FDA Panel Set to Vote on Milestone Neoadjuvant Pertuzumab Combo

The hope for many targeted therapies is that they will eventually be used in patients with earlier stage disease; for the breast cancer drug pertuzumab (Perjeta), that hope is being put to the test.

Dietmar Berger, MD

Most targeted therapies in cancer care are initially approved for the treatment of patients with metastatic disease. The hope is that these drugs will eventually be used in patients with earlier stage disease as well. For the breast cancer drug pertuzumab (Perjeta), that hope is being put to the test this Thursday.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) is convening tomorrow to discuss whether pertuzumab—which is now approved in combination with trastuzumab (Herceptin) and docetaxel as first-line therapy in HER2-positive breast cancer—can be moved up in the treatment spectrum and given to patients prior to surgery in the neoadjuvant setting. If approved in this indication, it would be the first neoadjuvant regimen formally approved by the FDA for the treatment of cancer.

While other drugs and regimens might already be used in the neoadjuvant setting, it’s important to note that this is a regimen that has been formally explored in large, international clinical trials and has demonstrated activity warranting its approval in this earlier setting.

“With the addition of Perjeta, we’re improving neoadjuvant therapy, and we’re improving outcomes,” said Dietmar Berger, MD, vice president of Clinical Oncology at Genentech, the company that manufactures pertuzumab.

Pertuzumab, like trastuzumab, is a monoclonal antibody that targets HER2 receptors. However, each drug binds to HER2 receptors at different sites, allowing the combination of the two drugs to create a dual blockade strategy. Pertuzumab works by preventing the receptor from linking to the HER3 protein and creating a dimer—a combination of two similar proteins or molecules—that signals tumor growth. The drug is able to induce antibody-dependent, cell-mediated toxicity when it binds to the protein.

Brian Leyland-Jones, MB BS, PhD

“The most potent heterodimer pair signaling in the HER2 pathway is the HER2-HER3 heterodimer, which this drug blocks,” said Brian Leyland-Jones, MB BS, PhD, director of Edith Sanford Breast Cancer Research, Sioux Falls, South Dakota. “This makes pertuzumab a remarkable drug.”

The FDA will not make its official approval decision on the neoadjuvant pertuzumab regimen this week. Instead, ODAC will vote on recommending whether or not the FDA should approve the drug. Specifically, ODAC will be voting on the question of whether pertuzumab has demonstrated “a favorable benefit to risk evaluation for the neoadjuvant treatment of early breast cancer,” according to a draft guidance made publicly available by the FDA.

Two Pivotal Trials Support Submission

Though the FDA is not required to follow ODAC’s decision, the government agency usually adheres to the panel’s recommendations. The pertuzumab filing was granted Priority Review by the FDA, and a decision regarding the drug’s approval for the neoadjuvant setting is expected to take place on or before October 31, 2013.Genentech’s regulatory filing for the neoadjuvant indication was based on the results of two pivotal trials: NEOSPHERE and TRYPHAENA.

In the NEOSPHERE trial, a multicenter, open-label, phase II study, treatment-naïve patients with HER2-positive breast cancer were randomly assigned in a 1:1:1:1 ratio and stratified by operable, locally advanced, and inflammatory breast cancer as well as hormone receptor expression.1 These patients received four neoadjuvant cycles of either trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2, escalating, if tolerated, to 100 mg/m2 every 3 weeks; n = 107; group A); pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) in combination with the group A trastuzumab and docetaxel regimen (n = 107; group B); the pertuzumab and trastuzumab regimens without docetaxel (n = 107; group C); and pertuzumab plus docetaxel (n = 96; group D). The primary endpoint of the study was pathological complete response (pCR).

Patients who received the combination of pertuzumab, trastuzumab, and docetaxel had a pCR rate of 45.8% (95% CI, 36.1-55.7), a significant improvement over patients who received trastuzumab and docetaxel without pertuzumab, who had a pCR rate of 29.0% (95% CI, 20.6 -38.5; P = .014). The PCR rates for the remaining two groups were 24.0% in those who received pertuzumab and docetaxel without trastuzumab (95% CI, 15.8-33.7), and 16.8% in patients who received pertuzumab and trastuzumab (95% CI, 10.3-25.3).

