Comments are due next Monday on
a draft guidance FDA hopes will spur development of targeted therapies
for neoadjuvant triple-negative breast cancer. Companies and researchers are
encouraged the agency is endorsing a new surrogate endpoint; however, they
caution that a poor understanding of the biology of triple-negative disease is
the bigger barrier to developing new drugs for this population.
The draft guidance, issued May
30, proposes the use of pathologic complete response (pCR) as a surrogate
endpoint for accelerated approval in the neoadjuvant setting. The guidance
defines pCR as complete absence of residual invasive cancer in resected breast
tissue and all sampled ipsilateral lymph nodes after drug therapy and surgery.
In neoadjuvant trials, patients
receive two to four months of therapy with pCR measured at the point of
According to the agency's
guidance as well as FDA's comments to BioCentury, the proposed randomized,
double-blind trials would measure superiority of an experimental agent plus SOC
vs. SOC alone by comparing the proportion of patients achieving a pCR.
The studies also would be
powered to assess disease-free survival (DFS), which would be included in the
trial design as a co-primary endpoint that matures later.
The pCR readout could be
available within about 2.5 years of starting the trial to support accelerated
approval, and DFS data could be available within about five years of the trial
start to support full approval.
FDA's intention is to speed
development of drugs with the potential to be curative as demonstrated by a
large therapeutic effect in the earliest stage of disease.
No drugs are approved in the
U.S. for the neoadjuvant setting. New breast cancer agents are often tested and
approved first for patients with relapsed or refractory metastatic disease,
followed by approval for earlier disease five to 10 years later.
"By developing agents in
the neoadjuvant setting, you are offering the greatest potential of effect and
possibly a cure," Richard Pazdur, director of FDA's Office of Hematology
Oncology Drug Products, told BioCentury.
However, the guidance applies
only to targeted agents developed for high-risk patients, which in this case means
triple-negative breast cancer. No drugs are approved specifically for any stage
of triple-negative breast cancer.
Companies and researchers had
mixed feelings about how much and how soon the guidance could actually spur
development of new drugs for triple-negative cancers.
Some believe it will encourage
companies to prioritize development of promising agents for the indication. But
others believe additional work needs to be done to identify drivers of
triple-negative disease, and that developing drugs first for the metastatic
setting will continue to be the fastest way to an initial approval.
Tatiana Prowell, medical
officer in FDA's Office of Hematology Oncology Drug Products, said pCR would be
measured first with the data used to support accelerated approval. DFS data
would be available about two to three years later to convert accelerated to
DFS is the length of time a
patient remains alive without evidence of disease. In contrast,
progression-free survival (PFS) is used when patients still have measurable
Pazdur noted FDA "would
want patients followed for overall survival for some level of assurance that
there is no decrement in survival. But looking at survival [as the confirmatory
endpoint] in this population becomes very difficult due to the long natural
history, as well as confounding by other therapies that might be introduced."
The agency plans to discuss
specific trial designs with companies case by case.
According to Pazdur, the agency
does not expect to provide an exact number for the rate of pCR needed for
approval or the magnitude of improvement in DFS that would be necessary for
confirmation of efficacy and conversion to full approval. However, a
meta-analysis by the agency could provide some insight.
The Breast Oncology Group in
Pazdur's office is conducting a meta-analysis of the relationship between pCR
and DFS/OS using primary source data from more than 12,000 patients enrolled in
published, randomized neoadjuvant trials with long-term follow-up.
The meta-analysis is looking at
trials three to five years in duration. The researchers also will look at
subgroups of patients, including triple-negative patients, to understand what
rate of pCR in different subgroups of patients correlates with DFS and/or OS.
According to Patricia Cortazar,
medical team leader in the Office of Hematology Oncology Drug Products, FDA
will use the analysis to update and inform the guidance. She said the agency
expects to complete the analysis by year end.
"It behooves us to get
some handle on the requisite details one would need to determine what magnitude
of benefit is clinically meaningful," Pazdur said, adding that statistical
significance would not be meaningful on its own.
Based on historical trials that
have measured pCR and followed patients for DFS or OS, researchers who spoke to
BioCentury think a doubling of pCR should be the minimum.
"Herceptin doubled pCR, taxanes doubled pCR, and those
are the drugs that we know improve survival. I'd go with doubling over the
control group, but that is a pretty high bar," said Anne Schott, associate
professor of medicine at University
of Michigan Comprehensive Cancer Center (see "Evidence for pCR,"
Prowell, however, noted that a
doubling over control alone doesn't necessarily translate into a clinical
"If you have 1% for the
control and 2% for the treatment, that is doubling, but it isn't going to
translate into anything meaningful. So it will be an assessment of the absolute
rate, as well as the relative," she told BioCentury.
Similar to its position on pCR,
FDA is not saying how much of an improvement in DFS would be sufficient to
convert an accelerated approval to full approval.
