Comments are due next Monday on a draft guidance FDA hopes will spur development of targeted therapies for neoadjuvant triple-negative breast cancer.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The draft guidance, issued May 30, proposes the use of pathologic complete response (pCR) as a surrogate endpoint for accelerated approval in the neoadjuvant setting.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 surgery.

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.

Fleshing out details

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 full approval.

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 disease.

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," A14).

Prowell, however, noted that a doubling over control alone doesn't necessarily translate into a clinical benefit.

"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 systemic therapy."

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 one year.

Five-year survival for non-triple-negative patients treated in the adjuvant or neoadjuvant setting is about 90%.

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 problem

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," she said.

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 company Agios Pharmaceuticals Inc., said the guidance is a positive signal that FDA is open to exploring alternative endpoints for diseases where there is an unmet need.

"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 breast cancer.

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.

Faster, maybe

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 BioCentury.

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).

COMPANIES AND INSTITUTIONS MENTIONED

Agios Pharmaceuticals Inc., Cambridge, Mass.

American Society for Clinical Oncology (ASCO), Alexandria, Va.

AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K.

Biomarkers Consortium, Bethesda, Md.

Celldex Therapeutics Inc. (NASDAQ:CLDX), Needham, Mass.

Genentech Inc., South San Francisco, Calif.

Keck School of Medicine, Los Angeles, Calif.

National Institutes of Health (NIH), Bethesda, Md.

Pfizer Inc. (NYSE:PFE), New York, N.Y.

Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland

Synta Pharmaceuticals Corp. (NASDAQ:SNTA), Lexington, Mass.

University of Michigan Comprehensive Cancer Center, Ann Arbor, Mich.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.

Washington University Medical School, St. Louis, Mo.