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I-SPY2 'Graduates' Neratinib; Puma Details Efficacy, Safety Insights in HER2-Positive Breast Cancer

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At the American Association for Cancer Research annual meeting this week, researchers involved in the adaptive design I-SPY2 trial reported detailed results showing that Puma Biotechnology's neratinib combined with a chemotherapy regimen had a 79 percent statistical probability of being a superior neoadjuvant treatment over standard chemo in a 300-patient study of hormone receptor-negative, HER2-positive patients.

Although Puma had reported top-line findings on neratinib from I-SPY2 in December, the more in-depth analysis discussed at the conference provided the first clinical data suggesting that neratinib may also be efficacious as a neoadjuvant treatment in HER2-negative breast cancer patients.

I-SPY2 is a randomized, adaptive design Phase II study that is investigating in multiple arms various neoadjuvant therapeutic strategies for breast cancer patients with Stage 2 or higher disease. Patients enrolled in the study must have a high risk of relapse based on their tumor size, hormone receptor status, HER2 status, and results from Agendia's MammaPrint 70-gene breast cancer recurrence test. The primary endpoint in the study is pathological complete response at the time of surgery. As patients are enrolled in the study and as their pathological complete response become known on a rolling basis, the adaptive design algorithm in I-SPY2 calculates accordingly and places patients into the treatment arm that they are most likely to benefit from based on their biomarker profile.

In this way, when an investigational therapeutic regimen shows superiority over standard treatment in one of 10 biomarker signatures, it graduates from the Phase II trial to the Phase III, I-SPY3. In the same way, when a drug doesn't do well over the standard therapy in any biomarker signature arm, it is dropped from the trial.

Based on the study results from I-SPY2, neratinib is eligible to be further investigated as a neoadjuvant treatment in the I-SPY3 in HER2-positive patients. "This represents the first data on neratinib in the neoadjuvant setting," Puma CEO Alan Auerbach said during a call with investors following presentation of the data at AACR.

Other than neratinib, the I-SPY2 has also graduated AbbVie's PARP inhibitor veliparib plus carboplatin with standard paclitaxel-based neoadjuvant chemo, giving it a 90 percent chance of success over standard neoadjuvant chemo in a 300-patient Phase III trial of triple-negative breast cancer patients.

In I-SPY2, for hormone receptor-negative, HER2-positive patients, researchers compared neratinib plus standard neoadjuvant chemotherapy (paclitaxel followed by doxorubicin and cyclophosphamide) versus Herceptin and standard chemo. In this cohort, patients receiving the neratinib-containing regimen had a pathological complete response of 55.6 percent compared to 32.6 percent in the standard therapy arm. This finding was statistically significant, and researchers further calculated that a paclitaxel plus neratinib regimen would have a 79 percent chance of being superior to Herceptin plus paclitaxel in a Phase III trial in hormone receptor-positive, HER2-positive patients. Roche/Genentech's Herceptin (trastuzumab) is the most commonly prescribed personalized treatment for HER2-positive breast cancer patients.

Out of 115 patients assigned in I-SPY2 to receive the neratinib-containing cocktail, 65 patients were HER2 positive. When researchers considered just HER2-positive patients, including both hormone receptor-positive and -negative subgroups, the neratinib arm still came out on top of standard therapy, 39.4 percent pathological complete response versus 22.8 percent, respectively. The success of a Phase III trial comparing neratinib plus paclitaxel versus Herceptin plus paclitaxel in the overall HER2-positive cohort researchers calculated to be nearly 73 percent. Auerbach noted that Puma will be interested in seeing how neratinib does in the HER2-positive patient population in the I-SPY3 trial, and that researches may be able to further home in on the responses according to hormone receptor status.

Auerbach said during the call that the more detailed I-SPY2 analysis suggests that combining neratinib with taxol, Herceptin, and a newer HER2-targeting agent, such as Genentech's Perjeta (pertuzumab), might bolster neoadjuvant efficacy in breast cancer patients with HER2 overexpression. In the future, "we would plan to add neratinib to the combination of taxol, plus Herceptin, plus Perjeta, which we believe would further increase the pathological complete response rate [based on] the results of the pathological complete response rate for neratinib in the I-SPY2 trial," Auerbach said. "We believe [such a regimen] could improve the absolute benefit compared to the previously published triplets of either Perjeta or Tykerb."

