American Association for Cancer Research (AACR)/ National Cancer Institute (NCI)/ European Organization for Research and Treatment of Cancer (EORTC): Molecular Targets and Cancer Therapeutics

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4897-15
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2015

Hold the checkpoint inhibitors when pneumonitis symptoms occur

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Hold the checkpoint inhibitors when pneumonitis symptoms occur

BOSTON – Treatment of pneumonitis associated with the PD-1 axis checkpoint inhibitors requires close monitoring of patients and rapid clinical response, an oncologist advised.

“We need to be vigilant when we treat our patients. If a patient has cough or shortness of breath, you take it seriously, even if [it is] a patient who has lung cancer and is a smoker,” said Dr. Scott Gettinger of Yale Cancer Center, New Haven, Conn.

He recommended that before starting patients on a programmed death-1 (PD-1) axis inhibitor such as pembrolizumab (Keytruda) or nivolumab (Opdivo), clinicians get baseline oxygen saturation levels to obtain an objective measure for following patients during therapy.

“When you suspect pneumonitis you have to start steroids right away, or patients can spiral down,” he said at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Pneumonitis – characterized by cough, dyspnea, and hypoxia – is a common adverse event associated with PD-1 and PD-ligand 1 (PD-L1) inhibitors, but is rarely seen in patients treated with CTLA-4 inhibitors such as ipilimumab (Yervoy). Current evidence suggests that pneumonitis is more prevalent in patients with non–small-cell lung cancer, occurring in approximately 4%-6% of patients cases, than in melanoma (1%). The difference is probably due to a history of smoking common to the majority of patients with NSCLC, Dr. Gettinger said.

“The other theme that we’re beginning to see is that maybe pneumonitis is a bit more common with anti-PD-1 vs. anti-PD-L1 antibodies,” he said.

It’s theorized that PD-1 inhibitors may block binding of PD-L2 to one of its binding partners, thereby interfering with respiratory tolerance, he said.

Evidence from the pivotal clinical trial of nivolumab in lung cancer (Checkmate 057) suggests that the time to onset of pneumonitis was a median of 31.1 weeks (range 11.7 to 56.9 weeks). The pneumonitis resolved in about 5-7 weeks.

Investigators at Memorial Sloan Kettering Cancer Center in New York City reported at the European Cancer Congress 2015 on pneumonitis in 36 of 653 patients treated with an anti PD-1/PD-L1 monoclonal antibody from 2009 through 2014, 33 of whom had received a PD-1 inhibitor, and 3 of whom received a PD-L1 inhibitor.

They found that pneumonitis in patients with lung cancer tended to resemble chronic obstructive pneumonia, whereas patients with melanoma were more likely to have ground-glass opacifications on radiography. There was a trend, falling just short of significance, toward association of COP-like pneumonitis with development of grade 3 or greater, and with a requirement for more than one type of immunosuppression, compared to other subtypes.

Algorithms for management

Dr. Gettinger briefly outlined an algorithm offered by Bristol-Myers Squibb for management of suspected pulmonary toxicity with nivolumab. For management of patients with grade 1 toxicities (asymptomatic, with radiographic changes only), it recommends that clinicians consider delay of immuno-oncologic (I-O) therapy, monitor for symptoms every 2-3 days, and consider consultations with pulmonary and infectious disease specialists.

For grade 2 pneumonitis, marked by mild to moderate new symptoms, the algorithm calls for clinicians to delay I-O therapy per protocol, consult with pulmonary and ID specialists, monitor symptoms daily and consider hospitalization, start the patient on steroids with 1.0 mg/kg per day methylprednisolone IV or the oral equivalent, and consider bronchoscopy and lung biopsy.

For patients with grade 3 or 4 toxicities, marked by severe new symptoms, new or worsening hypoxia, or other life-threatening symptoms, the algorithm states that clinicians should discontinue I-O therapy, hospitalize the patient, consult with pulmonary and ID, give 2-4 mg/kg per day methylprednisolone IV or the oral equivalent, add prophylactic antibiotics for opportunistic infections, and consider bronchoscopy and lung biopsy.

At Yale, Dr. Gettinger and colleagues, when presented with a symptomatic patient on a PD-axis inhibitor, will first rule out other etiologies such as infection, chronic obstructive pulmonary disease exacerbation, or cancer progression), typically with bronchoscopy.

