection fraction (LVEF) was monitored by ECHO. At a subset of investigator sites FDG-PET images were obtained at baseline and after 2 cycles of pertuzumab and centrally reviewed for changes in maximum standardized uptake values (SUVmax). Results: To date 33 patients have been enrolled and treated. Median age was 64 years with 58% male and 42% female. Histological subtypes included 46% adenocarcinoma and 24% squamous. 2 patients (6%) were never smokers. Median number of prior chemotherapy regimens was 2 (range 1-3). 27 patients received pertuzumab for 2 or more cycles and were evaluable for response. No patient met criteria for OR by RECIST. 14t27 (52%) patients had SD as best response. 5•27 (19%) patients received 5 or more cycles of portuzumab including 2 patients who received 9 cycles and continue on therapy. In the 12 patients who had central review of FDG-PET images, 3 (25%) had a decrease in SUVmax/>25% over the measured lesions. The major toxicity was diarrhea seen in 12/33 (36.4%) patients (10 Gr-1, 1 Gr-2, 1 Gr-3). No LVEF < 50% was recorded. Conclusions: Pertuzumab as a single agent is well-tolerated. Although no OR were observed, some patients experienced prolonged SD and decreases in SUVmax on FDG-PET. Enrollment continues and an update, including analysis of tissue biomarkers, will be reported. Phase II study of the EGFR tyrosine kinase inhibitor erlotinib (Tarceva) in patients >70 years of age with previously untreated advanced non-small cell lung carcinoma
EC 0
57 and 288 days, respectively. The third showed stable disease with TI-P of 134 days and survival of 405 days. KRAS mutations were detected in 55 of 264 cases (20.8%). Patients with KRAS mutations treated with erlotinib+CP had decreased eRR, median TI-P and OS compared to the other KRAS status/treatment groups (eRR: 8% vs. 23-26%; TI-P: 3.4 vs. 5.3-6 months; OS: 4.4 vs. 11.3-13.5 months). BRAF mutations were not detected in 141 cases examined. Conclusions: HER2 and BRAF mutations occur much less frequently than EGFN and KRAS in NSCLC. EGFN mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib and may predict greater likelihood of response to edotinib+CR HER2 mutations do not appear to be associated with response to edotinib+CIR Patients with KRAS-mutated NSCLC showed poorer clinical outcomes when treated with erlotinib+CP. These findings in a retrospective subset analysis with small sample size should be interpreted with caution and must be confirmed by further studies.
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Results: EGFR mutations were detected in 29 of 228 cases overall (12.7%), and were associated with a significantly higher objective response rate (eRR) to erlotinib+CP than was wild type (WT) EGFR (53% vs. 18%; p < 0.01). TTP with erlotinib+CP was also prolonged in EGFR-mutated patients compared to WT (12.5 vs. 4.5 months). The overall survival (OS) of EGFR-mutated patients (70% at >20 months) was significantly longer than that of WT patients (median 10 months) irrespective of treatment arm. HER2 mutations were identified in 3 of 248 cases (1.2%), all in the erlotinib+CP treatment arm. Two patients exhibited progressive disease with TTP of 43 and 88 days, and survivals of
D. Jackman 1, J. Lucca 1, IR Fidias 3, M. Rabin 1'2, T. Lynch 3, IR Ostler3, A. Skarin 1,2, J. Temel 3, B. Johnson 1,2, P. Janne 1,2. 1Dana Farber Cancer
Institute, Boston, MA, USA; 2Brigham and Women's Hospital, Boston, MA, USA; 3Massachusetts General Hospital, Boston, MA, USA Background: Chemotherapy for patients />70 with advanced NSCLC is associated with survival benefits but with increased toxicity. Erlotinib has shown promising activity, and a tolerable side effect profile, in the treatment of patients who have failed prior chemotherapy. We have conducted a single center, phase II trial of erlotinib in patients 970 years with previously untreated advanced NSCLC.