Moreover, 41 patients in I-SPY2 who had MammaPrint ultra-high scores – meaning they were at especially heightened risk for breast cancer recurrence – had pathological complete response rates of 47.5 percent in the neratinib arm compared to 29.4 percent in the control arm. In this group of patients with ultra-high MammaPrint scores, 80.5 percent were HER2 negative, and they had a pathological complete response of 46.9 percent in the neratinib arm versus 31.7 percent for those in the control arm. A neratinib/paclitaxel regimen in a Phase III study would have close to a 72 percent chance of being superior to paclitaxel in HER2-negative patients or superior to paclitaxel plus Herceptin in HER2-positive patients, the I-SPY2 researchers reported.

Auerbach noted on the call that the I-SPY2 data regarding neratinib's activity in HER2-negative patients confirms what the company has seen in preclinical studies. He added that Puma was interested in further studying neratinib in HER2-negative patients.

According to experts at AACR who discussed the I-SPY2 neratinib data, if the trial had continued, Puma's drug may have been able to "graduate" in other biomarker-defined patient subpopulations beyond the hormone receptor-negative, HER2-positive group.

In the MammaPrint ultra-high risk patient group, EGFR signaling may be playing a role in driving the disease, Auerbach noted. "We're doing some additional pre-clinical work to see if there is a way to further enrich the trial, either for all enrollees or just as a prospectively defined subgroup," he said. "Clearly, that would make a lot of sense as to why neratinib is showing so much more activity."

He further suggested that increasing the neratinib dose in HER2-negative patients may lead to improved efficacy in this subset of patients. "The signal you're looking at here is influenced by the fact that they didn't do a very good job controlling the diarrhea in the trial due to the minimal amount of loperamide [Imodium] they used for the prophylaxis," he noted. "Clearly, we would have an opportunity to dose higher with better prophylaxis and recognize that this trial would simply be taxol/neratinib versus taxol alone in a HER2-negative population. You wouldn't use any of the HER2-targeting agents."

In I-SPY2, 39 percent of patients receiving neratinib experienced grade 3/4 diarrhea, compared to 4 percent in the control arm. Although in I-SPY2 researchers tried to reduce the incidence of severe diarrhea in neratinib-treated patients with Imodium, the dose was too low to make a significant impact in reducing the adverse event, Auerbach said.

Among the first 23 patients treated with neratinib in I-SPY2, 43 percent had severe diarrhea. Then, investigators treated the next 52 patients enrolled with anti-diarrheal agents, which resulted in 33 percent experiencing grade 3/4 events. In the next 41 patients, researchers tried treating them with low-dose Imodium – 6 mg on the first day of neratinib treatment and then 4 mg for two weeks. With this strategy, 34 percent of patients had grade 3/4 diarrhea.

"After licensing neratinib from Pfizer, Puma began to look at using low doses and high doses of Imodium prophylactically in order to reduce and potentially prevent neratinib-related diarrhea," Auerbach said. Puma's investigations have shown that using high doses of Imodium, specifically 16 mg during the first three days of neratinib treatment and then tapering the dose in subsequent weeks, results in grade 3 diarrhea rates of under 5 percent and all grade diarrhea rates of between 10 percent and 20 percent.

In the studies Puma is conducting for neratinib, it is using a 16 mg starting dose of Imodium and the company is hoping this will adequately control the incidence of severe diarrhea, which appears to be worst during the first few days of neratinib therapy.

In June last year, Puma launched a Phase III trial of neratinib plus Xeloda (caoecitabine) versus Tykerb (lapatinib) plus Xeloda in 600 patients with HER2-positive metastatic breast cancer who have failed at least two prior treatments. Also last year, Puma launched a Phase II "bucket" study in which the company is exploring neratinib in a variety of tumors – bladder cancer, colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, and other solid tumors, such as prostate cancer, pancreatic cancer, and melanoma. The company plans to enroll seven patients for each disease "bucket" at first, and based on how well they respond to neratinib, enroll more patients into the study arms. Finally, the company is studying neratinib in non-small cell lung cancer patients with HER2 mutated tumors.

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