For patients with moderate pneumonitis, they may treat with prednisone for 1 or 2 weeks, with a 4-6 week taper begun as symptoms start to resolve.

“In a patient who has profound hypoxia and shortness of breath, we may want to go higher: We might give them 2 mg/kg twice a day of [methylprednisolone] in the hospital, wait until they get better, and then slowly taper them, whether it be over 4 or 6 weeks or longer. Occasionally our patients need to get even higher doses of steroids and there’s really nothing to guide us. Who knows if 1 gram of [methylprednisolone] may be better than 60 g of prednisone? But we do it, and patients do get better with the higher doses,” he said.

 

 

In rare instances, patients may required other immunosuppressive agents, such as infliximab (Remicade), cyclophosphamide, or mycophenolate mofetil.

Patients who require additional immunosuppressive agents to resolve severe pneumonitis tend to have poor outcomes, Dr. Gettinger said.

Re-challenge of patients with a PD-1 or PD-L1 inhibitor following resolution of pneumonitis appears to be inadvisable for all patients except possibly those with grade 1 (asymptomatic) toxicity, due to the high risk of recurrence, he said.

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BOSTON – Treatment of pneumonitis associated with the PD-1 axis checkpoint inhibitors requires close monitoring of patients and rapid clinical response, an oncologist advised.

“We need to be vigilant when we treat our patients. If a patient has cough or shortness of breath, you take it seriously, even if [it is] a patient who has lung cancer and is a smoker,” said Dr. Scott Gettinger of Yale Cancer Center, New Haven, Conn.

He recommended that before starting patients on a programmed death-1 (PD-1) axis inhibitor such as pembrolizumab (Keytruda) or nivolumab (Opdivo), clinicians get baseline oxygen saturation levels to obtain an objective measure for following patients during therapy.

“When you suspect pneumonitis you have to start steroids right away, or patients can spiral down,” he said at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Pneumonitis – characterized by cough, dyspnea, and hypoxia – is a common adverse event associated with PD-1 and PD-ligand 1 (PD-L1) inhibitors, but is rarely seen in patients treated with CTLA-4 inhibitors such as ipilimumab (Yervoy). Current evidence suggests that pneumonitis is more prevalent in patients with non–small-cell lung cancer, occurring in approximately 4%-6% of patients cases, than in melanoma (1%). The difference is probably due to a history of smoking common to the majority of patients with NSCLC, Dr. Gettinger said.

“The other theme that we’re beginning to see is that maybe pneumonitis is a bit more common with anti-PD-1 vs. anti-PD-L1 antibodies,” he said.

It’s theorized that PD-1 inhibitors may block binding of PD-L2 to one of its binding partners, thereby interfering with respiratory tolerance, he said.

Evidence from the pivotal clinical trial of nivolumab in lung cancer (Checkmate 057) suggests that the time to onset of pneumonitis was a median of 31.1 weeks (range 11.7 to 56.9 weeks). The pneumonitis resolved in about 5-7 weeks.

Investigators at Memorial Sloan Kettering Cancer Center in New York City reported at the European Cancer Congress 2015 on pneumonitis in 36 of 653 patients treated with an anti PD-1/PD-L1 monoclonal antibody from 2009 through 2014, 33 of whom had received a PD-1 inhibitor, and 3 of whom received a PD-L1 inhibitor.

They found that pneumonitis in patients with lung cancer tended to resemble chronic obstructive pneumonia, whereas patients with melanoma were more likely to have ground-glass opacifications on radiography. There was a trend, falling just short of significance, toward association of COP-like pneumonitis with development of grade 3 or greater, and with a requirement for more than one type of immunosuppression, compared to other subtypes.

Algorithms for management

Dr. Gettinger briefly outlined an algorithm offered by Bristol-Myers Squibb for management of suspected pulmonary toxicity with nivolumab. For management of patients with grade 1 toxicities (asymptomatic, with radiographic changes only), it recommends that clinicians consider delay of immuno-oncologic (I-O) therapy, monitor for symptoms every 2-3 days, and consider consultations with pulmonary and infectious disease specialists.

