【Cancer research】表皮生长因子受体酪氨酸激酶抑制剂
发布于 2008-10-21 · 浏览 2075 · IP 广东广东
这个帖子发布于 16 年零 195 天前，其中的信息可能已发生改变或有所发展。
EGFR tyrosine kinase inhibitors (TKIs)
A recent phase III trial of the combination of gemcitabine with erlotinib was associated with a significant prolongation of survival .
First reported at the 2005 ASCO GI Meeting, this was the first phase III trial to demonstrate an OS benefit using a combination therapy in pancreatic cancer . Five hundred sixty-nine chemotherapy naïve patients were randomized to receive weekly gemcitabine 1000 mg/m2 for 7 weeks with 1 week off followed by three out of 4 weeks combined with erlotinib at 100 mg/day (a small cohort of 48 patients was treated with 150 mg/day) or placebo. Eligibility was not dependent on EGFR status. The study was a double blind placebo controlled study adequately powered for OS as primary end-point. Secondary end-points included PFS, quality of life, RR and toxicity. OS was 6.24 months for the combination arm versus 5.9 for the control arm (P = 0.025). One-year survival was also better with erlotinib plus gemcitabine (23% versus 17%; P = 0.023). PFS was significantly longer with erlotinib plus gemcitabine (3.75 versus 3.5 months) with an estimated HR of 0.77 (95% CI, 0.64–0.92; P = 0.004). Objective RR was not significantly different between the arms, although more patients treated with erlotinib had clinical benefit. Treatment was generally well-tolerated. Patients in the combination arm experienced higher frequencies of rash, diarrhea, infection, and stomatitis, but these were generally grade 1 or 2. Hematologic toxicity was similar in the arms with grade 3/4 neutropenia and thrombocytopenia seen in 24 and 10% of erlotinib and gemcitabine patients and 27 and 11% of placebo and gemcitabine patients, respectively. Grade 3 or greater elevations of AST were reported in 11 and 8% of patients receiving erlotinib and placebo, respectively. There were six protocol-related deaths, all in the experimental arm. Two were treatment-related complications (interstitial pneumonitis and sepsis) and four were due to a combination of cancer and protocol treatment complications (interstitial pneumonitis, sepsis, cerebrovascular accident, and neutropenic sepsis). A total of eight patients had an interstitial lung disease (ILD)-like syndrome, seven receiving erlotinib and gemcitabine and one receiving placebo and gemcitabine.
Erlotinib is also being evaluated in combination with capecitabine in patients who failed first-line therapy with gemcitabine . Preliminary results of 28 patients accrued in a phase II trial were presented at the 2005 ASCO Meeting. Capecitabine was given at 1000 mg/m2 twice a day for 14 out of 21 days and the dose of erlotinib was 150 mg. Median number of cycles received was almost 4. The regimen was generally well tolerated with 14% of patients experiencing grade 3 and 4 rash and diarrhea. Eleven percent have achieved partial response and 57% have achieved stable disease with median OS of 6.7 months.
A phase I trial evaluating the combination of gemcitabine, bevacizumab and erlotinib in patients with unresectable locally advanced or metastatic pancreatic cancer was presented at the 2007 ASCO Annual Meeting. Two cohorts of 6 patients have been treated with erlotinib (150 mg/day p.o.), bevacizumab (5 mg/kg i.v.), and either 10 mg/m2/min infusion of gemcitabine 850 mg/m2 (cohort A) or gemcitabine 1000 mg/m2 (cohort B). Twelve patients have been included in this study (6 cohort 1 and 6 cohort 2). Eleven patients have concluded the study and 7 have received complete treatment as per protocol. Three of 6 patients in cohort 1 developed grade 3 asthenia (50%), 2 patients grade 3 neutropenia (33.3%), whereas 1 patient had grade 3 leucopenia and grade 3 skin rash. In cohort 2, most severe adverse events were: 1 case of grade 4 γ-GT elevation, 1 patient grade 3 skin rash and 1 patient experienced asthenia grade 3. No severe hematological toxicity in cohort 2 was reported. One patient of each cohort required dose reduction of erlotinib, both due to skin rash. Mild diarrhea was reported in 11 of the 12 patients evaluated. No dose limiting toxicities have been reported and MTD has not been reached. Two patients obtained partial response (both included in cohort 1) and 7 had stabilization (3 and 4 in cohorts 1 and 2, respectively) for an overall disease control of 75%.