The most common grade 3 or higher side effects observed in the four groups were neutropenia (61, 48, 1, and 52 patients in the four groups, respectively), febrile neutropenia (8, 9, 0, and 7, respectively), and leukopenia (13, 5, 0, and 7, respectively). The number of adverse events was similar in the three groups (A, B, and D) that received chemotherapy as part of their treatment regimen, with 15 to 20 serious adverse events per group in 10% to 17% of patients, but was much lower in group C, which did not receive chemotherapy (four serious adverse events in 4% of patients).

Since the regimen that included pertuzumab, trastuzumab, and docetaxel added very little toxicity, Sanford’s Leyland-Jones believes that these results are very encouraging.

“If you think about taking a woman with a lump in her breast who has lymph nodes as well, at the adjuvant setting, when you think now that [approximately] half of the time, you can get a pathological complete response rate before they go into surgery, that in itself is a remarkable statement,” Leyland-Jones said.

The results of the TRYPHAENA trial were presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium,2 and updated safety results were recently published in the journal Annals of Oncology. This study was a phase II, multicenter, open-label study that enrolled 225 patients with operable, locally advanced, or inflammatory breast cancer. Patients were randomized in a 1:1:1 ratio to receive six neoadjuvant cycles every 3 weeks. The first group, Arm A, received a regimen of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by docetaxel, with trastuzumab and pertuzumab given concurrently throughout the treatment. Arm B received FEC followed by docetaxel plus trastuzumab and pertuzumab. Arm C received docetaxel and carboplatin plus trastuzumab and pertuzumab. After patients were treated with neoadjuvant therapy, they underwent surgery and continued on trastuzumab until they completed 1 year of treatment. The study was not powered to compare the three study arms.

pCR as a Surrogate Endpoint

The study found that the pCR rates were 61.6% in the concurrent group (A), 57.3% in the sequential group (B), and 66.2% in the anthracycline-free arm (C). The most common severe adverse events (AEs) observed in the three arms were neutropenia (47.2%, 42.7%, and 46.1%, in the three arms, respectively), leukopenia (19.4%, 12.0%, and 11.8%), and febrile neutropenia (18.1%, 9.3%, and 17.1%). Additional high AE rates observed with the anthracycline-free arm included anemia (17.1%), thrombocytopenia (11.8%), and diarrhea (11.8%).The approval of the pertuzumab regimen based on the pCR data from these trials would be historic. This is the first time that the FDA is considering pCR as an appropriate surrogate endpoint when reviewing a treatment regimen for approval. While definitions of pCR have varied slightly from study to study, the FDA has proposed that the definition of this endpoint should be, “the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant systemic therapy.”

Richard Pazdur, MD

In an article published in the New England Journal of Medicine in June 2012, Tatiana M. Prowell, MD, a breast cancer scientific lead at the FDA, and Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, explained that promising drugs like pertuzumab “should be incorporated into standard treatment for early-stage breast cancer as rapidly as possible to provide the greatest benefit to the most patients.”3

Prowell and Pazdur said that pCR appears to be an appropriate surrogate endpoint, since the FDA is able to grant accelerated approval based on an endpoint other than an improvement in survival if that endpoint is “reasonably likely to predict clinical benefit.” A Cochrane meta-analysis of 5500 patients enrolled in 14 randomized trials that compared preoperative with postoperative chemotherapy found that patients who had a pCR had about half of the risk of death when compared with patients who had residual tumor when they received surgery.

Additionally, at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, another meta-analysis was presented that showed a clear association between pCR and long-term survival benefits. When researchers looked at data from 13,125 patients in 12 clinical trials, patients who achieved a pCR experienced significantly improved event-free survival (hazard ratio [HR] = 0.48) and overall survival (HR = 0.36) compared with patients who did not achieve a pCR.4

In the briefing document made available to ODAC for Thursday’s meeting, the FDA asked ODAC to consider several pCR-related points in their evaluation of the pertuzumab regimen.

The first point is that even though neoadjuvant trials require less time to assess the pCR endpoint and differences can be detected in a smaller sample size than what is required by adjuvant trials, there is a concern that patients with curable disease may be exposed to unknown rare and late toxicities. Therefore, the FDA maintains that with any particular application, the benefits derived from the drug or regimen must outweigh these concerns. To address this issue, the filing under consideration includes the favorable survival and toxicity data from the phase III CLEOPATRA trial that formed the basis of pertuzumab’s approval in the metastatic setting.

