Pan-HER inhibitor ‘graduates’ from I-SPY 2 trial

SAN DIEGO – Efficacy results from an adaptive trial demonstrated that the investigational pan-HER inhibitor neratinib in combination with standard chemotherapy benefited patients with newly diagnosed hormone receptor–negative, HER2-positive primary breast cancer.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. John W. Park said that neratinib, an investigational agent being developed by Los Angeles–based Puma Biotechnology, "graduated" in the HR-negative/HER-positive signature, with a 79% probability of success in a phase III study of neratinib plus paclitaxel vs. trastuzumab plus paclitaxel. In addition, the Bayesian probability of superiority for the neratinib-containing regimen, compared with standard therapy, is 95% (P = .051).

©2014 AACR/Todd Buchanan

The findings come from the I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) trial, a randomized, phase II clinical study of women with newly diagnosed stage II breast cancer with a tumor size of at least 2.5 cm and who are considered to be at high risk for recurrence via MammaPrint test.

I-SPY 2 is designed to investigate whether adding investigational drugs such as neratinib to standard chemotherapy is better than standard therapy alone, said Dr. Park, one of the study investigators who is professor of medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

The study’s primary endpoint is pathological complete response (pCR) in the breast and in the lymph nodes at the time of surgery. The trial employs an adaptive design based on Bayesian predictive probability that a regimen will be shown to be statistically superior to standard therapy in an equally randomized 300-patient confirmatory trial. "If at any point in the trial this endpoint is not met, the trial continues to learn from the responses obtained to date, and the randomization is revised to reflect the results that have been obtained thus far," Dr. Park explained. "The trial continues to accrue patients in this weighted randomization fashion until graduation or futility is the result."

Dr. Park presented findings from 115 patients (median age, 51 years) who were assigned to receive paclitaxel plus neratinib (followed by doxorubicin and cyclophosphamide). The rates of pCR in the neratinib arm were compared with those of 78 patients (median age, 48 years) who were concurrently randomized to the control arm containing standard chemotherapy, which consisted of paclitaxel plus trastuzumab (followed by doxorubicin and cyclophosphamide). The researchers also compared 10 biomarker signatures prospectively defined by categories of HR, HER2, and MammaPrint.

Among patients with HR-negative, HER2-positive breast cancer (one of the 10 biomarker signatures), the estimated pCR rate was 56% for the neratinib-containing regimen, compared with 33% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 79%.

Among the 65 patients in the neratinib-containing regimen who were HER2-positive (a separate biomarker signature), the estimated pCR rate was 39% for the neratinib-containing regimen, compared with 23% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 73%.

Neratinib was "largely well tolerated," Dr. Park said, but 39% of patients in the neratinib arm experienced grade 3 or 4 diarrhea, compared with 4% of patients in the control arm. "There was not a particular cardiac safety event that was frequent in either arm, and there are no congestive heart failure events noted to date," he said.

After noticing high rates of diarrhea symptoms, the trial investigators modified the diarrhea supportive care guideline "to include vigorous patient monitoring and early institution of supportive care, which appeared to make a difference in terms of the frequency of diarrhea and amelioration of that side effect," Dr. Park said. "Further to that, there was also the institution of a prophylactic loperamide regimen, which was also instituted later in the trial."

There was no apparent difference in the time to surgery from initiation of treatment in the control versus the neratinib-treated groups (a median of 168 days for both). "Early discontinuation was somewhat more frequently observed with neratinib, primarily due to toxicity, whereas early discontinuation due to progression was observed more frequently in the control group," Dr. Park said.

He concluded his remarks by noting that I-SPY 2 "is a biomarker-rich trial. Additional response predictors and biomarker developments are under investigation, and we anticipate they will be reported in a subsequent forum. Based on these results, neratinib is under consideration for phase III testing in the neoadjuvant population."

In an interview, Dr. Thomas Lynch, director of the Yale Cancer Center in New Haven, Conn., and a member of the American Association for Cancer Research’s annual meeting program committee, praised the novel design of the I-SPY 2 trial, "the fact that it allows rapid evaluation of both biomarkers and new drugs and the interaction between biomarkers and new drugs.

"It’s not a definitive [trial] design; it’s not going to lead to drug approval in and of itself. But it does have a lot of power to sort out which biomarkers and which agents are the most important to combine and look at in putting together treatments for patients," Dr. Lynch said.

He went on to describe the findings regarding neratinib as "intriguing, but I have to see a bigger study to have a sense of magnitude of benefit. What the interaction of the biomarker is, is hard to know."

The study is sponsored by the QuantumLeap Healthcare Collaborative, a 501(3) charitable foundation. Dr. Park said that he had no relevant financial conflicts to disclose. Dr. Lynch disclosed that he is on the board of directors of Bristol-Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board of Arvinas and receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation testing patent and receives royalties.