For grade 2 pneumonitis, marked by mild to moderate new symptoms, the algorithm calls for clinicians to delay I-O therapy per protocol, consult with pulmonary and ID specialists, monitor symptoms daily and consider hospitalization, start the patient on steroids with 1.0 mg/kg per day methylprednisolone IV or the oral equivalent, and consider bronchoscopy and lung biopsy.

For patients with grade 3 or 4 toxicities, marked by severe new symptoms, new or worsening hypoxia, or other life-threatening symptoms, the algorithm states that clinicians should discontinue I-O therapy, hospitalize the patient, consult with pulmonary and ID, give 2-4 mg/kg per day methylprednisolone IV or the oral equivalent, add prophylactic antibiotics for opportunistic infections, and consider bronchoscopy and lung biopsy.

At Yale, Dr. Gettinger and colleagues, when presented with a symptomatic patient on a PD-axis inhibitor, will first rule out other etiologies such as infection, chronic obstructive pulmonary disease exacerbation, or cancer progression), typically with bronchoscopy.

For patients with moderate pneumonitis, they may treat with prednisone for 1 or 2 weeks, with a 4-6 week taper begun as symptoms start to resolve.

“In a patient who has profound hypoxia and shortness of breath, we may want to go higher: We might give them 2 mg/kg twice a day of [methylprednisolone] in the hospital, wait until they get better, and then slowly taper them, whether it be over 4 or 6 weeks or longer. Occasionally our patients need to get even higher doses of steroids and there’s really nothing to guide us. Who knows if 1 gram of [methylprednisolone] may be better than 60 g of prednisone? But we do it, and patients do get better with the higher doses,” he said.

 

 

In rare instances, patients may required other immunosuppressive agents, such as infliximab (Remicade), cyclophosphamide, or mycophenolate mofetil.

Patients who require additional immunosuppressive agents to resolve severe pneumonitis tend to have poor outcomes, Dr. Gettinger said.

Re-challenge of patients with a PD-1 or PD-L1 inhibitor following resolution of pneumonitis appears to be inadvisable for all patients except possibly those with grade 1 (asymptomatic) toxicity, due to the high risk of recurrence, he said.

BOSTON – Treatment of pneumonitis associated with the PD-1 axis checkpoint inhibitors requires close monitoring of patients and rapid clinical response, an oncologist advised.

“We need to be vigilant when we treat our patients. If a patient has cough or shortness of breath, you take it seriously, even if [it is] a patient who has lung cancer and is a smoker,” said Dr. Scott Gettinger of Yale Cancer Center, New Haven, Conn.

He recommended that before starting patients on a programmed death-1 (PD-1) axis inhibitor such as pembrolizumab (Keytruda) or nivolumab (Opdivo), clinicians get baseline oxygen saturation levels to obtain an objective measure for following patients during therapy.

“When you suspect pneumonitis you have to start steroids right away, or patients can spiral down,” he said at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Pneumonitis – characterized by cough, dyspnea, and hypoxia – is a common adverse event associated with PD-1 and PD-ligand 1 (PD-L1) inhibitors, but is rarely seen in patients treated with CTLA-4 inhibitors such as ipilimumab (Yervoy). Current evidence suggests that pneumonitis is more prevalent in patients with non–small-cell lung cancer, occurring in approximately 4%-6% of patients cases, than in melanoma (1%). The difference is probably due to a history of smoking common to the majority of patients with NSCLC, Dr. Gettinger said.

“The other theme that we’re beginning to see is that maybe pneumonitis is a bit more common with anti-PD-1 vs. anti-PD-L1 antibodies,” he said.

It’s theorized that PD-1 inhibitors may block binding of PD-L2 to one of its binding partners, thereby interfering with respiratory tolerance, he said.

Evidence from the pivotal clinical trial of nivolumab in lung cancer (Checkmate 057) suggests that the time to onset of pneumonitis was a median of 31.1 weeks (range 11.7 to 56.9 weeks). The pneumonitis resolved in about 5-7 weeks.

Investigators at Memorial Sloan Kettering Cancer Center in New York City reported at the European Cancer Congress 2015 on pneumonitis in 36 of 653 patients treated with an anti PD-1/PD-L1 monoclonal antibody from 2009 through 2014, 33 of whom had received a PD-1 inhibitor, and 3 of whom received a PD-L1 inhibitor.

