On May 2, 2013, AVEO Oncology is set to face the FDA’s
Oncologic Drugs Advisory Committee (ODAC) for a review of the company’s New
Drug Application (NDA) for tivozanib, the proposed indication being for treatment
of patients with advanced renal cell carcinoma. The PDUFA goal date for the
final decision is by July 28, 2013.
The vascular endothelial growth factor (VEGF) pathway plays
a significant role in angiogenesis, which is critical in cancer. Angiogenesis,
the formation of new blood vessels, is essential for endothelial cell
proliferation, migration and survival. Tivozanib is a potent, selective, long
half-life inhibitor of VEGF receptors 1,2, and 3, that is designed to
optimize VEGF blockade while minimizing off-target toxicities. Several agents targeting VEGF are already
approved for the treatment of advanced renal cell cancer (RCC) including
sorafenib, sunitinib, pazopanib, axitinib and bevacizumab.
The NDA submission for Tivozanib is based on the TIVO-1
study, a global, randomized, open-label, phase 3 superiority clinical trial
evaluating the efficacy and safety of tivozanib, 1.5mg p.o. daily, given in 3
weeks on/1 week off cycle, compared to sorafenib 400mg continuous daily dosing,
in 517 patients with advanced RCC. Eighty-six centers participated in the
TIVO-1 study, including centers in Europe (the majority) and North America. The
primary efficacy endpoint progression free survival (PFS) was ascertained for
each subject by a central panel of blinded independent radiologists. Patients
randomized to the sorafenib arm were eligible to cross over to tivozanib
therapy under a separate protocol after radiographic confirmation of disease
progression. No crossover protocol was available for patients randomized to the
tivozanib arm. Importantly, the study was powered at 90% to detect a >45%
improvement in median PFS from 6.7months for sorafenib to 9.7 months for
tivozanib.
Results of TIVO-1
were first released in full at ASCO
2012. 70% of the patients enrolled in the study were treatment naive, and
30% had received prior systemic therapy with cytokines. As reported by the
company, based on independent radiological reviews, tivozanib demonstrated a
statistically significant improvement in PFS with a median PFS of 11.9 months
compared to a median PFS of 9.1 months for sorafenib in the overall (Intent To
Treat) study population (HR=0.797, 95% CI 0.639–0.993; P=0.042). This
represents a 30% improvement in PFS. Objective response rate for tivozanib was
33% compared to 23% for sorafenib (p=0.014). The efficacy advantage of
tivozanib over sorafenib was consistent across subgroups in the study. Those who were treatment naïve for advanced RCC (70%
of total study population), tivozanib demonstrated a statistically significant
improvement in PFS with a median PFS of 12.7 months compared to a median PFS of
9.1 months for sorafenib (HR 0.756, 95% CI 0.580–0.985; P=0.037). This is the
longest median PFS reported to date in treatment naïve advanced RCC patients in
a pivotal study. This advantage was also
consistently observed in the subpopulation of patients who were pretreated with
systemic therapy (30% of total study population), tivozanib demonstrated an
improvement in PFS with a median PFS of 11.9 months compared to a median PFS of
9.1 months for sorafenib.
Data for overall survival matured later and were presented
in early 2013.
The final OS analysis, as specified by the protocol, showed a median OS of 28.8
months (95% confidence interval [CI]: 22.5–NA) for tivozanib versus a median OS
of 29.3 months (95% CI: 29.3–NA) for the comparator arm, sorafenib. No
statistical difference between the two arms (HR=1.245, p=0.105) was observed.
Of note, 70% of the patients randomized to the sorafenib
arm, went on to receive therapy with tivozanib following adjudicated
progression. However, in the tivozanib arm, only 36% received subsequent
therapy following progression. This likely accounts for the positive survival
observed in the comparator arm.
