metastases that were previously treated either with crizotinib or platinum-based
chemotherapy were treated with ceritinib or chemotherapy [56]. Finally, ceritinib
demonstrated potency against naive ALK-inhibitor NSCLC patients. The ASCEND-4
study revealed a median progression-free survival of 16.6 months of patients with
advanced ALK-positive NSCLC treated with ceritinib versus 8.1 months of the
chemotherapy-treated group [57]. The results from this study led to approval of
ceritinib in 2017 by FDA as first-line treatment for patients with ALK-positive
NSCLC [58]. Alectinib is another selective ALK inhibitor (Fig. 2). It was approved
by FDA in 2015 for the treatment of NSCLC patients with acquired resistance to
crizotinib (NP28673 and NP28761 phase-II clinical trials) [59, 60]. Later, the
randomized phase-III clinical trial ALEX showed extended beneficial activity of
alectinib in ALK-positive NSCLC patients. In particular, results demonstrated a
superior progression-free survival rate of alectinib compared to crizotinib in naive
ALK-inhibitor patients. In addition, alectinib was found to be less toxic and more
active toward CNS. Only 12% of patients in the alectinib group showed a CNS
progression event compared to 45% of the crizotinib group. Taking into account the
previous results, FDA approved alectinib as first-line treatment of ALK-positive,
metastatic NSCLC in 2017 [58, 61]. Latest additions to the ALK inhibitors’ list
include brigatinib and lorlatinib. Brigatinib is an ALK inhibitor used for NSCLC
resistant to crizotinib (Fig. 2). It has received accelerated approval by the FDA in
2017 after phase-II clinical trial ALTA demonstrated significant results for the
treatment of patients with progressed NSCLC [62, 63]. Lorlatinib was accepted for
the same treatment in 2018 (Fig. 2). Both drugs demonstrate significant intracranial
activity making them very potent in decreasing the formation of brain metastasis
[63, 64]. Phase-III clinical trial CROWN is currently ongoing for comparison of
lorlatinib with crizotinib as first-line treatments [58, 65].
4 VEGFR Inhibitors
More than 40 years ago, the hypothesis of targeting angiogenesis as a tumor therapy
was established [66]. Although many factors are involved in mechanisms leading to
blood vessel formation, activation of vascular endothelial growth factor (VEGF)
pathways was described to be critical in pro-angiogenic signaling. Several types of
solid cancers overexpress VEGF-A, making initially this protein to a highly relevant
target for selective antiangiogenic therapeutic strategy [67, 68]. Another strategy for
inhibiting angiogenesis is the blockage of tyrosine kinase activity of the
corresponding receptors VEGFR1, VEGFR2, and VEGFR3. Many receptor tyrosine
kinase inhibitors targeting VEGFR have been approved so far. Sorafenib, sunitinib,
axitinib, regorafenib, pazopanib, vandetanib, cabozantinib, and lenvatinib are used
for treatment of different solid carcinomas such as renal cell carcinoma (RCC),
hepatocellular carcinoma (HCC), thyroid cancer, pancreatic neuroendocrine tumor,
gastrointestinal stromal tumor (GIST), and metastatic colorectal cancer (CRC)
(Fig. 3). Sorafenib and sunitinib represent pioneer kinase inhibitors for the inhibition
134
A. Moschopoulou et al.
chemotherapy were treated with ceritinib or chemotherapy [56]. Finally, ceritinib
demonstrated potency against naive ALK-inhibitor NSCLC patients. The ASCEND-4
study revealed a median progression-free survival of 16.6 months of patients with
advanced ALK-positive NSCLC treated with ceritinib versus 8.1 months of the
chemotherapy-treated group [57]. The results from this study led to approval of
ceritinib in 2017 by FDA as first-line treatment for patients with ALK-positive
NSCLC [58]. Alectinib is another selective ALK inhibitor (Fig. 2). It was approved
by FDA in 2015 for the treatment of NSCLC patients with acquired resistance to
crizotinib (NP28673 and NP28761 phase-II clinical trials) [59, 60]. Later, the
randomized phase-III clinical trial ALEX showed extended beneficial activity of
alectinib in ALK-positive NSCLC patients. In particular, results demonstrated a
superior progression-free survival rate of alectinib compared to crizotinib in naive
ALK-inhibitor patients. In addition, alectinib was found to be less toxic and more
active toward CNS. Only 12% of patients in the alectinib group showed a CNS
progression event compared to 45% of the crizotinib group. Taking into account the
previous results, FDA approved alectinib as first-line treatment of ALK-positive,
metastatic NSCLC in 2017 [58, 61]. Latest additions to the ALK inhibitors’ list
include brigatinib and lorlatinib. Brigatinib is an ALK inhibitor used for NSCLC
resistant to crizotinib (Fig. 2). It has received accelerated approval by the FDA in
2017 after phase-II clinical trial ALTA demonstrated significant results for the
treatment of patients with progressed NSCLC [62, 63]. Lorlatinib was accepted for
the same treatment in 2018 (Fig. 2). Both drugs demonstrate significant intracranial
activity making them very potent in decreasing the formation of brain metastasis
[63, 64]. Phase-III clinical trial CROWN is currently ongoing for comparison of
lorlatinib with crizotinib as first-line treatments [58, 65].
4 VEGFR Inhibitors
More than 40 years ago, the hypothesis of targeting angiogenesis as a tumor therapy
was established [66]. Although many factors are involved in mechanisms leading to
blood vessel formation, activation of vascular endothelial growth factor (VEGF)
pathways was described to be critical in pro-angiogenic signaling. Several types of
solid cancers overexpress VEGF-A, making initially this protein to a highly relevant
target for selective antiangiogenic therapeutic strategy [67, 68]. Another strategy for
inhibiting angiogenesis is the blockage of tyrosine kinase activity of the
corresponding receptors VEGFR1, VEGFR2, and VEGFR3. Many receptor tyrosine
kinase inhibitors targeting VEGFR have been approved so far. Sorafenib, sunitinib,
axitinib, regorafenib, pazopanib, vandetanib, cabozantinib, and lenvatinib are used
for treatment of different solid carcinomas such as renal cell carcinoma (RCC),
hepatocellular carcinoma (HCC), thyroid cancer, pancreatic neuroendocrine tumor,
gastrointestinal stromal tumor (GIST), and metastatic colorectal cancer (CRC)
(Fig. 3). Sorafenib and sunitinib represent pioneer kinase inhibitors for the inhibition
134
A. Moschopoulou et al.