$62
outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). One explanation is antagonism due to TKI-induced G1 arrest, reducing cell cycle phase-dependent activity of chemotherapy (Gumedock: ASCO, 2003). We hypothesized that pharmacodynamic separation by intermittent delivery of EGFR-TKI with chemotherapy would increase efficacy and overcome the hypothesized antagonism of concurrent administration. Based on our pre-clinical studies and pharmacologic considerations, we proposed two schedules for testing intermittent erlotinib in combination with D e c . Methods: Two dose escalating phase I trials (Arm A and Arm B) were conducted simultaneously. D e c every 21 days in both arms (70-75 mg/m 2 IV). Arm A: erlotinib given weekly days 2, 9, 16 (600 800 mg). Arm B: erlotinib given days 2-16 (150-300 mg). Dose limiting toxicity (DLT) was defined as: grade 4 platelets, grade 3 platelets with bleeding, febrile neutropenia, grade 4 ANC />7 days, or any ~>grade 3 non-heme toxicity. Results: 42 pts with advanced solid tumors were treated, including 22 NSCLC. Characteristics: Age range 34-83; Gender: 22 M; KPS />90/<90: 19123; Median cycles: 4. Treatment was generally well tolerated. DLTs included febrile neutropenia, mucositis, and diarrhea. Grade 1/2 acneform rash' 88% Arm A MTD: D e c 70 mg/m 2 and weekly erlotinib 600 mg. Arm B MTD: D e c 70 mg/m 2 and erlotinib 200 mg day 2-16. Arm A was associated with more febrile neutropenia. Of 22 NSCLC patients there were 4 partial responses, 4 minor responses, and 5 stable disease. 4 NSCLC patients remain on therapy at 24, 23, 16 and 11 months. Further clinical updates and correlative science studies will be available at the time of presentation. Conclusions: 1. We report the first clinical trial testing intermittent EGFR inhibition plus chemotherapy to overcome hypothesized antagonism of concurrent administration. 2. Intermittent dosing of erlotinib plus D e c is feasible and has promising activity in advanced NSCLC. 3. Due to a more tolerable toxicity profile Arm B regimen was chosen to examine efficacy in a phase II trial for second-line NSCLC.
[ O ~ 6 ] Mutations in EGFR, HER2, KRAS and BRAF in NSCLC: Prevalences and correlations with clinical outcomes in patients treated With carboplatin and paclitaxel with or without erlotinib D. Eberhard 1, B. Johnson 2, A. Goddard 1, R. Herbst 3, P. Janne 2, D. Johnson 4, Iq Klein 1, M. Ostland 1, S. Seshagiri 1, K. Hillan 1. lGenentech, Inc., South
San Francisco, California, USA; 2Dana Farber Cancer Institute, Boston, USA; 3M.D. Anderson Cancer Center, Houston, USA, 4Vanderbilt Medical Center, Nashville, USA Background: Recent studies have suggested that mutations in the EGFR tyrosine kinase domain (TKD) may be closely linked to NSCLC responses to the EGFR inhibitors erlotinib and gefitinib as single agents in 2nd /3 rd line after chemotherapy failure. EGFR mutations have been detected in 2% to 40% of unselected NSCLC series. Recently, TKD mutations in the EGFR]Her family co-receptor Her2 were described in 5 of 120 (4.2%) of an unselected NSCLC series. The relationship of Her2 mutations to response to Her inhibitors is not known. Activating mutations in downstream signaling molecules may also affect responses to Her inhibitors. K-ras mutations occur in 10-30% of NSCLC. B-raf mutations are less common, occurring in 1.5-3% of NSCLC. In the present study, we investigated the frequency of EGFR, HER2, KRAS and BRAF mutations and their relationships to clinical outcome in a randomized phase III study (TRIBUTE) of advanced NSCLC patients treated with first-line carboplatin and paclitaxel (CP) in combination with either edotinib (Tarceva TM) or placebo. Methods: Patients enrolled in TRIBUTE were assessed for survival, response, and time to progression (TTP). Archival tumor samples were collected with informed consent and EGFR exons 18-21, HER2 exon 20, KRAS exon 2 and BRAF exerts 11 and 15 were sequenced. Outcomes were correlated with mutation status in retrospective subset analyses.
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Efficacy and safety of single agent pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in Non-Small Cell Lung Cancer (NSCLC) patients after prior chemotherapy
R. Herbst 1, A. Davies 2, B. Johnson 3, R. Natale 4, T. Dang s, J. Murren 6, J. Schiller 7, L. Gadand 8, V. Miller£, D. Mendelson 1°, Y. Melenevsky11, D. Devries 11, A. Van Den Abbeele 11, D. Eberhard 12, B. Lyons 12, S. /utzker 12.
