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I-SPY2 Adaptive Trial Predicts Late-Stage Success for AbbVie's PARP Inhibitor Veliparib in TNBC


Originally published Dec. 13.

SAN ANTONIO, Texas – I-SPY2, an adaptive multi-drug, Phase II breast cancer trial, has predicted based on data from more than 100 HER2-negative patients that if drug developer AbbVie performs a late-stage trial investigating its PARP inhibitor veliparib in combination with carboplatin and standard neoadjuvant chemotherapy in triple-negative patients, it would have a 90 percent chance of success.

I-SPY2, is evaluating several investigational drugs for breast cancer in the neoadjuvant setting using an adaptive randomization design, developed by Laura Esserman of University of California, San Francisco's Helen Diller Family Comprehensive Cancer Center, and Don Berry at MD Anderson Cancer Center. The data on veliparib represents one out of seven experimental arms in the study.

In the adaptive randomization model, “each new patient enrolled benefits from the last patient's experience,” said Hope Rugo, one of the lead researchers in I-SPY2 and director of breast oncology and clinical trials education at the Helen Diller Family Comprehensive Cancer Center.

“On a rolling basis, patients who were eligible and enrolled into the trial have serial MRI screening and that screening, which is confirmed by [pathologic complete response] data when it's available, informs the randomization process,” Rugo told PGx Reporter at the San Antonio Breast Cancer Symposium held here this week. “So, after a certain number of patients, you see more responses in one of these biomarker-signature groups.” The adaptive randomization algorithm then puts more patients with that particular signature into the experimental arm they're most likely to benefit from, while still including a similar number of controls.

In this way, I-SPY2 predicted that a Phase III trial including triple-negative patients and comparing veliparib/carboplatin with standard paclitaxel-based neoadjuvant chemo versus just standard neoadjuvant chemo has a 90 percent likelihood of success in favor of the veliparib arm.

AbbVie is currently investigating veliparib in BRCA-deficient breast cancer and in other cancers. The firm is working with Myriad Genetics to use its BRACAnalysis test and identify patients with BRCA mutations who are likely to respond particularly well to the drug. In an interview with PGx Reporter at SABCS, Myriad Chief Scientific Officer Jerry Lanchbury expressed interest in using its test in an I-SPY2-type design to investigate drugs.

Rugo said that AbbVie has planned a Phase III trial in triple-negative breast cancer looking at veliparib plus carboplatin versus carbplatin with standard chemotherapy, Rugo said. However, an AbbVie spokesperson wouldn't disclose details about the studies the firm is conducting for veliparib. “AbbVie is encouraged by the data presented on veliparib from the I-SPY 2 trial and we expect the results from I-SPY to be important as we move forward with development,” the spokesperson said.

To be eligible to enroll in I-SPY2, breast cancer patients must have tumors 2.5 cm or greater in size, be at high risk of early disease recurrence by Agendia's 70-gene MammaPrint test, or have HER2-positive or triple-negative breast cancer regardless of MammaPrint results. In the veliparib arm, only patients with HER2-negative breast cancer were evaluated, because researchers were concerned about safety issues that HER2-positive patients would experience, particularly if they didn't benefit from therapy.

The study compared pathologic complete responses in 71 patients on veliparib/carboplatin with standard neoadjuvant chemotherapy against 44 HER2-negative controls receiving standard neoadjuvant chemo. The adaptive randomization process looked at pathologic complete response to veliparib/carboplatin in three biomarker groups: all HER2-negative patients; HER2-negative, hormone receptor-positive patients; and triple-negative (HER2-negative, hormone-receptor negative) patients.

“Only 15 percent of breast cancer patients have triple-negative disease,” Rugo noted. “But they are going to be enhanced in a trial like I-SPY2 that takes patients with high-risk breast cancer and all triple-negatives are eligible regardless of MammaPrint [results]. So, we had already enhanced the number of triple-negative patients, but this randomization process further enhanced it so that half of the patients in the trial were triple-negative.”

In triple-negative breast cancer patients, 52 percent of those receiving the veliparib-containing regimen experienced a pathologic complete response compared to 26 percent in the control arm. In the overall HER2-negative population, 33 percent treated with veliparib and 22 percent receiving standard neoadjuvant chemo had a pathologic complete response. Meanwhile, in HER2-negative, hormone receptor positive patients, 14 percent of those treated with veliparib had a pathologic complete response compared to 19 percent in the control arm.

While this study was not designed to assess the efficacy of veliparib and carboplatin separately, the effect size for the combined treatment is large, according to I-SPY2 researchers.

Carboplatin is a DNA-damaging agent and veliparib is a PARP inhibitor. “It's thought that in sporadic triple-negative breast cancer, adding a PARP inhibitor to a DNA-damaging chemotherapy agent is more effective than using a PARP inhibitor by itself,” Rugo said. “We knew that in order for the PARP inhibitor to work well it needed to have that [DNA-damaging] partner. And the degree of benefit that we've seen [with the combination] suggests that there is a contribution from veliparib.”