These clinical data should be evaluated in the context of
data from comparable oral tyrosine kinase inhibitors approved for RCC. Comparisons across studies are difficult to make as the
study populations and comparator arms differ. However, we note the following:
The performance of the comparator arm in TIVO-1 far exceeded
the projected PFS in this setting, or that observed in prior trials. Despite a
vastly over-performing comparator arm, the tivozanib arm still demonstrated a
30% improvement in PFS vs. sorafenib in the primary end point, which was
statistically significant. The median OS for the tivozanib arm is longer than
that observed with sunitinib, which is considered the current standard of first-line
care. The high rate of crossover from
sorafenib to tivozanib, (which is highly active as a single agent), is likely
to account for the improved OS observed in the comparator arm. Finally a nonsignificant
OS is not a barrier to full approval in this setting.
Currently approved therapies for RCC are toxic. Tivozanib
possesses a superior safety and tolerability profile compared with sorafenib.
The dosing schedule of once a day, 3 weeks on and 1 week off provides patients
with a “drug holiday” which helps improve quality of life. As observed in the clinical study, the rate
of adverse events and treatment discontinuations was lower in the tivozanib
treatment arm. Unlike some currently approved therapies, there are no
suggestions of significant hepatotoxicity or severe myelosuppression. Additionally, treatment with tivozanib is associated with
lower rates of diarrhea, hand-foot syndrome, and significantly less alopecia
compared with sorafenib. All of these are highly meaningful to improving a
patients’ quality of life and will be important to oncologists.
In summary, with Robert Motzer, MD as principal investigator
highly likely to be presenting on behalf of the sponsor (he a veteran at RCC
ODAC meetings), we see very little to suggest that a panel would vote against
approval of this drug. While some may argue that the RCC market is crowded, we
see tivozanib being used as an alternative to other oral therapies in the
frontline setting. The agent’s
beneficial dosing cycle and superior tolerability profile make this an exciting
addition to the current armamentarium. We believe oncologists would want to
have this available in the clinic to offer patients. It also adds a useful
alternative to more toxic agents used in sequencing for subsequent lines of
therapy.
There are some potential issues which could hinder initial
uptake. The trial was conducted head to head with sorafenib as a comparator and
not versus sunitinib which is the preferred agent of choice in the first-line
setting. Some oncologists may want to
see comparative data vs. sunitinib before selecting this agent in their first-line
patients. Another possible concern is
that the study was conducted almost exclusively in eastern europe. However,
given that the events for the primary end point were all independently
adjudicated by central radiographic review, and that all the sub-group analyses
appear supportive, we do not see this as significant regulatory barrier to
approval. Furthermore, we expect the sponsor to present sub-analyses from the
US centers at ODAC which should help mitigate concerns.
In the near term, the RCC market is estimated to grow to
$1.6Bn by 2016, 80% of which is occupied by angiogenesis inhibitors. Front-line
treatment accounts for ~65% of this market, of which we see tivozanib playing a
significant role. If 1 in 7 treatment naïve patients are receiving tivozanib as
initial therapy by 2016, this would represent near term sales potential of:
$1.6 Bn x 0.8 x 0.65 x 0.14 = $116.5 in first-line sales.
This does not represent peak sales potential and does not include further upside
from use in the second-, third- and subsequent lines therapy where it will also
play a role. Given that AVEO has a
worldwide (ex-Asia) partnership with Astellas, the company could also be
eligible to receive up to $90 MM in milestone payments in connection with
regulatory approval as well as > $780MM in commercial milestones. Subject to
regulatory approval, AVEO will lead commercialization of tivozanib in North
America and Astellas will lead commercialization of tivozanib in the European
Union (EU). The companies will share equally all North American and EU
development and commercialization costs and profits for tivozanib. Outside of
North America and EU, Astellas will be responsible for the development and
commercialization costs of tivozanib and will be obligated to pay AVEO a
tiered, double-digit royalty on sales in those territories. In the past 12
months, the stock has traded well above the current levels and expect is to
rise above $10 on a positive vote.
In summary, we expect a positive ODAC panel vote in favor of
approval with a positive FDA decision by July 28, 2013.
Disclosure: The
author is long in $AVEO
This article is not intended as trading advice. Please perform your own due diligence before buying or selling securities.
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