1MD Anderson Cancer Group Houston, USA; 2UC Davis Cancer Center, Sacramento, USA; 3Dana Farber Cancer/nstitute/Lowe Center for Thoracic Once/ogy, Boston, USA; 4Cedars-Sinai Cancer Center, Los Angeles, USA; 5 Vanderbi/t-/ngram Cancer Center, Knoxville, USA; 6Yale University School of Medicine, Section of Medica/ Onco/ogy, New Haven, USA; 7University of Wisconsin, Madison, USA; 8Arizona Cancer Center, Tucscon, USA; 9Memeria/-S/oan Kettering Cancer Center, New York, USA; 1°Arizona Cancer Center, Scettsda/e, USA Background: Partuzumab (rhuMAb 2C4), a humanized HER2 antibody, represents a new class of targeted therapeutics (HER Dimerization Inhibitor or HDI) that inhibits dimerization of HER2 with ligand-activated EGFR, HER3 and HER4. Preclinical xenograft studies have demonstrated efficacy of pertuzumab in treating NSCLC. Interim data from a phase II multi-center tdal of single agent pertuzumab in NSCLC is presented. Methods: Patients with advanced or recurrent NSC/C that progressed on or after at least one chemotherapy regimen were eligible. There was no upper limit on the number of prior chemotherapy regimens. Pertuzumab was administered with an 840 mg IV loading dese with repeat doses of 420 mg IV every 3 weeks until progressive disease, death or toxicity Mandatory fresh tumor biopsies were obtained prior to pertuzumab treatment for biomarker analysis. CT scans were obtained after 2, 4, 8, 12 and 16 cycles. Tumor overall response (OR) rate by RECIST was the primary endpoint. Left ventricular ejection fraction (LVEF) was monitored by ECHO. At a subset of investigator sites FDG-PET images were obtained at baseline and after 2 cycles of pertuzumab and centrally reviewed for changes in maximum standardized uptake values (SUVmax). Results: To date 33 patients have been enrolled and treated. Median age was 64 years with 58% male and 42% female. Histological subtypes included 46% adenocarcinoma and 24% squamous. 2 patients (6%) were never smokers. Median number of prior chemotherapy regimens was 2 (range 1-3). 27 patients received pertuzumab for 2 or more cycles and were evaluable for response. No patient met criteria for OR by RECIST. 14t27 (52%) patients had SD as best response. 5•27 (19%) patients received 5 or more cycles of portuzumab including 2 patients who received 9 cycles and continue on therapy. In the 12 patients who had central review of FDG-PET images, 3 (25%) had a decrease in SUVmax/>25% over the measured lesions. The major toxicity was diarrhea seen in 12/33 (36.4%) patients (10 Gr-1, 1 Gr-2, 1 Gr-3). No LVEF < 50% was recorded. Conclusions: Pertuzumab as a single agent is well-tolerated. Although no OR were observed, some patients experienced prolonged SD and decreases in SUVmax on FDG-PET. Enrollment continues and an update, including analysis of tissue biomarkers, will be reported. Phase II study of the EGFR tyrosine kinase inhibitor erlotinib (Tarceva) in patients >70 years of age with previously untreated advanced non-small cell lung carcinoma
EC 0
57 and 288 days, respectively. The third showed stable disease with TI-P of 134 days and survival of 405 days. KRAS mutations were detected in 55 of 264 cases (20.8%). Patients with KRAS mutations treated with erlotinib+CP had decreased eRR, median TI-P and OS compared to the other KRAS status/treatment groups (eRR: 8% vs. 23-26%; TI-P: 3.4 vs. 5.3-6 months; OS: 4.4 vs. 11.3-13.5 months). BRAF mutations were not detected in 141 cases examined. Conclusions: HER2 and BRAF mutations occur much less frequently than EGFN and KRAS in NSCLC. EGFN mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib and may predict greater likelihood of response to edotinib+CR HER2 mutations do not appear to be associated with response to edotinib+CIR Patients with KRAS-mutated NSCLC showed poorer clinical outcomes when treated with erlotinib+CP. These findings in a retrospective subset analysis with small sample size should be interpreted with caution and must be confirmed by further studies.
72
Results: EGFR mutations were detected in 29 of 228 cases overall (12.7%), and were associated with a significantly higher objective response rate (eRR) to erlotinib+CP than was wild type (WT) EGFR (53% vs. 18%; p < 0.01). TTP with erlotinib+CP was also prolonged in EGFR-mutated patients compared to WT (12.5 vs. 4.5 months). The overall survival (OS) of EGFR-mutated patients (70% at >20 months) was significantly longer than that of WT patients (median 10 months) irrespective of treatment arm. HER2 mutations were identified in 3 of 248 cases (1.2%), all in the erlotinib+CP treatment arm. Two patients exhibited progressive disease with TTP of 43 and 88 days, and survivals of
D. Jackman 1, J. Lucca 1, IR Fidias 3, M. Rabin 1'2, T. Lynch 3, IR Ostler3, A. Skarin 1,2, J. Temel 3, B. Johnson 1,2, P. Janne 1,2. 1Dana Farber Cancer
Institute, Boston, MA, USA; 2Brigham and Women's Hospital, Boston, MA, USA; 3Massachusetts General Hospital, Boston, MA, USA Background: Chemotherapy for patients />70 with advanced NSCLC is associated with survival benefits but with increased toxicity. Erlotinib has shown promising activity, and a tolerable side effect profile, in the treatment of patients who have failed prior chemotherapy. We have conducted a single center, phase II trial of erlotinib in patients 970 years with previously untreated advanced NSCLC.