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Study Suggests Surrogate Endpoint May Reflect Longer Benefit of Early HER2 Breast Cancer Treatment


NEW YORK (GenomeWeb) – Last year at the American Society of Clinical Oncology's annual meeting, some experts questioned whether pathologic complete response as an endpoint was truly reflecting longer-term outcomes for early-stage breast cancer patients treated before surgery with HER2-targeting breast cancer agents.

A year later, at the same meeting, Luca Gianni from the San Raffaele Hospital reported new data from the Phase II NeoSphere trial, showing that HER2-postiive breast cancer patients who received neoadjuvant treatment (before surgery) with Roche/Genentech's Perjeta (pertuzumab), Herceptin (trastuzumab), and docetaxel chemotherapy lived longer without their cancer getting worse or coming back than those receiving Herceptin and chemo. "All of us who have been doing neoadjuvant therapy have for some time believed that when you have a pathologic complete response you can expect that there is going to be a better outcome," Julie Margenthaler, an associate professor and breast surgical oncologist at Washington University, told GenomeWeb.

Neoadjuvant treatment has been traditionally given to early-stage breast cancer patients with large tumors so they can be reduced to a point where surgery is feasible. It may also help some patients avoid mastectomies and provide oncologists early prognostic data on patients' illness. However, until recently, there wasn't a standardized way of determining if neoadjuvant treatment was helping early-stage breast cancer patients live longer. Metastatic patients don't live long, and so, relatively quickly it is evident whether or not treatments are extending their lives. This could take years to figure out in early-stage breast cancer patients.

For example, in 1998, when Herceptin initially came to market as the first personalized breast cancer drug alongside a companion diagnostic for identifying best responders, it was approved for patients with HER2-positive, metastatic disease. It wasn't until 2006 that the FDA approved Herceptin in the adjuvant (post-surgery) treatment of early-stage HER2-positive breast cancer patients. In the even earlier neoadjuvant setting, the impact of treatment "has been very hard to measure simply because of some of the studies that had been done prior to NeoSphere," Margenthaler reflected.

In 2012, the US Food and Drug Administration addressed this in a draft guidance and discussed measuring the benefit of neoadjuvant treatment in breast cancer using an endpoint, called pathologic complete response. The term describes the scenario when, at the time of surgery, a patient who has received neoadjuvant treatment has no residual or in situ cancer in breast tissue or lymph nodes. Experts believe pathologic complete response could serve as a surrogate measure for survival in clinical trials, providing earlier access to drugs for patients at the onset of their cancer, when they have the best shot at completely staving off disease.

Certainly, with the use of complete pathologic response in NeoSphere, Genentech was able to bring Perjeta to market as a neoadjuvant option in breast cancer in record time. In 2012, the FDA first approved the drug for late-stage HER2-positive breast cancer, and just over a year later, the agency again approved the treatment in the neoadjuvant setting.

However, whether pathologic complete response actually translates to a survival advantage for breast cancer patients hasn't been definitely proven. NeoSphere wasn't powered to detect statistically significant survival differences. Still, oncologists are encouraged by the data. "It's very clear in NeoSphere that the pathologic complete response rate … does translate to an improved survival for those patients," Margenthaler said.

In 2012, researchers reported early data from NeoSphere in Lancet Oncology, showing that the Perjeta/Herceptin/docetaxel regimen significantly improved patient's complete pathologic response compared to those receiving either of the HER2-targeted agents with docetaxel, or the combination of Herceptin and Perjeta without docetaxel. Since then, researchers have followed the more than 400 NeoSphere patients for an additional three years, and treated them with one year of Herceptin plus chemotherapy in the adjuvant setting.

The latest findings show that the progression-free survival was 90 percent in the Perjeta-containing arm compared to 86 percent in the Herceptin/chemo arm; disease-free survival was 92 percent versus 85 percent, respectively. Importantly, lead NeoSphere researcher Gianni highlighted at the meeting that, looking across all arms, patients who experienced pathologic complete response had a reduced risk of experiencing a progression-free survival and disease-free survival event. For example, out of around 90 patients who achieved pathologic complete response in the neo-adjuvant portion of NeoSphere, 85 percent experienced five-year progression-free survival, compared to 76 percent of around 300 patients who didn't achieve pathologic complete response.

