as VEGFR. Sorafenib inhibits VEGFR1 with an IC 50 of 26 nM and VEGFR2 with
an IC 50 ¼ 90 nM. Other kinases that were found to be influenced by sorafenib are
FLT-3 (IC 50 ¼ 33 nM), p38 (IC 50 ¼ 38 nM), RET (IC 50 ¼ 47 nM), c-KIT
(IC 50 ¼ 68 nM), and FGFR1 (IC 50 ¼ 580 nM) [109, 126, 130]. A phase-III clinical
trial testing sorafenib in advanced HCC (SHARP trial) was performed with
602 patients that were treated either with 400 mg sorafenib twice daily (299 patients)
or with placebo (303 patients) [74, 129]. In that trial, 7 patients (2%) showed partial
response, and 211 patients (71%) had a stable disease in the sorafenib group,
whereas 2 patients (1%) showed partial response and 204 patients (67%) had a
stable disease in placebo group. The median overall survival was 10.7 months upon
sorafenib and 7.9 months upon placebo treatment. Median time to symptomatic
progression was 4.1 months in the sorafenib group and 4.9 months in the placebo
group. In addition, median time to radiological progression was 5.5 months in the
sorafenib group and 2.8 months in the placebo group [109].
As mentioned before, phase-III clinical trials of sorafenib were also conducted
against other tumor entities such as RCC and thyroid carcinoma [74, 128, 131]. In a
trial against radioactive iodine refractory thyroid cancer (DECISION), 417 patients
were treated either with 400 mg sorafenib twice per day (207 patients) or with
placebo (210 patients) [132]. Sorafenib triggered a partial response in 12.2% of
patients which was seen in only 0.5% of patients treated with the placebo. Furthermore, the sorafenib-treated group showed a median overall survival of 10.8 months
compared to 5.8 months in the placebo-treated group.
Adverse effects associated with sorafenib were fatigue, anorexia, hypertension,
nausea, vomiting, alopecia, flushing, constipation, voice change, diarrhea, headache,
joint pain, pruritus, weight loss, hemorrhage (upper GI), neuropathy, stomatitis,
hypophosphatemia, musculoskeletal pain, and abdominal pain [74, 109, 118, 125,
129, 132].
The molecular mechanisms for resistance against sorafenib are complex. It was
shown that activation of p38alpha signaling during sorafenib therapy circumvents
sorafenib-mediated inhibition of Raf in HCC. In line with this, inhibition of
p38alpha improved the outcome of sorafenib in HCC mouse models [133].
For patients that show a progressive disease under sorafenib, recently the RAF
inhibitor regorafenib (which targets also several other kinases, such as VEGFR,
PDGFR) was approved by the FDA [77] (Fig. 5). In the RESORCE trial, 573 patients
that progressed under sorafenib received either 160 mg regorafenib or placebo. The
median survival under regorafenib was 10.6 months compared to 7.8 months under
placebo treatment [77]. Furthermore, regorafenib was approved by the FDA for the
treatment of metastatic colorectal cancer and advanced gastrointestinal stromal
tumor (GIST) [75, 76].
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A. Moschopoulou et al.
an IC 50 ¼ 90 nM. Other kinases that were found to be influenced by sorafenib are
FLT-3 (IC 50 ¼ 33 nM), p38 (IC 50 ¼ 38 nM), RET (IC 50 ¼ 47 nM), c-KIT
(IC 50 ¼ 68 nM), and FGFR1 (IC 50 ¼ 580 nM) [109, 126, 130]. A phase-III clinical
trial testing sorafenib in advanced HCC (SHARP trial) was performed with
602 patients that were treated either with 400 mg sorafenib twice daily (299 patients)
or with placebo (303 patients) [74, 129]. In that trial, 7 patients (2%) showed partial
response, and 211 patients (71%) had a stable disease in the sorafenib group,
whereas 2 patients (1%) showed partial response and 204 patients (67%) had a
stable disease in placebo group. The median overall survival was 10.7 months upon
sorafenib and 7.9 months upon placebo treatment. Median time to symptomatic
progression was 4.1 months in the sorafenib group and 4.9 months in the placebo
group. In addition, median time to radiological progression was 5.5 months in the
sorafenib group and 2.8 months in the placebo group [109].
As mentioned before, phase-III clinical trials of sorafenib were also conducted
against other tumor entities such as RCC and thyroid carcinoma [74, 128, 131]. In a
trial against radioactive iodine refractory thyroid cancer (DECISION), 417 patients
were treated either with 400 mg sorafenib twice per day (207 patients) or with
placebo (210 patients) [132]. Sorafenib triggered a partial response in 12.2% of
patients which was seen in only 0.5% of patients treated with the placebo. Furthermore, the sorafenib-treated group showed a median overall survival of 10.8 months
compared to 5.8 months in the placebo-treated group.
Adverse effects associated with sorafenib were fatigue, anorexia, hypertension,
nausea, vomiting, alopecia, flushing, constipation, voice change, diarrhea, headache,
joint pain, pruritus, weight loss, hemorrhage (upper GI), neuropathy, stomatitis,
hypophosphatemia, musculoskeletal pain, and abdominal pain [74, 109, 118, 125,
129, 132].
The molecular mechanisms for resistance against sorafenib are complex. It was
shown that activation of p38alpha signaling during sorafenib therapy circumvents
sorafenib-mediated inhibition of Raf in HCC. In line with this, inhibition of
p38alpha improved the outcome of sorafenib in HCC mouse models [133].
For patients that show a progressive disease under sorafenib, recently the RAF
inhibitor regorafenib (which targets also several other kinases, such as VEGFR,
PDGFR) was approved by the FDA [77] (Fig. 5). In the RESORCE trial, 573 patients
that progressed under sorafenib received either 160 mg regorafenib or placebo. The
median survival under regorafenib was 10.6 months compared to 7.8 months under
placebo treatment [77]. Furthermore, regorafenib was approved by the FDA for the
treatment of metastatic colorectal cancer and advanced gastrointestinal stromal
tumor (GIST) [75, 76].
140
A. Moschopoulou et al.