They found that pneumonitis in patients with lung cancer tended to resemble chronic obstructive pneumonia, whereas patients with melanoma were more likely to have ground-glass opacifications on radiography. There was a trend, falling just short of significance, toward association of COP-like pneumonitis with development of grade 3 or greater, and with a requirement for more than one type of immunosuppression, compared to other subtypes.

Algorithms for management

Dr. Gettinger briefly outlined an algorithm offered by Bristol-Myers Squibb for management of suspected pulmonary toxicity with nivolumab. For management of patients with grade 1 toxicities (asymptomatic, with radiographic changes only), it recommends that clinicians consider delay of immuno-oncologic (I-O) therapy, monitor for symptoms every 2-3 days, and consider consultations with pulmonary and infectious disease specialists.

For grade 2 pneumonitis, marked by mild to moderate new symptoms, the algorithm calls for clinicians to delay I-O therapy per protocol, consult with pulmonary and ID specialists, monitor symptoms daily and consider hospitalization, start the patient on steroids with 1.0 mg/kg per day methylprednisolone IV or the oral equivalent, and consider bronchoscopy and lung biopsy.

For patients with grade 3 or 4 toxicities, marked by severe new symptoms, new or worsening hypoxia, or other life-threatening symptoms, the algorithm states that clinicians should discontinue I-O therapy, hospitalize the patient, consult with pulmonary and ID, give 2-4 mg/kg per day methylprednisolone IV or the oral equivalent, add prophylactic antibiotics for opportunistic infections, and consider bronchoscopy and lung biopsy.

At Yale, Dr. Gettinger and colleagues, when presented with a symptomatic patient on a PD-axis inhibitor, will first rule out other etiologies such as infection, chronic obstructive pulmonary disease exacerbation, or cancer progression), typically with bronchoscopy.

For patients with moderate pneumonitis, they may treat with prednisone for 1 or 2 weeks, with a 4-6 week taper begun as symptoms start to resolve.

“In a patient who has profound hypoxia and shortness of breath, we may want to go higher: We might give them 2 mg/kg twice a day of [methylprednisolone] in the hospital, wait until they get better, and then slowly taper them, whether it be over 4 or 6 weeks or longer. Occasionally our patients need to get even higher doses of steroids and there’s really nothing to guide us. Who knows if 1 gram of [methylprednisolone] may be better than 60 g of prednisone? But we do it, and patients do get better with the higher doses,” he said.

 

 

In rare instances, patients may required other immunosuppressive agents, such as infliximab (Remicade), cyclophosphamide, or mycophenolate mofetil.

Patients who require additional immunosuppressive agents to resolve severe pneumonitis tend to have poor outcomes, Dr. Gettinger said.

Re-challenge of patients with a PD-1 or PD-L1 inhibitor following resolution of pneumonitis appears to be inadvisable for all patients except possibly those with grade 1 (asymptomatic) toxicity, due to the high risk of recurrence, he said.

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Hold the checkpoint inhibitors when pneumonitis symptoms occur
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Key clinical point: Pneumonitis is an uncommon but potentially serious adverse event associated with PD-1/PD-L1 checkpoint inhibitor therapy.

Major finding: Pneumonitis occurs in about 4%-6% of patients with non–small-cell lung cancer treated with a PD-1 axis inhibitor.

Data source: Review of current understanding of pneumonitis associated with anti-PD-1/PD-L1 therapeutic agents.

Disclosures: Dr. Gettinger disclosed serving as a consultant for BMS.

Antibody drug conjugate induces responses in heavily pretreated TNBC

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Antibody drug conjugate induces responses in heavily pretreated TNBC

BOSTON An antibody conjugated to the active metabolite of irinotecan was associated with a good overall response rate in patients with heavily pretreated triple-negative breast cancer, with lower toxicities than seen with systemic irinotecan therapy, investigators reported.

Among 54 patients with triple-negative breast cancer (TNBC) in a phase II trial who had undergone a median of six prior lines of therapy, treatment with the conjugate, labeled IMMU-132 (sacituzumab govitecan) was associated with a 31.5% overall response rate, including two complete responses, reported Dr. Aditya Bardia of Massachusetts General Hospital, Boston, and his colleagues, at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Dr. David M. Goldenberg

The compound consists of a monoclonal antibody (RS7-3G11) targeted to the Trop-2/EGP-1 panepithelial cancer antigen that is conjugated with the active metabolite of irinotecan (SN-38). The antibody has been shown in preclinical studies to bind to human breast, lung, colon, renal, prostate, and urothelial cancer and other solid malignancies. Trop-2 is expressed in more than 80% of triple-negative breast cancers, said coauthor Dr. David M. Goldenberg, chairman of Immunomedics, the maker of the compound.