[email protected]

SAN DIEGO – Efficacy results from an adaptive trial demonstrated that the investigational pan-HER inhibitor neratinib in combination with standard chemotherapy benefited patients with newly diagnosed hormone receptor–negative, HER2-positive primary breast cancer.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. John W. Park said that neratinib, an investigational agent being developed by Los Angeles–based Puma Biotechnology, "graduated" in the HR-negative/HER-positive signature, with a 79% probability of success in a phase III study of neratinib plus paclitaxel vs. trastuzumab plus paclitaxel. In addition, the Bayesian probability of superiority for the neratinib-containing regimen, compared with standard therapy, is 95% (P = .051).

©2014 AACR/Todd Buchanan

The findings come from the I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) trial, a randomized, phase II clinical study of women with newly diagnosed stage II breast cancer with a tumor size of at least 2.5 cm and who are considered to be at high risk for recurrence via MammaPrint test.

I-SPY 2 is designed to investigate whether adding investigational drugs such as neratinib to standard chemotherapy is better than standard therapy alone, said Dr. Park, one of the study investigators who is professor of medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

The study’s primary endpoint is pathological complete response (pCR) in the breast and in the lymph nodes at the time of surgery. The trial employs an adaptive design based on Bayesian predictive probability that a regimen will be shown to be statistically superior to standard therapy in an equally randomized 300-patient confirmatory trial. "If at any point in the trial this endpoint is not met, the trial continues to learn from the responses obtained to date, and the randomization is revised to reflect the results that have been obtained thus far," Dr. Park explained. "The trial continues to accrue patients in this weighted randomization fashion until graduation or futility is the result."

Dr. Park presented findings from 115 patients (median age, 51 years) who were assigned to receive paclitaxel plus neratinib (followed by doxorubicin and cyclophosphamide). The rates of pCR in the neratinib arm were compared with those of 78 patients (median age, 48 years) who were concurrently randomized to the control arm containing standard chemotherapy, which consisted of paclitaxel plus trastuzumab (followed by doxorubicin and cyclophosphamide). The researchers also compared 10 biomarker signatures prospectively defined by categories of HR, HER2, and MammaPrint.

Among patients with HR-negative, HER2-positive breast cancer (one of the 10 biomarker signatures), the estimated pCR rate was 56% for the neratinib-containing regimen, compared with 33% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 79%.

Among the 65 patients in the neratinib-containing regimen who were HER2-positive (a separate biomarker signature), the estimated pCR rate was 39% for the neratinib-containing regimen, compared with 23% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 73%.

Neratinib was "largely well tolerated," Dr. Park said, but 39% of patients in the neratinib arm experienced grade 3 or 4 diarrhea, compared with 4% of patients in the control arm. "There was not a particular cardiac safety event that was frequent in either arm, and there are no congestive heart failure events noted to date," he said.

After noticing high rates of diarrhea symptoms, the trial investigators modified the diarrhea supportive care guideline "to include vigorous patient monitoring and early institution of supportive care, which appeared to make a difference in terms of the frequency of diarrhea and amelioration of that side effect," Dr. Park said. "Further to that, there was also the institution of a prophylactic loperamide regimen, which was also instituted later in the trial."

There was no apparent difference in the time to surgery from initiation of treatment in the control versus the neratinib-treated groups (a median of 168 days for both). "Early discontinuation was somewhat more frequently observed with neratinib, primarily due to toxicity, whereas early discontinuation due to progression was observed more frequently in the control group," Dr. Park said.

He concluded his remarks by noting that I-SPY 2 "is a biomarker-rich trial. Additional response predictors and biomarker developments are under investigation, and we anticipate they will be reported in a subsequent forum. Based on these results, neratinib is under consideration for phase III testing in the neoadjuvant population."

In an interview, Dr. Thomas Lynch, director of the Yale Cancer Center in New Haven, Conn., and a member of the American Association for Cancer Research’s annual meeting program committee, praised the novel design of the I-SPY 2 trial, "the fact that it allows rapid evaluation of both biomarkers and new drugs and the interaction between biomarkers and new drugs.

"It’s not a definitive [trial] design; it’s not going to lead to drug approval in and of itself. But it does have a lot of power to sort out which biomarkers and which agents are the most important to combine and look at in putting together treatments for patients," Dr. Lynch said.

He went on to describe the findings regarding neratinib as "intriguing, but I have to see a bigger study to have a sense of magnitude of benefit. What the interaction of the biomarker is, is hard to know."

The study is sponsored by the QuantumLeap Healthcare Collaborative, a 501(3) charitable foundation. Dr. Park said that he had no relevant financial conflicts to disclose. Dr. Lynch disclosed that he is on the board of directors of Bristol-Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board of Arvinas and receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation testing patent and receives royalties.

