Veliparib-carboplatin combo is first 'graduate' of I-SPY2 trial

SAN ANTONIO – The combination of veliparib and carboplatin is the first "graduate" of the I-SPY 2 trial, investigators reported at the San Antonio Breast Cancer Symposium.

The phase 2 trial uses an adaptive design to screen novel agents and regimens by assessing whether they improve response when added to neoadjuvant chemotherapy, with the aim of matching them to breast cancer biomarker signatures most likely to respond.

The novel agents or regimens graduate, or meet the bar for further testing, if there is a 85% probability or better that they will be superior to chemotherapy alone for at least one signature in a modestly sized phase 3 neoadjuvant trial.

First results from 115 patients, reported in a session and press briefing by lead author Dr. Hope S. Rugo, showed that based on the estimated pathologic complete responses (pCRs) seen, there was a 90% probability that the combination of veliparib—an oral investigational inhibitor of poly-ADP-ribose, or PARP—and carboplatin added to chemotherapy would be superior to chemotherapy alone among patients with triple-negative disease.

In contrast, the probability in all patients with HER2-negative disease was only slightly better than a coin toss. And the probability in the subset with hormone receptor–positive, HER2-negative disease was less than one in 10.

"Veliparib and carboplatin has graduated with the triple-negative signature, the subset recommended for this drug’s subsequent development," said Dr. Rugo, who is a professor of medicine and director of breast oncology and clinical trials education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

"We identified a biomarker signature–drug pair for veliparib and carboplatin on the basis of a modest number of patients...This trial design will accelerate the process of identifying drugs that are effective for specific breast cancer subtypes and thereby reduce the cost, time, and numbers of patients needed to get effective drugs to market," she noted.

The trial was not designed to assess the contribution of each agent—veliparib (ABT-888, manufactured by AbbVie) and carboplatin—individually, Dr. Rugo acknowledged; regardless, their combination had a large effect size.

"I-SPY 2 is a biomarker-rich trial. Additional response predictors are under evaluation," such as BRCA status, she further noted.

"A lot of work has been done with the FDA [Food and Drug Administration] recently evaluating drugs for accelerated approval based on their response in the neoadjuvant setting. How this plays out in the future for other drugs [besides pertuzumab] remains to be seen," Dr. Rugo commented. "Clearly there needs to be a plan for outcome data that can correspond to the pCR rates in order for these drugs to obtain final approval. But there is the hope that this will be a mechanism for accelerated approval."

The trial has six other arms testing investigational regimens. Results for the arm that is testing neratinib (PB272, Puma Biotechnology), a tyrosine kinase inhibitor, are expected shortly.

Women are eligible for I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2) if they have tumors measuring at least 2.5 cm. Those whose tumors have all of three favorable characteristics (hormone receptor positive, HER2 negative, and Low MammaPrint result) are excluded.

Eight biomarker signatures are created according to hormone receptor status, HER2 status, and MammaPrint result (High or Ultra High).

The trial uses adaptive randomization, whereby each patient’s MRI and pCR data are fed into an algorithm, affecting how the next patient is randomized. "This allows us to learn and adapt from each patient as we go along, and each new patient benefits from information obtained from the prior patient. In addition, this allows us to add and drop agents as we go along based on success of each agent or regimen," explained Dr. Rugo, who disclosed no conflicts of interest related to the trial.

Patients are randomized to receive weekly paclitaxel plus a novel agent/regimen or weekly paclitaxel alone—each followed by standard doxorubicin and cyclophosphamide (AC) chemotherapy and then surgery. The endpoint of pCR is defined as no residual cancer in the breast or lymph nodes at the time of surgery.

The results are used to predict the probability of superiority in a phase 3 neoadjuvant trial having just 300 patients and using pCR as its endpoint.

The findings that Dr. Rugo presented were based on 115 patients with HER2-negative disease: 71 randomized to veliparib-carboplatin plus chemotherapy and 44 randomized to chemotherapy alone.

Among patients with triple-negative disease, the estimated rate of pCR was 52% with veliparib-carboplatin and 26% without it. There was a 90% predictive probability that the combination with chemotherapy would be superior to chemotherapy alone in phase 3 testing in this subset.

In contrast, the difference in estimated pCR rates with addition of veliparib-carboplatin was much smaller among all patients with HER2-negative disease (33% vs. 22%) and in the opposite direction among the subset with hormone receptor–positive, HER2-negative disease (14% vs. 19%). The predictive probabilities that the combination with chemotherapy would be superior in phase 3 testing in these groups were just 55% and 9%, respectively.

"The toxicity was moderately increased as expected, but it was well managed with dose reduction and delay," Dr. Rugo reported.

