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Lung Cancer
Table 1: Bevacizumab as the First-line Treatment of Advanced Non-small-cell Lung Cancer – Phase III Trials
Trial Treatment Patients Response Rate Median PFS (months) Median OS (months)
ECOG 4599
4
PC 433 59/392 (15%) 4.5 10.3
Bevacizumab + PC 417 133/381 (35%) 6.2 12.3
p<0.001 HR 0.66 (95% CI 0.57–0.077) HR 0.79 (95% CI 0.67–0.92)
p<0.001 p=0.003
AVAiL
5
GC 347 20% 6.1
Bevacizumab (7.5mg/kg) + GC 345 34% 6.7
p<0.0001 HR 0.75 (95% CI 0.62–0.91) NS*
p=0.0026
Bevacizumab (15mg/kg) + GC 351 30% 6.5
p=0.0017 HR 0.82 (95% CI 0.68–0.98) NS*
p=0.03
ECOG = Eastern Cooperative Oncology Group; AVAiL = Avastin® in Lung Cancer; PFS = progression-free survival; OS = overall survival; HR = hazard ratio; CI = confidence interval;
NS = not significant; GC = gemcitabine/cisplatin; PC = paclitaxel/carboplatin.
* Genentech press release, April 20, 2008.
Table 2: Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors as the First-line Treatment of Advanced Non-small-cell
Lung Cancer – Phase II and III Trials
Trial Treatment Patients Response Rate (%) Median PFS (months) Median OS (months)
INTACT1
9
GC 363 47.2 6 10.9
(phase III) Gefitinib (500mg/day) + GC 365 50.3 5.5 9.9
Gefitinib (250mg/day) + GC 365 51.2 5.8 9.9
p=NS p=0.763 p=0.456
INTACT2
10
PC 345 28.7 5 9.9
(phase III) Gefitinib (500mg/day) + PC 347 30.4 5.3 9.8
Gefitinib (250mg/day) + PC 345 30 4.6 8.7
p=NS p=0.056 p=0.639
TRIBUTE
11
PC 540 19.3 4.9 10.5
(phase III) Erlotinib + PC 539 21.5 5.1 10.6
p=0.36 p=0.36 HR 0.995 (95% CI 0.86–1.16)
p=0.95
Subgroup – never smoker
PC 44 11 4.3 10.1
Erlotinib + PC 72 30 6 22.5
p=0.02 HR 0.5 (95% CI 0.31–0.8) HR 0.49 (95% CI 0.28–0.85)
p=0.002 p=0.01
TALET
12
GC 579 29.9 24.6 weeks 44.1 weeks
(phase III) Erlotinib + GC 580 31.5 23.7 weeks 43 weeks
p=NS HR 0.98 (95% CI 0.86–1.11) HR 1.06 (95% CI 0.90–1.23)
p=0.74 p=0.49
FAST-ACT
15
GP 78 24.4 5.5 NR
(phase II) Erlotinib* + GP 76 36.8 7.2 NR
OR 1.85 (95% CI 0.91–3.76) HR 0.57 (95% CI 0.38–0.84)
p=0.089 p=0.005
INTACT = iressa non-small-cell lung cancer trial assessing combination treatment; TRIBUTE = tarceva responses in conjunction with paclitaxel and carboplatin; TALENT = tarceva lung
cancer investigation trial; PFS = progression-free survival; OS = overall survival; HR = hazard ratio; CI = confidence interval; NS = not significant; NR = not reported; GC = gemcitabine/cisplatin;
PC = paclitaxel/carboplatin; GP = gemcitabine/platinum; * erlotinib (150mg/day) was taken on days 15–28.
platinum-based chemotherapy as the first-line therapy in patients with a possible sequence-dependent antagonism between EGFR-TKIs and
advanced NSCLC (see Table 2).
10–13
Although the addition of erlotinib to cytotoxic agents as a result of G1 arrest of tumour cells by EGFR-TKIs,
carboplatin and paclitaxel (CP) significantly prolonged survival in the which protect tumour cells from cell-cycle-specific cytotoxic agents.
subgroup of patients who had never smoked,
12
most clinical trials did not Therefore, the combination of EGFR-TKIs with chemotherapy could be
demonstrate any survival advantage with the addition of erlotinib or synergic if exposure of EGFR-TKIs before chemotherapy is avoided.
14
These
gefitinib to chemotherapy.
10,11,13
One possible explanation for the negative results have led to clinical trials of sequential administration of
results may be the lack of patient selection for known prognostic factors chemotherapy and EGFR-TKIs. Recently, a phase II randomised double-
in these trials. Since only one subgroup of patients with NSCLC has blind trial of sequential erlotinib and chemotherapy as the first-line
tumours that are dependent on the EGFR pathway, such as never having treatment (FAST-ACT) in patients with advanced NSCLC found that
been a smoker and EGFR mutations, few patients would have a clinical sequential administration of erlotinib with gemcitabine plus either cisplatin
benefit from EGFR-TKIs, thus overall trials could be underpowered to or carboplatin chemotherapy significantly prolonged PFS compared with
detect an effective therapy.
9
In addition, these trials used the continuous the placebo arm, which met the primary end-point of this study at 7.2
administration schedule of gefitinib or erlotinib from the beginning of versus 5.5 months, respectively; p=0.005 (see Table 2).
15
As well as the
chemotherapy. Recently, there has been growing pre-clinical evidence of sequence-dependent synergic antitumour activity, several in vitro studies
42 ASIA-PACIFIC ONCOLOGY & HAEMATOLOGY
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