“What distinguishes this antibody-drug conjugate, or ADC, is that we have used the active metabolite of irinotecan, which is 100 to 1,000 times more toxic than its parent drug, and the reason it’s tolerated is that it’s conjugated to the antibody, and we have shown preclinically that we can deliver approximately 136 times more SN-38 to the cancer cell than if you give irinotecan and measure how much SN-38 gets to the tumor,” he said at a briefing.

The conjugate has good activity in patients who have experienced relapses after multiple prior lines of therapy, and it can be delivered repeatedly over a long course of therapy with toxicities that are manageable, he noted.

The compound was found to have good activity in several solid tumors in a phase I trial, which led to an expanded phase II trial including, as of May 10, 2015, a total of 56 patients with TNBC, 2 of whom had received fewer than three doses of the study drug by the data cutoff, and therefore were not included in the efficacy analysis.

Patients received IMMU-132 intravenously in doses of 8 or 10 mg/kg on days 1 and 8 of each 21-day cycle, which could be repeated until progression or unacceptable toxicity.

Among 54 assessable patients, the overall response rate (percentage change from baseline according to RECIST [Response Evaluation Criteria in Solid Tumors] 1.1 guidelines) was 31.5%, (17 of 54) consisting of 2 confirmed complete responses and 15 partial responses. Additionally, there were 24 cases of stable disease (4 confirmed), 9 of which had a greater than 20% regression of tumor, but had not met the definition of a partial response by the time of the analysis.

The combined clinical benefit rate, a composite of complete and partial responses and stable disease for 6 months or more, was 44%.

Median progression-free survival in an intent to treat analysis was 7 months. Median overall survival had not been reached, with 87% of patients alive at the data cutoff.

Among all patients in the study, including those with TNBC and other tumors, adverse events at the 10 mg/kg dose included diarrhea in 37% (grade 3 or 4 in 6%); Dr. Goldenberg noted that severe diarrhea is one of the common adverse effects of the parent compound irinotecan, earning it a black-box warning. Other common adverse events associated with irinotecan were neutropenia in 26% (grade 3 or 4 in 15%), febrile neutropenia, all grade 3 or 4, in 4%, and anemia in 20% (grade 3/4 in 6%).

“I have to say that for me, SN-38 was a brilliant idea,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md.

He said that the data showing less severe diarrhea with IMMU-132 than with the parent irinotecan are encouraging, because it may allow more patients to benefit from the therapy.

“This is a very active drug, irinotecan. It gets activated to SN-38 through enterohepatic metabolism, and therefore, it has a very difficult toxicity, which is diarrhea. In fact, I’ve had patients who are responding, who have come off the drug because they can’t stand the diarrhea,” he said.

Dr. Helman moderated a briefing in which Dr. Goldenberg presented the data but was not involved in the study.

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BOSTON An antibody conjugated to the active metabolite of irinotecan was associated with a good overall response rate in patients with heavily pretreated triple-negative breast cancer, with lower toxicities than seen with systemic irinotecan therapy, investigators reported.

Among 54 patients with triple-negative breast cancer (TNBC) in a phase II trial who had undergone a median of six prior lines of therapy, treatment with the conjugate, labeled IMMU-132 (sacituzumab govitecan) was associated with a 31.5% overall response rate, including two complete responses, reported Dr. Aditya Bardia of Massachusetts General Hospital, Boston, and his colleagues, at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Dr. David M. Goldenberg

The compound consists of a monoclonal antibody (RS7-3G11) targeted to the Trop-2/EGP-1 panepithelial cancer antigen that is conjugated with the active metabolite of irinotecan (SN-38). The antibody has been shown in preclinical studies to bind to human breast, lung, colon, renal, prostate, and urothelial cancer and other solid malignancies. Trop-2 is expressed in more than 80% of triple-negative breast cancers, said coauthor Dr. David M. Goldenberg, chairman of Immunomedics, the maker of the compound.