Dr. Rugo disclosed no relevant conflicts of interest.

SAN ANTONIO – The combination of veliparib and carboplatin is the first "graduate" of the I-SPY 2 trial, investigators reported at the San Antonio Breast Cancer Symposium.

The phase 2 trial uses an adaptive design to screen novel agents and regimens by assessing whether they improve response when added to neoadjuvant chemotherapy, with the aim of matching them to breast cancer biomarker signatures most likely to respond.

The novel agents or regimens graduate, or meet the bar for further testing, if there is a 85% probability or better that they will be superior to chemotherapy alone for at least one signature in a modestly sized phase 3 neoadjuvant trial.

First results from 115 patients, reported in a session and press briefing by lead author Dr. Hope S. Rugo, showed that based on the estimated pathologic complete responses (pCRs) seen, there was a 90% probability that the combination of veliparib—an oral investigational inhibitor of poly-ADP-ribose, or PARP—and carboplatin added to chemotherapy would be superior to chemotherapy alone among patients with triple-negative disease.

In contrast, the probability in all patients with HER2-negative disease was only slightly better than a coin toss. And the probability in the subset with hormone receptor–positive, HER2-negative disease was less than one in 10.

"Veliparib and carboplatin has graduated with the triple-negative signature, the subset recommended for this drug’s subsequent development," said Dr. Rugo, who is a professor of medicine and director of breast oncology and clinical trials education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

"We identified a biomarker signature–drug pair for veliparib and carboplatin on the basis of a modest number of patients...This trial design will accelerate the process of identifying drugs that are effective for specific breast cancer subtypes and thereby reduce the cost, time, and numbers of patients needed to get effective drugs to market," she noted.

The trial was not designed to assess the contribution of each agent—veliparib (ABT-888, manufactured by AbbVie) and carboplatin—individually, Dr. Rugo acknowledged; regardless, their combination had a large effect size.

"I-SPY 2 is a biomarker-rich trial. Additional response predictors are under evaluation," such as BRCA status, she further noted.

"A lot of work has been done with the FDA [Food and Drug Administration] recently evaluating drugs for accelerated approval based on their response in the neoadjuvant setting. How this plays out in the future for other drugs [besides pertuzumab] remains to be seen," Dr. Rugo commented. "Clearly there needs to be a plan for outcome data that can correspond to the pCR rates in order for these drugs to obtain final approval. But there is the hope that this will be a mechanism for accelerated approval."

The trial has six other arms testing investigational regimens. Results for the arm that is testing neratinib (PB272, Puma Biotechnology), a tyrosine kinase inhibitor, are expected shortly.

Women are eligible for I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2) if they have tumors measuring at least 2.5 cm. Those whose tumors have all of three favorable characteristics (hormone receptor positive, HER2 negative, and Low MammaPrint result) are excluded.

Eight biomarker signatures are created according to hormone receptor status, HER2 status, and MammaPrint result (High or Ultra High).

The trial uses adaptive randomization, whereby each patient’s MRI and pCR data are fed into an algorithm, affecting how the next patient is randomized. "This allows us to learn and adapt from each patient as we go along, and each new patient benefits from information obtained from the prior patient. In addition, this allows us to add and drop agents as we go along based on success of each agent or regimen," explained Dr. Rugo, who disclosed no conflicts of interest related to the trial.

Patients are randomized to receive weekly paclitaxel plus a novel agent/regimen or weekly paclitaxel alone—each followed by standard doxorubicin and cyclophosphamide (AC) chemotherapy and then surgery. The endpoint of pCR is defined as no residual cancer in the breast or lymph nodes at the time of surgery.

The results are used to predict the probability of superiority in a phase 3 neoadjuvant trial having just 300 patients and using pCR as its endpoint.

The findings that Dr. Rugo presented were based on 115 patients with HER2-negative disease: 71 randomized to veliparib-carboplatin plus chemotherapy and 44 randomized to chemotherapy alone.

Among patients with triple-negative disease, the estimated rate of pCR was 52% with veliparib-carboplatin and 26% without it. There was a 90% predictive probability that the combination with chemotherapy would be superior to chemotherapy alone in phase 3 testing in this subset.

In contrast, the difference in estimated pCR rates with addition of veliparib-carboplatin was much smaller among all patients with HER2-negative disease (33% vs. 22%) and in the opposite direction among the subset with hormone receptor–positive, HER2-negative disease (14% vs. 19%). The predictive probabilities that the combination with chemotherapy would be superior in phase 3 testing in these groups were just 55% and 9%, respectively.

"The toxicity was moderately increased as expected, but it was well managed with dose reduction and delay," Dr. Rugo reported.

Dr. Rugo disclosed no relevant conflicts of interest.