The adaptive randomization design of I-SPY2 “graduates” a particular treatment paradigm when it has calculated that the biomarker-driven strategy has reached an 85 percent likelihood of success in a 300-patient Phase III study. When researchers considered triple-negative breast cancer patients, the chance of success in Phase III was 90 percent. However, if the same trial were done including all HER2-negative patients, the chance of Phase III success would go down to 55 percent, while conducting the trial only in hormone receptor-positive patients yielded a 28 percent probability of success.

“Our development program will evaluate options for a variety of different patient populations,” the AbbVie spokesperson said, without elaborating. According to, AbbVie is conducting a Phase I study of veliparib and carboplatin in HER2-negative metastatic breast cancer, in which researchers will look at hormone receptor and BRCA mutation status. The company is also recruiting triple-negative breast cancer patients in a Phase II study of carboplatin and combination chemotherapy with or without veliparib.

According to the published literature, patients with BRCA1 mutations are more likely to have triple-negative breast cancer. BRCA1 genes also play a role in DNA damage repair. “As part of I-SPY2, which is a biomarker-rich trial, there are investigations ongoing looking at markers of DNA repair and BRCA mutations,” Rugo said.

“It's clear that some of these sporadic cancers are associated with what's called BRCA-ness or sort of a defect in DNA repair,” she added. “And many people are trying to figure out the best tests to be able to look at problems in DNA repair associated with enhanced sensitivity to these agents. And that's an ongoing work in progress, which I-SPY should be well suited to address.”

Myriad Genetics, the leading provider of BRCA mutation testing, has inked a number of companion diagnostic collaborations with drug firms developing PARP inhibitors and DNA damaging agents. The test developer has a partnership with veliparib sponsor AbbVie, to use its genetic test to gauge best responders in clinical trials involving the drug.

"I would certainly think about using our test in that [adaptive randomization] design and I would certainly think about using our test in the [I-SPY2] study," Myriad's Lanchbury said. "Veliparib is a promising investigational drug that may have synergies with platinum agents and be an even more efficacious therapy in combination in high HRD tumor patients."

Myriad is advancing its BRACAnalysis test as a companion diagnostic for several late-stage PARP inhibitors. The company also has a next-generation sequencing Homologous Recombination Deficiency test that several developers of PARP inhibitors and DNA damaging agents are applying in drug trials.

"We look forward to collaborating with the I-SPY2 team," Lanchbury said.

Ultimately, the benefit of an adaptive randomization design is that it allows researchers to evaluate a number of experimental agents quickly, in a small cohort, incurring less cost than would be possible with a traditional randomized, controlled trial. Given that in I-SPY2, an experimental arm needs between 60 to 120 patients to “graduate” a drug, sponsors can quickly gain insights on the success probability of their agents.

In contrast, Rugo cited the BETH study, also presented at SABCS, as an example of the challenges of the traditional drug development model. “Think about a trial like BETH, that gave bevacizumab to all these patients with HER2-positive disease, thousands of patients,” she said. “You didn't need to do that trial.”

In the 3,500-patient BETH trial, Dennis Slamon and colleagues aimed to look at whether adding Avastin (bevacizumab) to Herceptin plus chemotherapy in the adjuvant setting improved disease-free survival in HER2-positive breast cancer patients compared to the standard of care. In one cohort researchers randomized the majority of patients to Taxotere/Carboplatin/Herceptin (TCH) or TCH with Avastin. In another cohort, more than 250 patients were randomized to receive either anthracycline epirubicin plus Herceptin or epirubicin/Herceptin with Avastin.

At median follow up of 38 months, disease-free survival was 92 percent in both arms of cohort 1. Meanwhile, in cohort 2, disease-free survival was 92 percent in the Avastin plus Hercpetin/epirubicin arm compared to 89 percent in the Herceptin/epirubicin arm. Although adding Avastin didn't make a difference in patients' treatment outcomes in the BETH trial, researchers believe the study showed that a docetaxel/carboplatin regimen may be better for HER2-positive breast cancer patients than anthracycline-based treatments.

Using an adaptive randomization strategy “you could have subsetted that down. You would have had to do additional work over and above HER2 but you would have then looked at your biomarkers to determine who would have benefited with only up to 120 patients,” Rugo explained. “And then you could have powered [another] trial with 300 patients in the neoadjuvant setting and gotten the right subgroup. So, I think [adaptive randomization] has a lot of power to change the way we do things.”

She noted that the I-SPY researchers are also going to conduct an I-SPY3 trial, which will use the adaptive randomization strategy in the 300-patient Phase III setting. The Biomarker Consortium, a public/private partnership of the Foundation of the National Institutes of Health, launched I-SPY2 in 2010. The trial involves drug developers, patient advocacy groups, and 20 cancer centers in the US and Canada. Funding for the study comes form pharmaceutical firms, philanthropic donors, and several non-profit foundations.