[email protected]

SAN DIEGO – Efficacy results from an adaptive trial demonstrated that the investigational pan-HER inhibitor neratinib in combination with standard chemotherapy benefited patients with newly diagnosed hormone receptor–negative, HER2-positive primary breast cancer.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. John W. Park said that neratinib, an investigational agent being developed by Los Angeles–based Puma Biotechnology, "graduated" in the HR-negative/HER-positive signature, with a 79% probability of success in a phase III study of neratinib plus paclitaxel vs. trastuzumab plus paclitaxel. In addition, the Bayesian probability of superiority for the neratinib-containing regimen, compared with standard therapy, is 95% (P = .051).

©2014 AACR/Todd Buchanan

The findings come from the I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) trial, a randomized, phase II clinical study of women with newly diagnosed stage II breast cancer with a tumor size of at least 2.5 cm and who are considered to be at high risk for recurrence via MammaPrint test.

I-SPY 2 is designed to investigate whether adding investigational drugs such as neratinib to standard chemotherapy is better than standard therapy alone, said Dr. Park, one of the study investigators who is professor of medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

The study’s primary endpoint is pathological complete response (pCR) in the breast and in the lymph nodes at the time of surgery. The trial employs an adaptive design based on Bayesian predictive probability that a regimen will be shown to be statistically superior to standard therapy in an equally randomized 300-patient confirmatory trial. "If at any point in the trial this endpoint is not met, the trial continues to learn from the responses obtained to date, and the randomization is revised to reflect the results that have been obtained thus far," Dr. Park explained. "The trial continues to accrue patients in this weighted randomization fashion until graduation or futility is the result."

Dr. Park presented findings from 115 patients (median age, 51 years) who were assigned to receive paclitaxel plus neratinib (followed by doxorubicin and cyclophosphamide). The rates of pCR in the neratinib arm were compared with those of 78 patients (median age, 48 years) who were concurrently randomized to the control arm containing standard chemotherapy, which consisted of paclitaxel plus trastuzumab (followed by doxorubicin and cyclophosphamide). The researchers also compared 10 biomarker signatures prospectively defined by categories of HR, HER2, and MammaPrint.

Among patients with HR-negative, HER2-positive breast cancer (one of the 10 biomarker signatures), the estimated pCR rate was 56% for the neratinib-containing regimen, compared with 33% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 79%.

Among the 65 patients in the neratinib-containing regimen who were HER2-positive (a separate biomarker signature), the estimated pCR rate was 39% for the neratinib-containing regimen, compared with 23% for standard chemotherapy. The Bayesian probability of superiority for the neratinib-containing regimen, compared with standard chemotherapy, is 95%, while the Bayesian probability of success in a phase III trial, compared with standard chemotherapy, is 73%.

Neratinib was "largely well tolerated," Dr. Park said, but 39% of patients in the neratinib arm experienced grade 3 or 4 diarrhea, compared with 4% of patients in the control arm. "There was not a particular cardiac safety event that was frequent in either arm, and there are no congestive heart failure events noted to date," he said.

After noticing high rates of diarrhea symptoms, the trial investigators modified the diarrhea supportive care guideline "to include vigorous patient monitoring and early institution of supportive care, which appeared to make a difference in terms of the frequency of diarrhea and amelioration of that side effect," Dr. Park said. "Further to that, there was also the institution of a prophylactic loperamide regimen, which was also instituted later in the trial."

There was no apparent difference in the time to surgery from initiation of treatment in the control versus the neratinib-treated groups (a median of 168 days for both). "Early discontinuation was somewhat more frequently observed with neratinib, primarily due to toxicity, whereas early discontinuation due to progression was observed more frequently in the control group," Dr. Park said.

He concluded his remarks by noting that I-SPY 2 "is a biomarker-rich trial. Additional response predictors and biomarker developments are under investigation, and we anticipate they will be reported in a subsequent forum. Based on these results, neratinib is under consideration for phase III testing in the neoadjuvant population."

In an interview, Dr. Thomas Lynch, director of the Yale Cancer Center in New Haven, Conn., and a member of the American Association for Cancer Research’s annual meeting program committee, praised the novel design of the I-SPY 2 trial, "the fact that it allows rapid evaluation of both biomarkers and new drugs and the interaction between biomarkers and new drugs.

"It’s not a definitive [trial] design; it’s not going to lead to drug approval in and of itself. But it does have a lot of power to sort out which biomarkers and which agents are the most important to combine and look at in putting together treatments for patients," Dr. Lynch said.

He went on to describe the findings regarding neratinib as "intriguing, but I have to see a bigger study to have a sense of magnitude of benefit. What the interaction of the biomarker is, is hard to know."

The study is sponsored by the QuantumLeap Healthcare Collaborative, a 501(3) charitable foundation. Dr. Park said that he had no relevant financial conflicts to disclose. Dr. Lynch disclosed that he is on the board of directors of Bristol-Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board of Arvinas and receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation testing patent and receives royalties.

[email protected]