Velcade in solid tumors - part I
Piper Jaffray (Thomas Wei].
MLNM :Assessing Velcade In Solid Tumors
Overview
We undertook a review of relevant data for Velcade in solid tumors to try
to assess the opportunity for upside to our Velcade sales estimates. In
addition, we believe investors will become increasingly focused on the
solid tumor opportunity ahead of Millennium's goal of making several
investment decisions on Velcade over the next several months. As part of
Millennium's original 2004 goals for future development of Velcade, the
Company highlighted a number of "high priority" solid tumor indications,
including lung, breast, ovarian, and prostate cancers.
Over the past several years, investigators have presented data on Velcade
in all of these indications at the American Society for Clinical Oncology
(ASCO) meeting. In the following sections, we review the publicly
available data, as well as our perspective on these indications based on
recent conversations we have had with our oncology consultants. We believe
that none of the solid tumor studies with data available to date would
support FDA approval of Velcade in these settings without additional
clinical development, and that decisions Millennium will announce shortly
involve a level of investment it and its partner J&J are willing to incur
to expand Velcade's market potential. A "go" decision would mean that
additional trials are planned, likely Phase III, although additional Phase
II work may be required. A "no-go" decision means that the companies are
not planning to put significant capital into label expansion via that
particular indication, although Millennium will likely continue to sponsor
small investigator-led studies for Velcade in combination with other
agents. In Table 1, we summarize key solid tumor trials for Velcade
initiated or reported on to date.
Breast Cancer—"No-Go" Decision Already Made. At this year's ASCO meeting,
researchers from Northwestern University presented results from a Phase II
study of Velcade monotherapy in second-line metastatic breast cancer
patients. Velcade was given IV at a dose of 1.5 mg/m2 on days 1, 4, 8, and
11 every three weeks, with the potential to increase to 1.7 mg/m2. All 12
patients studied progressed on Velcade therapy, with a median time to
progression of 25 days (range from 10-62 days) and no responses were
observed. Six patients died at the time of the report, with a median time
to death of 136 days. Based on the lack of objective responses, the study
was terminated. A separate Velcade monotherapy study sponsored by MD
Anderson in Stage IV relapsed/refractory breast cancer was subsequently
terminated, presumable due to the lack of responses seen at Northwestern.
Based on these early data, Millennium has opted not to pursue breast
cancer as a high priority indication for Velcade label expansion.
Lung Cancer—Where Expectations Are Highest. Millennium has put significant
resources into studying Velcade in non-small cell lung cancer (NSCLC). In
December 2002, Millennium initiated a 155-patient randomized, open-label
study comparing Velcade monotherapy to Velcade plus Taxotere in patients
that have failed a maximum of one chemotherapy agent (prior paclitaxel
allowed, but prior Taxotere not allowed). At this year's ASCO meeting,
investigators presented data from an interim analysis conducted on the
first 60 patients enrolled in the study. Patients in the Velcade only arm
were dosed at 1.5 mg/m2, while the combination arm received a lower 1.3
mg/m2 dose. The response rate was 10% in the Velcade monotherapy arm (3/29
PRs) and 16% in the combination arm (5/31 PRs). Duration of response was
not available at the ASCO meeting, although anecdotal reports from
investigators involved in the trial suggest time to progression in the
range of 3-5 months. One physician consultant mentioned that the duration
of response data he has seen to date were unremarkable, while another
indicated there was enough data to suggest Velcade possesses some activity
in lung cancer. As a reference, Taxotere has shown response rates of 7-12%
in the second-line setting with median survival of 8-9 months and one-year
survival in approximately 30% of patients across a number of studies. We
believe the most comparable trial is a recent study comparing Lilly's
Alimta to Taxotere in the second-line setting, which restricted enrollment
to patients with one prior chemotherapy, with prior paclitaxel treatment
allowed. In this 571-patient trial, response rate was 8.8% for Taxotere
patients (11.1% in patients with a prior CR, 10.2% in patients with a
prior PR, and 4.6% in patients with prior SD). Median survival was 7.9
months, duration of response was 5.3 months, and time to response was 2.9
months for Taxotere patients. If the response rate for Velcade plus
Taxotere from a second analysis is similar to those from the preliminary
analysis, then our consultants would be encouraged that Velcade was
providing some anti-tumor synergies in the second-line setting, although
they also noted that combination therapies in the second-line setting
historically have not proven superior to single agent regimens. None of
the investigators with whom we spoke had seen updated data since the ASCO
meeting.
In a separate Velcade monotherapy second-line NSCLC study run at the
University of Pennsylvania, data reported at this year's ASCO were less
impressive. No patients in this study responded at the 1.3 mg/m2 dose, and
there was one PR at the 1.5 mg/m2 dose out of a total of 25 evaluable
patients (4% response rate). Unfortunately, the responder removed himself
from the trial before progression was documented, so the only data
available indicates that his response lasted a minimum of 18 weeks.
Finally, in a single arm trial assessing Velcade as a front-line agent in
chemotherapy naïve patients in combination with carboplatin and
gemcitabine, data on 12 evaluable patients (of 16 total) at this year's
ASCO meeting showed 4 patients with partial responses (33%). These data do
not appear impressive relative to a small Italian study on 27 patients
involving carboplatin and gemcitabine, which recorded a total response
rate of 32%, with 8% CRs and 24% PRs.
