The family of tyrosine kinase inhibitors is still growing. After sunitinib, sorafenib
and more recently pazopanib, and axitinib, we probably now should count on tivozanib
(1). This pan-VEGFR inhibitor (VEGF-R1,-R2,-R3) is more selective and potent in vitro
than previous known TK inhibitors. Tivozanib was tested in a phase II trial reported
by Nosov et al. (1) Tivozanib was administered at a daily dose of 1.5 mg, for 3 weeks
followed by a break of 1 week. Of the 272 patients treated during the first period
of 16 weeks, 78, who presented tumour shrinkage of at least 25%, were maintained on
tivozanib. All of the 118 patients who presented less than 25% change in the tumour,
were randomized between placebo and tivozanib, during the next 12 weeks. Finally,
76 patients discontinued the treatment and were excluded from the analysis, mainly
due to progressive disease (50/76). The main clinical characteristics include clear
cell histology (83%), and prior nephrectomy (73%) with no previous treatment (54%).
Considering all the patients, the median progression-free survival (PFS) and objective
response rate (ORR) were 11.7 and 24% respectively. Results may be considered according
to the two sequential periods of treatment. The ORR during the sixteen week open-label
period reached 18% (95%CI, 14-23%), with 66% of stable disease (SD). At the end of
the second double-blind period, significantly more patients in the tivozanib arm (49%,
n=30) were progression-free, compared with the placebo-arm (21%, n=12), (P=0,001);
median progression-free survival was also statistically longer in the tivozanib arm
compared to placebo, 11.9 months (9.3-14.7 months) and 9.1 (7.3-9.5) respectively,
HR=0.797, P=0.042. The ORR were 33% and 23% in the two groups respectively, P=0.014.
In terms of toxicity, the hypothesis suggesting that the specificity of the target
would permit a decrease in off-targeted toxicity was confirmed with less adverse events
apart from hypertension, a class effect. The two more frequent adverse effects of
any grade reported were: hypertension (45%), and dysphonia (22%). Other toxicities,
frequently reported with other TKIs, such as asthenia, diarrhea, stomatitis or hand-foot
syndrome, were reported in 10%, 12%, 4% and 4% respectively, all grades. Dose-reduction
concerned only 8% of the patients, and interruptions 4% (n=11). According to the data,
the authors concluded that tivozanib demonstrated promising activity and an acceptable
safety and tolerability profile.
Furthermore, these results are in accordance with the data presented by Robert Motzer
at the ASCO 2012 meeting concerning a phase III trial, comparing tivozanib and sorafenib
in the first-line setting (2). The same schedule of tivozanib was compared to 400
mg, twice daily of sorafenib continuously. The trial demonstrated a statistically
significant benefit in progression-free survival in the 260 patients treated with
tivozanib compared to the sorafenib group (n=257): 11.9 months (9.3-14.7 months) and
9.1 months (7.3-9.5 months) respectively, HR=0.797, P=0.042. The toxicity profile
was as expected according to the results of this phase II trial, with 26% of grade
3/4 hypertension, and 21% of grade 3/4 dysphonia. The incidence of hypertension should
be interpreted along with previous data reporting this effect, as a biomarker of pharmacological
activity. Furthermore, its predictive role of a therapeutic effect, with sunitinib
and more recently with axitinib has also been reported (3,4). Lastly, the safer toxicity
profile may allow better exposure of the patient to the drug. However, the recent
titration data concerning axitinib has begun to shed light on the question of the
fixed pre-defined dose of tyrosine kinase agents.
In conclusion, tivozanib is really a new anti-angiogenic drug in the landscape of
treatment in RCC and not only a me-too drug as sunitinib, sorafenib and pazopanib
are. The next challenge is the position in 1st line between tivozanib and axitinib,
waiting for forthcoming planned trials.