Gefitinib has also been tested as part of a salvage regimen for pancreatic cancer based on preclinical data that demonstrated increased efficacy in combination with docetaxel as compared to docetaxel alone. Preliminary results of a phase II study were presented at the 2006 ASCO Annual Meeting . In this study with 31 patients enrolled thus far, the best response was stable disease in 5 patients with a median OS of 4.4 months. Given the high incidence of neutropenic fever, the dose of docetaxel has been subsequently reduced from 75 to 60 mg/m2. These results are summarized in Table 2.
A phase II study of gemcitabine combined with gefitinib in 54 patients with inoperable or metastatic pancreatic cancer was presented at the 2007 ASCO Annual Meeting [96]. Gemcitabine (1000 mg/m2) was administered weekly for 7 cycles. Gefitinib (250 mg) was given orally. EGFR, HER-2 and PTEN were assessed by IHC and FISH. Tumor biopsies were evaluated for the presence of somatic mutations in exons 18–21 of EGFR and exon 2 of RAS by bi-directional sequencing. Ten patients (19%) completed treatment, while 36 patients (67%) progressed before the completion of the treatment. Three patients (6%) had a partial response and 11 patients (20%) a stable disease. After a median follow-up of 9 months, median OS was 7.4 months, while median TTP was 3.9 months. The 1-year survival rate was 23%. Rash of any grade was reported in 28 patients (52%). The most common severe toxicities were neutropenia (13%) and leucopenia (6%). RAS mutations were identified in 18/34 patients (53%). Two additional patients had an EGFR point mutation in exon 20. EGFR expression was found in 23/30 patients (77%), while EGFR amplification was not observed. HER-2 gain was detected in 4/20 patients and PTEN deletion in 14/20 patients. PTEN expression was detected in 7/30 patients and it was the only marker associated with significantly increased TTP (P = 0.008).
A phase II study evaluated gefitinib and docetaxel as second-line therapy . Forty-five patients were enrolled of whom 41 are evaluable. Common treatment-related grade 3/4 toxicities were: febrile neutropenia / infection in 11 pts (27%); fatigue (7%), nausea (7%), diarrhea (5%) and vomiting (2%). Only 3 patients discontinued treatment due to toxicities and more than 2 cycles were administered to 40% of patients. The median OS was 4.7 months. TTP was 1.8 months. There was one partial response and stable disease in 14 patients.
A preliminary analysis of a phase II study randomizing patients to gemcitabine and bevacizumab with either cetuximab (GBC) or erlotinib (GBE) was presented at the 2007 ASCO Meeting [98]. Both the arms demonstrated significant activity with response rates of 19 and 21%, respectively, and stable disease rate of 59 and 67%, respectively.
Several phase I studies have also been performed to assess the feasibility and efficacy of EGFR TKIs in combination with radiotherapy. One of these trials used a novel regimen of concomitant gemcitabine, paclitaxel and erlotinib concurrent with radiotherapy followed by maintenance erlotinib until disease progression . The maximum tolerated dose of erlotinib during the radiotherapy phase was 50 mg. There were multiple dose limiting toxicities described including diarrhea, rash, myelosuppression and small bowel stricture but results were encouraging with a reported 46% rate of partial response.
The results of two randomized trials looking at the combination of bevacizumab and cetuximab are awaited. Potential combinations with other biologic agents are being investigated. Also the combination of different target agents, such as combining the EGFR blockers – such as erlotinib and the cyclooxygenase-2 inhibitor (celecoxib) – needs to be investigated in clinical trials. Similarly, the combination of cetuximab with bevacizumab warrants investigation, especially in patients where chemotherapy is either not an option or not desired.