Table 1
Source: ASCO posters and abstracts, clinicaltrials.gov
To Go Or Not To Go In Lung Cancer. Although Millennium has yet to present
additional results for its large Phase II Velcade plus/minus Taxotere
study in NSCLC, one of our lung cancer consultants believes Velcade has
demonstrated sufficient data to warrant further examination in this
setting. Another investigator believes that, if the interim findings hold
up (specifically a response rate of about 15% of Velcade in combination
with Taxotere), that this would be indicative of sufficiently promising
Velcade activity in NSCLC. None of the investigators with whom we spoke
had seen a Phase III protocol yet or were aware of any final decision made
by Millennium to move Velcade forward into Phase III trials. However, one
investigator indicated there was a strong chance of Millennium making a
"go" decision. We believe a Phase III trial would most likely examine
Velcade in combination with another active agent based on the mixed single
agent activity reported to date. When asked to speculate on what the Phase
III trial would look like, two investigators believed the optimal design
would examine Taxotere plus/minus Velcade in second-line NSCLC, given the
experience with Velcade to date. However, one of these investigators was
worried that this design would yield less than meaningful data, based on
her belief that Alimta was increasingly dominating the second-line NSCLC
setting. She believes a better route would be to assess Velcade in
combination with Alimta in the Phase II setting, ahead of initiating Phase
III trials. We are not aware of any ongoing trials studying Velcade in
combination with Alimta. Given the increasingly crowded second and third
line NSCLC market (AstraZenca's Iressa, Lilly's Alimta, OSI and
Genentech's Tarceva) and those in clinical development (ImClone's Erbitux,
Genentech's Avastin, Novartis and Schering's PTK 787, and Pfizer's
SU011248 and AG-013736), we believe Velcade we need to show significant
improvements in overall survival or progression-free survival to be
approved in NSCLC. Assuming enrollment takes approximately one year and
the trial begins in 1H05, Millennium could announce top-line Phase III
data by the end of 2006 or 1H07.
Ovarian Cancer—Waiting On GOG Results. Results from a dose-ranging, single
arm Velcade plus carboplatin study in 12 recurrent ovarian cancer patients
were presented at ASCO 2003. Velcade doses were 0.75 (n=3), 1.0 (n=3), 1.3
(n=4), and 1.5 mg/m2 (n=2), twice weekly for two weeks with a one week
rest period between cycles (2-6 cycles given). The maximum tolerated dose
was 1.3 mg/m2. Eight of 12 patients had major responses, with 3 CRs and 5
PRs. Importantly, medical literature from the field demonstrate that
patients with significantly longer treatment free intervals (TFI) after
receiving front-line carboplatin are more likely to respond to a
subsequent regimen of carboplatin. Not surprisingly, the patients in this
study with the longest TFIs all responded to Velcade/carboplatin. Two of
the three CRs had TFIs greater than six months (8 months and 28 months)
and were classified as platinum-sensitive, while one of the CRs had a TFI
of only four months and was classified as platinum resistant. All of the
five PRs were platinum-sensitive, with three patients having a TFI close
to two years (7, 7, 21, 21, 28 months). Based on these data alone, we
believe it is difficult to assess if Velcade has activity in ovarian
cancer.
We believe that the future development of Velcade in ovarian cancer hinges
on the results of an ongoing Gynecologic Oncology Group (GOG) study, which
will follow 22-60 platinum-sensitive patients in a Velcade single arm
monotherapy study. Based on feedback from an investigator in the study,
the study protocol was amended recently from dosing Velcade at 1.5 mg/m2
to 1.3 mg/m2 based on toxicity seen at the higher dose. According to
clinicaltrials.gov, the study was opened in September 2001, before the MTD
was shown to be 1.3 mg/m2 at ASCO 2003. To date, this investigator was not
aware of any responses to Velcade, although our contact also mentioned
that it is too early to tell if Velcade has any activity in this study.
Enrollment appears to be going well according to our contact, and we
expect the first results to be presented as early as ASCO 2005. A key
enrollment criterion for this trial requires patients to have a TFI to
prior platinum-based therapy of greater than 6 months but not more than 12
months. If we were to assess response from the Phase I study on this
basis, five patients would have qualified for entry, including one CR, two
PRs, and two patients with stable disease, too small of a sample size from
which to draw any conclusions. Millennium expects to make an investment
decision in 1H05 for Velcade in ovarian cancer, based on the data from the
carboplatin combination study as well as the monotherapy study.
Prostate Cancer—Too Early To Tell. At this year's ASCO meeting,
investigators presented a first look at an ongoing Velcade+Taxotere
combination study in 102 patients with metastatic androgen-independent
prostate cancer. Patients were dosed with Velcade 1.3 mg/m2 on days two
and nine every three weeks. As of June when the data were presented, 6/25
patients had PSA level reductions at or greater than 50%, while 3 of 13
patients were classified as partial responders. As the study does not have
a comparator arm, it is difficult to draw conclusions from the data.
However, we note that Aventis recently completed two large randomized
studies of Taxotere in androgen-independent prostate cancer. Data from
these studies showed an average of 45-50% of patients with PSA reductions
greater than 50%, and a response rate of 8-17% depending on the course of
Taxotere given. It is unclear if the different Taxotere dose in the
Velcade study (40 mg/m2 days 1 and 8 every 3 weeks) compared to the
Aventis run studies (60-70 mg/m2 once every 3 weeks, 75 mg/m2 every 3
weeks, and 30 mg/m2 weekly for 5-6 weeks) could play a role in patient
responses. Additional response rate data, duration of response, and
survival data will be critical for better assessing Velcade's opportunity
in this setting. We expect Millennium to make a formal investment decision
for prostate cancer in 1H05. |