Not naming names
The guidance explicitly states
estrogen receptor- and progesterone receptor-positive patients should not be
enrolled in trials with a pCR endpoint because previous studies have not shown
a strong correlation between pCR and survival or DFS benefit in these patients.
At the same time, the guidance
does not specify which populations should be enrolled. Rather, it describes the
appropriate patients as those "judged to have a high risk of distant
disease recurrence and mortality despite the use of optimal modern local and
The only example the document
gives is triple-negative patients. Pazdur and Prowell told BioCentury this is
the population the agency had in mind when it drafted the guidance.
Triple-negative tumors do not
express estrogen receptor, progesterone receptor or HER2 (EGFR2; ERBB2; neu)
and thus do not respond to several commonly prescribed targeted therapies.
About 10-20% of breast cancer
patients, or 23,000-45,000 patients per year, have triple-negative disease. The
five-year survival rate for triple-negative patients treated in the neoadjuvant
setting is about 70%. But in patients who progress, the median survival is just
Five-year survival for
non-triple-negative patients treated in the adjuvant or neoadjuvant setting is
Standard of care for triple-negative breast cancer is
chemotherapy, which is approved for all subgroups of adjuvant and metastatic
breast cancer. Avastin bevacizumab from Genentech
Inc. and Roche
is used off-label for metastatic disease and is in the Phase III BEATRICE trial in the adjuvant
setting. The primary endpoint of the open-label trial is invasive
disease-free survival. Data are expected this year.
Biology is the
Prowell believes a shorter path
to approval using pCR will encourage companies to devote more time and effort
to exploring new pathways and targets.
"We want to encourage
companies to invest more in pathways responsible for those types of cancer that
don't respond to available targeted treatments, especially triple-negative,"
Several companies and clinical
researchers who spoke to BioCentury noted the absence of treatments for
triple-negative breast cancer isn't due to a lack of trying.
Nevertheless, David Schenkein, CEO of cancer metabolism
Pharmaceuticals Inc., said the guidance is a positive signal that FDA
is open to exploring alternative endpoints for diseases where there is an unmet
"If a surrogate like this
can get your drug on the market, it may move the needle in the disease and
allow you to do other things like test the drug in other areas of unmet need,"
he told BioCentury.
He added: "If you know the
pathway and know that it won't require 3,000 patients with overall survival as
the endpoint, the ability for a small company to raise money from investors
will be different."
Schenkein was formerly SVP of
clinical hematology/oncology at Genentech and worked on the development of
Avastin for breast cancer.
Thomas Davis, SVP and CMO at Celldex
Therapeutics Inc., also suggested FDA's proposed pathway would have an
impact. "This guidance will definitely lead to more people trying their
drugs in triple-negative patients first," he said.
Celldex's glembatumumab vedotin
(formerly CDX-011) is in Phase IIb testing to treat advanced, refractory or
resistant glycoprotein NMB (GPNMB)-expressing breast cancer, including
triple-negative breast cancer. The product is a human mAb against GPNMB linked
to the tubulin inhibitor monomethyl auristatin E (MMAE).
Preliminary results reported in
May from 117 evaluable patients in the open-label Phase IIb EMERGE trial showed
patients on glembatumumab had an ORR of 19% vs. 14% for those on single agent
chemotherapy of the investigator's choosing.
In 33 patients with
triple-negative breast cancer, glembatumumab led to an ORR of 21% vs. 0% for
chemotherapy, and a disease control rate of 71% vs. 33%. In 14 triple-negative
patients with high GPNMB expression, glembatumumab led to an ORR of 36% vs. 0%
for chemotherapy and a disease control rate of 82% vs. 33%. Disease control was
defined as the sum of complete and partial response plus stable disease.
Davis said Celldex originally
planned to discuss with FDA the design of a Phase III trial in metastatic
breast cancer with high GPNMB expression, including triple-negative patients,
using ORR as the primary endpoint for accelerated approval. Now, he said the
company may also discuss testing glembatumumab in the neoadjuvant setting as an
alternative path to approval.
"The first few companies
that go through the process will be validating the endpoint while others are
learning from their experience," Davis added. "If the first few
companies are successful, you might see 10 more companies try it because they
realize it is a good way to get a drug approved."
Philippe Bishop, VP of clinical
development for Genentech's Avastin, agreed the guidance will encourage
companies to prioritize development in the triple-negative population.
"Because pCR is an almost
immediate measure and you don't have to wait for disease to come back, I think
it would be enough to encourage companies to test new targeted agents in
triple-negative patients," Bishop told BioCentury.
But University of Michigan's Schott and Safi Bahcall,
president and CEO of Synta
Pharmaceuticals Corp., said poor understanding of what drives
triple-negative disease is what has hampered development of targeted drugs -
not development timelines.