A recent phase III trial of the combination of gemcitabine with erlotinib was associated with a significant prolongation of survival .
First reported at the 2005 ASCO GI Meeting, this was the first phase III trial to demonstrate an OS benefit using a combination therapy in pancreatic cancer . Five hundred sixty-nine chemotherapy naïve patients were randomized to receive weekly gemcitabine 1000 mg/m2 for 7 weeks with 1 week off followed by three out of 4 weeks combined with erlotinib at 100 mg/day (a small cohort of 48 patients was treated with 150 mg/day) or placebo. Eligibility was not dependent on EGFR status. The study was a double blind placebo controlled study adequately powered for OS as primary end-point. Secondary end-points included PFS, quality of life, RR and toxicity. OS was 6.24 months for the combination arm versus 5.9 for the control arm (P = 0.025). One-year survival was also better with erlotinib plus gemcitabine (23% versus 17%; P = 0.023). PFS was significantly longer with erlotinib plus gemcitabine (3.75 versus 3.5 months) with an estimated HR of 0.77 (95% CI, 0.64–0.92; P = 0.004). Objective RR was not significantly different between the arms, although more patients treated with erlotinib had clinical benefit. Treatment was generally well-tolerated. Patients in the combination arm experienced higher frequencies of rash, diarrhea, infection, and stomatitis, but these were generally grade 1 or 2. Hematologic toxicity was similar in the arms with grade 3/4 neutropenia and thrombocytopenia seen in 24 and 10% of erlotinib and gemcitabine patients and 27 and 11% of placebo and gemcitabine patients, respectively. Grade 3 or greater elevations of AST were reported in 11 and 8% of patients receiving erlotinib and placebo, respectively. There were six protocol-related deaths, all in the experimental arm. Two were treatment-related complications (interstitial pneumonitis and sepsis) and four were due to a combination of cancer and protocol treatment complications (interstitial pneumonitis, sepsis, cerebrovascular accident, and neutropenic sepsis). A total of eight patients had an interstitial lung disease (ILD)-like syndrome, seven receiving erlotinib and gemcitabine and one receiving placebo and gemcitabine.
Erlotinib is also being evaluated in combination with capecitabine in patients who failed first-line therapy with gemcitabine . Preliminary results of 28 patients accrued in a phase II trial were presented at the 2005 ASCO Meeting. Capecitabine was given at 1000 mg/m2 twice a day for 14 out of 21 days and the dose of erlotinib was 150 mg. Median number of cycles received was almost 4. The regimen was generally well tolerated with 14% of patients experiencing grade 3 and 4 rash and diarrhea. Eleven percent have achieved partial response and 57% have achieved stable disease with median OS of 6.7 months.
A phase I trial evaluating the combination of gemcitabine, bevacizumab and erlotinib in patients with unresectable locally advanced or metastatic pancreatic cancer was presented at the 2007 ASCO Annual Meeting. Two cohorts of 6 patients have been treated with erlotinib (150 mg/day p.o.), bevacizumab (5 mg/kg i.v.), and either 10 mg/m2/min infusion of gemcitabine 850 mg/m2 (cohort A) or gemcitabine 1000 mg/m2 (cohort B). Twelve patients have been included in this study (6 cohort 1 and 6 cohort 2). Eleven patients have concluded the study and 7 have received complete treatment as per protocol. Three of 6 patients in cohort 1 developed grade 3 asthenia (50%), 2 patients grade 3 neutropenia (33.3%), whereas 1 patient had grade 3 leucopenia and grade 3 skin rash. In cohort 2, most severe adverse events were: 1 case of grade 4 γ-GT elevation, 1 patient grade 3 skin rash and 1 patient experienced asthenia grade 3. No severe hematological toxicity in cohort 2 was reported. One patient of each cohort required dose reduction of erlotinib, both due to skin rash. Mild diarrhea was reported in 11 of the 12 patients evaluated. No dose limiting toxicities have been reported and MTD has not been reached. Two patients obtained partial response (both included in cohort 1) and 7 had stabilization (3 and 4 in cohorts 1 and 2, respectively) for an overall disease control of 75%.