The second point concerns a follow-up trial to assess more concrete, long-term endpoints regarding the survival benefit derived from the drug. Genentech is already conducting the phase III, randomized, placebo-controlled APHINITY trial with this pertuzumab regimen in the adjuvant setting. The estimated completion date of the trial is 2023, although results are expected to become available as early as 2016 or 2017, according to Genentech. There is a risk in approving a drug before this data becomes available, which is why these adjuvant trials must be underway in order for any drug to be approved on the basis of pCR in the neoadjuvant setting.

Mark Pegram, MD

“You can’t just come in with a neoadjuvant data set in isolation and expect approval,” said Mark Pegram, MD, director of the Breast Cancer Program at the Stanford Women’s Cancer Center, in an interview. “It has to be that data set at a minimum plus a commitment to large phase III randomized trials with adjuvant outcome data that are clinically meaningful like relapse-free survival and overall survival.”

The FDA is also asking ODAC to consider the fact that the pCR rate observed in the pivotal NEOSPHERE adjuvant trial might not accurately predict the level of benefit that might be seen in the APHINITY trial; the fact that the definition of pCR varies among clinical studies; the need for further research to determine the efficacy of the pertuzumab regimen in hormone-receptor-positive patients; and the safety profile of the drug.

If pCR does prove to be an acceptable surrogate endpoint, it would exponentially accelerate the approval process. Genentech’s Berger used trastuzumab as an example. In 1998, the drug was approved in the metastatic setting. It was not until 2006 that its approval was expanded to treat patients in the adjuvant setting.

Cost Factors

“It took eight years to go from the metastatic approval of Herceptin to the early breast cancer approval,” Berger said. “Now we would be down to less than two years for Perjeta. And we believe that’s really good news for patients.”Even if the pCR data lead to the approval of the pertuzumab regimen, cost might still inhibit patient access. The three-drug combination includes two expensive targeted therapies.

According to Genentech, the pertuzumab and trastuzumab component of the regimen would cost between $27,000 and $49,000, depending on how long the patient receives treatment. The supplemental biologics license application recommends treatment with the combination regimen for three to six cycles given every 3 weeks. That price does not include the cost of docetaxel.

Leyland-Jones said that an FDA approval could be helpful in getting insurance companies to cover the regimen. Additionally, though expensive, the treatment’s benefit may ultimately be worth it in the long run.

“When you’re considering practically a 50% pathological complete response rate in the disease and the fact that this may be adding literally years of life to the woman who is being treated, if you’re working it out from a pharmacoeconomic point of view, I would have thought that this was extremely competitive,” Leyland-Jones said.

Additionally, Berger said that Genentech has a broad patient assistance program for patients who are concerned about the cost.

However, Pegram said that the cost of new oncologic drugs is “unsustainable” and that even with an approval from the FDA, pertuzumab might not be given to the thousands of patients who could potentially benefit from the combination. He gave the example of ziv-aflibercept (Zaltrap), a drug that was approved by the FDA for the treatment of advanced colorectal cancer but was nearly twice the cost of bevacizumab (Avastin), a similar drug, while proving to have a similar efficacy. The hospital formulary committee at Memorial Sloan-Kettering Cancer Center in New York City refused to approve the drug based on its high cost and the fact that it was not substantially better than an existing drug.

“That won’t be the last example of that kind of action,” Pegram said.

Still, Genentech stands to generate a significant amount of revenue from this expanded approval of pertuzumab. A recent report from the BioTrends Research Group found that after 1 year on the market, approximately 77% of US-based oncologists had prescribed pertuzumab to an average of six patients who overexpress HER2, and among those physicians who had not prescribed pertuzumab, 76% of those surveyed planned to do so within the next 3 months. Genentech projects that about 15,000 early-stage, HER2 positive, breast cancer patients could receive pertuzumab-based neoadjuvant treatment each year. Looking ahead, estimates from five analysts compiled by Bloomberg suggest that pertuzumab could generate annual revenue of $1.9 billion in 2016.


  1. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomized, multicenter, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.
  2. Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracycline-containing or concurrent with an anthracycline-free standard regimen: a randomized phase II study (TRYPHAENA). 2011 CTRC-AACR San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, Texas. Abstract S5-6.
  3. Prowell TR, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med. 2012;366(26):2438-2441.
  4. Cortazar P, Zhang L, Untch M, et al. Meta-analysis results from the collaborative trials in neoadjuvant breast cancer (CTNeoBC). Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S1-11.