"What's slowing us down
with triple-negative patients is the heterogeneity of the group because, while
they lack three receptors, the other types of receptors on these patients'
tumors is somewhat heterogeneous," Schott said.
Bahcall agreed. "The lack
of new endpoints isn't related to why we don't have drugs for triple-negative
disease," he said.
"The reason it has been so
difficult to treat these patients is because, by definition, triple-negative
means that you are negative for all the known disease drivers - HER2, estrogen
receptor and progesterone receptor. It is just shorthand for 'we don't know
what is driving the disease,'" Bahcall said.
In December, Synta announced
data from the first stage of a Phase II open-label trial in 22 patients with
metastatic breast cancer. In 13 triple-negative patients, ganetespib produced
two partial responses and six cases of stable disease.
Ganetespib is a small molecule
inhibitor of heat shock protein 90 (Hsp90).
Synta plans to start a Phase
I/II trial this year using ganetespib in combination with paclitaxel and
Herceptin to treat HER2+ breast cancer, as well as triple-negative metastatic
Parvin Peddi, chief resident at Washington
University Medical School, told BioCentury that researchers are
identifying targets for drug development in triple-negative patients, including
a subset of patients who carry the androgen receptor. This group accounts for
12% of triple-negative patients.
Phase II data from an
investigator-sponsored trial in 436 triple-negative androgen receptor-positive
patients showed that the androgen receptor antagonist Casodex bicalutamide had
a clinical benefit rate of 19%. Clinical benefit was defined as the sum of
complete and partial response plus stable disease.
Casodex is marketed by AstraZeneca
plc for advanced prostate cancer. The data were presented at the American
Society for Clinical Oncology (ASCO) meeting in Chicago.
There also was no consensus on
whether the ability to use pCR for accelerated approval in the neoadjuvant
setting will provide a faster path to market than the traditional development
paradigm, which begins with metastatic disease.
Prowell noted that getting
approval in the metastatic setting first is the "fastest way to get
approval currently because the median survival is two years, three at the most."
But Mark Benyunes, Genentech's
senior group medical director for clinical hematology/oncology, argued that
using pCR as the basis for accelerated approval in the adjuvant setting would
take about 2.5 years.
"The benefit is that the
pCR endpoint can be assessed much earlier and it doesn't take thousands of
patients and years to see progress as it does" when PFS or DFS are used as
endpoint in the adjuvant setting, he said.
Debasish Tripathy, professor of medicine at Keck
School of Medicine, estimated the time to accelerated approval could be
cut by more than half compared with adjuvant trials that require the use of DFS
as an endpoint.
Tripathy is an investigator on
I-SPY 2, an adaptive trial in neoadjuvant breast cancer that is using pCR to
estimate the probability of success of experimental agents for Phase III trials
(see BioCentury, March 22, 2010).
I-SPY is managed by the Biomarkers
Consortium, which is led by the NIH.
However, Schott argued that
using pCR in neoadjuvant disease may not be a shorter route to first approval
of a drug, given survival of less than two years in the metastatic setting.
Additionally, Schott noted that
triple-negative patients make up a smaller proportion of neoadjuvant patients,
so the time needed to find and enroll these patients could cause trials to take
almost as long as those in the adjuvant setting.
"Maybe once you finish
enrollment and look at pCR it took only two years, instead of waiting five
years after enrollment. But I don't expect to see a reduction in the size of
the trial if it is powered to measure [disease-free] survival and the
patient population is rarer, so the enrollment is going to take longer than if
you just did it in the adjuvant setting," she said.
The guidance does not say how
large the trials should be, but most researchers contacted by BioCentury
suggested 200-400 patients would be enough to power a study for co-primary
endpoints of pCR and DFS.
Celldex's Davis also doesn't
think the use of pCR will shorten development timelines.
"The guidance suggests you
will need to test the new drug in combination with standard of care. So there
may be preliminary work you have to do to understand how your drug works in combination
with standard of care before you move into the pivotal trial," he told
This additional testing could
erase any potential time savings, Davis said.
Comments on the draft guidance
are due by July 30 (see Online Links, A5).
Pharmaceuticals Inc., Cambridge, Mass.
Society for Clinical Oncology (ASCO), Alexandria, Va.
plc (LSE:AZN; NYSE:AZN), London, U.K.
Consortium, Bethesda, Md.
Therapeutics Inc. (NASDAQ:CLDX), Needham, Mass.
Inc., South San Francisco, Calif.
School of Medicine, Los Angeles, Calif.
Institutes of Health (NIH), Bethesda, Md.
Inc. (NYSE:PFE), New York, N.Y.
(SIX:ROG; OTCQX:RHHBY), Basel, Switzerland
Pharmaceuticals Corp. (NASDAQ:SNTA), Lexington, Mass.
of Michigan Comprehensive Cancer Center, Ann Arbor, Mich.
Food and Drug Administration (FDA), Silver Spring, Md.
University Medical School, St. Louis, Mo.