SAN ANTONIO – The combination of veliparib and carboplatin is the first "graduate" of the I-SPY 2 trial, investigators reported at the San Antonio Breast Cancer Symposium.

The phase 2 trial uses an adaptive design to screen novel agents and regimens by assessing whether they improve response when added to neoadjuvant chemotherapy, with the aim of matching them to breast cancer biomarker signatures most likely to respond.

The novel agents or regimens graduate, or meet the bar for further testing, if there is a 85% probability or better that they will be superior to chemotherapy alone for at least one signature in a modestly sized phase 3 neoadjuvant trial.

First results from 115 patients, reported in a session and press briefing by lead author Dr. Hope S. Rugo, showed that based on the estimated pathologic complete responses (pCRs) seen, there was a 90% probability that the combination of veliparib—an oral investigational inhibitor of poly-ADP-ribose, or PARP—and carboplatin added to chemotherapy would be superior to chemotherapy alone among patients with triple-negative disease.

In contrast, the probability in all patients with HER2-negative disease was only slightly better than a coin toss. And the probability in the subset with hormone receptor–positive, HER2-negative disease was less than one in 10.

"Veliparib and carboplatin has graduated with the triple-negative signature, the subset recommended for this drug’s subsequent development," said Dr. Rugo, who is a professor of medicine and director of breast oncology and clinical trials education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

"We identified a biomarker signature–drug pair for veliparib and carboplatin on the basis of a modest number of patients...This trial design will accelerate the process of identifying drugs that are effective for specific breast cancer subtypes and thereby reduce the cost, time, and numbers of patients needed to get effective drugs to market," she noted.

The trial was not designed to assess the contribution of each agent—veliparib (ABT-888, manufactured by AbbVie) and carboplatin—individually, Dr. Rugo acknowledged; regardless, their combination had a large effect size.

"I-SPY 2 is a biomarker-rich trial. Additional response predictors are under evaluation," such as BRCA status, she further noted.

"A lot of work has been done with the FDA [Food and Drug Administration] recently evaluating drugs for accelerated approval based on their response in the neoadjuvant setting. How this plays out in the future for other drugs [besides pertuzumab] remains to be seen," Dr. Rugo commented. "Clearly there needs to be a plan for outcome data that can correspond to the pCR rates in order for these drugs to obtain final approval. But there is the hope that this will be a mechanism for accelerated approval."

The trial has six other arms testing investigational regimens. Results for the arm that is testing neratinib (PB272, Puma Biotechnology), a tyrosine kinase inhibitor, are expected shortly.

Women are eligible for I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2) if they have tumors measuring at least 2.5 cm. Those whose tumors have all of three favorable characteristics (hormone receptor positive, HER2 negative, and Low MammaPrint result) are excluded.

Eight biomarker signatures are created according to hormone receptor status, HER2 status, and MammaPrint result (High or Ultra High).

The trial uses adaptive randomization, whereby each patient’s MRI and pCR data are fed into an algorithm, affecting how the next patient is randomized. "This allows us to learn and adapt from each patient as we go along, and each new patient benefits from information obtained from the prior patient. In addition, this allows us to add and drop agents as we go along based on success of each agent or regimen," explained Dr. Rugo, who disclosed no conflicts of interest related to the trial.

Patients are randomized to receive weekly paclitaxel plus a novel agent/regimen or weekly paclitaxel alone—each followed by standard doxorubicin and cyclophosphamide (AC) chemotherapy and then surgery. The endpoint of pCR is defined as no residual cancer in the breast or lymph nodes at the time of surgery.

The results are used to predict the probability of superiority in a phase 3 neoadjuvant trial having just 300 patients and using pCR as its endpoint.

The findings that Dr. Rugo presented were based on 115 patients with HER2-negative disease: 71 randomized to veliparib-carboplatin plus chemotherapy and 44 randomized to chemotherapy alone.

Among patients with triple-negative disease, the estimated rate of pCR was 52% with veliparib-carboplatin and 26% without it. There was a 90% predictive probability that the combination with chemotherapy would be superior to chemotherapy alone in phase 3 testing in this subset.

In contrast, the difference in estimated pCR rates with addition of veliparib-carboplatin was much smaller among all patients with HER2-negative disease (33% vs. 22%) and in the opposite direction among the subset with hormone receptor–positive, HER2-negative disease (14% vs. 19%). The predictive probabilities that the combination with chemotherapy would be superior in phase 3 testing in these groups were just 55% and 9%, respectively.

"The toxicity was moderately increased as expected, but it was well managed with dose reduction and delay," Dr. Rugo reported.

Dr. Rugo disclosed no relevant conflicts of interest.