"Progression-free survival and disease-free survival are in line with the results of the primary endpoint [of pathologic complete response], and suggests a persisting benefit of neoadjuvant pertuzumab added to trastuzumab and docetaxel, despite the use of identical adjuvant therapy," Gianni concluded. It's "as if there was a carryover factor of four cycles of pertuzumab in the neoadjuvant arm."

Adverse events, such as a diarrhea, are associated with Perjeta-containing regimens. In the adjuvant portion of NeoSphere, most of the more severe toxicities, such as decreasing white blood cells, were due to the addition of chemotherapy, researchers said. There were no additional cardio toxicities seen in patients receiving Perjeta combinations.

Since NeoSphere wasn't powered to determine statistically significant differences in long term endpoints, breast cancer experts are hopeful that future studies, such as APHINITY, will provide a definitive answer as to the relationship with pathologic complete response and survival. In the meantime, Margenthaler believes that with NeoSphere oncologists have reason to expect that when a patient experiences a pathologic complete response to HER2 targeted treatment, she will be better off in the long run. In the past, this is the hope she has given her breast cancer patients who have experienced pathologic complete responses to neoadjuvant treatment. "Now, I have some survival data to back that up."

However, at the 2014 ASCO annual meeting, the results of the ALTTO study gave some experts reason to doubt this. In that trial, breast cancer patients receiving adjuvant treatment with Herceptin and another HER2-targeted drug, Tykerb (lapatinib), didn't live much longer than those who received just Herceptin. The ALTTO trial was conducted after researchers reported that early-stage breast cancer patients in the neoadjuvant setting experienced a doubling of pathologic complete response with Herceptin and Tykerb compared to single agent Herceptin.

Following presentation of the ALTTO data, former ASCO President and breast cancer expert George Sledge put forth that pathologic complete response as an endpoint may not truly reflect whether a therapy will improve survival outcomes for breast cancer patients. This suggestion didn't sit well with many in the field at the time, particularly since the FDA had already issued its draft guidance outlining the use of pathologic complete response in early breast cancer studies and many researchers were using the endpoint in their drug trial designs. 

Important design differences between ALTTO and NeoSphere make it hard to distill precisely why the latter suggested an association between pathologic complete response and survival, while the former didn't. Margenthaler noted that the NeoSphere data are encouraging because it included a more homogeneous patient population than ALTTO.

In Gianni's view, NeoSphere supports the use of pathologic complete response as a primary endpoint in future neoadjuvant studies of HER2 targeted agents. Margenthaler further said that pathologic complete response should be the first endpoint that researchers consider in looking at HER2-postive breast cancer patients' prognosis.

She cautioned, though, that the likely positive association between pathologic complete response and survival can't be taken for granted across all neoadjuvant breast cancer studies. "In the triple-negative [breast cancer] population … I don't know that we can necessarily say that pathologic complete response is going to translate in the same way," she said.

The overall prognosis of women with HER2-positive disease has greatly benefitted from the availability of multiple targeted agents, such as Herceptin and Perjeta, which effectively kill tumors by blocking aberrant HER2 receptor signaling in different ways. In triple-negative breast cancer there aren't such targeted options.

Genentech is awaiting data from the ongoing Phase III APHINITY trial to convert the accelerated approval for Perjeta into full approval. In that study, researchers will compare Perjeta/Herceptin/chemo against Herceptin/chemo in the adjuvant setting for patients with early HER2 positive breast cancer. Roche also said it has submitted a marketing authorization application with European regulators for Perjeta in the neoadjuvant setting.

This article has been corrected to note that data from the APHINITY trial will draw definitive conclusions about the relationship between pathologic complete response and survival endpoints. An earlier version named TRYPHENA as one of the studies that might provide such insight, but that study will also not be powered to assess long term survival.