Gefitinib has also been tested as part of a salvage regimen for pancreatic cancer based on preclinical data that demonstrated increased efficacy in combination with docetaxel as compared to docetaxel alone. Preliminary results of a phase II study were presented at the 2006 ASCO Annual Meeting . In this study with 31 patients enrolled thus far, the best response was stable disease in 5 patients with a median OS of 4.4 months. Given the high incidence of neutropenic fever, the dose of docetaxel has been subsequently reduced from 75 to 60 mg/m2. These results are summarized in Table 2.
A phase II study of gemcitabine combined with gefitinib in 54 patients with inoperable or metastatic pancreatic cancer was presented at the 2007 ASCO Annual Meeting [96]. Gemcitabine (1000 mg/m2) was administered weekly for 7 cycles. Gefitinib (250 mg) was given orally. EGFR, HER-2 and PTEN were assessed by IHC and FISH. Tumor biopsies were evaluated for the presence of somatic mutations in exons 18–21 of EGFR and exon 2 of RAS by bi-directional sequencing. Ten patients (19%) completed treatment, while 36 patients (67%) progressed before the completion of the treatment. Three patients (6%) had a partial response and 11 patients (20%) a stable disease. After a median follow-up of 9 months, median OS was 7.4 months, while median TTP was 3.9 months. The 1-year survival rate was 23%. Rash of any grade was reported in 28 patients (52%). The most common severe toxicities were neutropenia (13%) and leucopenia (6%). RAS mutations were identified in 18/34 patients (53%). Two additional patients had an EGFR point mutation in exon 20. EGFR expression was found in 23/30 patients (77%), while EGFR amplification was not observed. HER-2 gain was detected in 4/20 patients and PTEN deletion in 14/20 patients. PTEN expression was detected in 7/30 patients and it was the only marker associated with significantly increased TTP (P = 0.008).
A phase II study evaluated gefitinib and docetaxel as second-line therapy . Forty-five patients were enrolled of whom 41 are evaluable. Common treatment-related grade 3/4 toxicities were: febrile neutropenia / infection in 11 pts (27%); fatigue (7%), nausea (7%), diarrhea (5%) and vomiting (2%). Only 3 patients discontinued treatment due to toxicities and more than 2 cycles were administered to 40% of patients. The median OS was 4.7 months. TTP was 1.8 months. There was one partial response and stable disease in 14 patients.
A preliminary analysis of a phase II study randomizing patients to gemcitabine and bevacizumab with either cetuximab (GBC) or erlotinib (GBE) was presented at the 2007 ASCO Meeting [98]. Both the arms demonstrated significant activity with response rates of 19 and 21%, respectively, and stable disease rate of 59 and 67%, respectively.
Several phase I studies have also been performed to assess the feasibility and efficacy of EGFR TKIs in combination with radiotherapy. One of these trials used a novel regimen of concomitant gemcitabine, paclitaxel and erlotinib concurrent with radiotherapy followed by maintenance erlotinib until disease progression . The maximum tolerated dose of erlotinib during the radiotherapy phase was 50 mg. There were multiple dose limiting toxicities described including diarrhea, rash, myelosuppression and small bowel stricture but results were encouraging with a reported 46% rate of partial response.
The results of two randomized trials looking at the combination of bevacizumab and cetuximab are awaited. Potential combinations with other biologic agents are being investigated. Also the combination of different target agents, such as combining the EGFR blockers – such as erlotinib and the cyclooxygenase-2 inhibitor (celecoxib) – needs to be investigated in clinical trials. Similarly, the combination of cetuximab with bevacizumab warrants investigation, especially in patients where chemotherapy is either not an option or not desired.
最后编辑于 2008-11-09 · 浏览 2075
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