“What distinguishes this antibody-drug conjugate, or ADC, is that we have used the active metabolite of irinotecan, which is 100 to 1,000 times more toxic than its parent drug, and the reason it’s tolerated is that it’s conjugated to the antibody, and we have shown preclinically that we can deliver approximately 136 times more SN-38 to the cancer cell than if you give irinotecan and measure how much SN-38 gets to the tumor,” he said at a briefing.

The conjugate has good activity in patients who have experienced relapses after multiple prior lines of therapy, and it can be delivered repeatedly over a long course of therapy with toxicities that are manageable, he noted.

The compound was found to have good activity in several solid tumors in a phase I trial, which led to an expanded phase II trial including, as of May 10, 2015, a total of 56 patients with TNBC, 2 of whom had received fewer than three doses of the study drug by the data cutoff, and therefore were not included in the efficacy analysis.

Patients received IMMU-132 intravenously in doses of 8 or 10 mg/kg on days 1 and 8 of each 21-day cycle, which could be repeated until progression or unacceptable toxicity.

Among 54 assessable patients, the overall response rate (percentage change from baseline according to RECIST [Response Evaluation Criteria in Solid Tumors] 1.1 guidelines) was 31.5%, (17 of 54) consisting of 2 confirmed complete responses and 15 partial responses. Additionally, there were 24 cases of stable disease (4 confirmed), 9 of which had a greater than 20% regression of tumor, but had not met the definition of a partial response by the time of the analysis.

The combined clinical benefit rate, a composite of complete and partial responses and stable disease for 6 months or more, was 44%.

Median progression-free survival in an intent to treat analysis was 7 months. Median overall survival had not been reached, with 87% of patients alive at the data cutoff.

Among all patients in the study, including those with TNBC and other tumors, adverse events at the 10 mg/kg dose included diarrhea in 37% (grade 3 or 4 in 6%); Dr. Goldenberg noted that severe diarrhea is one of the common adverse effects of the parent compound irinotecan, earning it a black-box warning. Other common adverse events associated with irinotecan were neutropenia in 26% (grade 3 or 4 in 15%), febrile neutropenia, all grade 3 or 4, in 4%, and anemia in 20% (grade 3/4 in 6%).

“I have to say that for me, SN-38 was a brilliant idea,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md.

He said that the data showing less severe diarrhea with IMMU-132 than with the parent irinotecan are encouraging, because it may allow more patients to benefit from the therapy.

“This is a very active drug, irinotecan. It gets activated to SN-38 through enterohepatic metabolism, and therefore, it has a very difficult toxicity, which is diarrhea. In fact, I’ve had patients who are responding, who have come off the drug because they can’t stand the diarrhea,” he said.

Dr. Helman moderated a briefing in which Dr. Goldenberg presented the data but was not involved in the study.

BOSTON An antibody conjugated to the active metabolite of irinotecan was associated with a good overall response rate in patients with heavily pretreated triple-negative breast cancer, with lower toxicities than seen with systemic irinotecan therapy, investigators reported.

Among 54 patients with triple-negative breast cancer (TNBC) in a phase II trial who had undergone a median of six prior lines of therapy, treatment with the conjugate, labeled IMMU-132 (sacituzumab govitecan) was associated with a 31.5% overall response rate, including two complete responses, reported Dr. Aditya Bardia of Massachusetts General Hospital, Boston, and his colleagues, at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Dr. David M. Goldenberg

The compound consists of a monoclonal antibody (RS7-3G11) targeted to the Trop-2/EGP-1 panepithelial cancer antigen that is conjugated with the active metabolite of irinotecan (SN-38). The antibody has been shown in preclinical studies to bind to human breast, lung, colon, renal, prostate, and urothelial cancer and other solid malignancies. Trop-2 is expressed in more than 80% of triple-negative breast cancers, said coauthor Dr. David M. Goldenberg, chairman of Immunomedics, the maker of the compound.

“What distinguishes this antibody-drug conjugate, or ADC, is that we have used the active metabolite of irinotecan, which is 100 to 1,000 times more toxic than its parent drug, and the reason it’s tolerated is that it’s conjugated to the antibody, and we have shown preclinically that we can deliver approximately 136 times more SN-38 to the cancer cell than if you give irinotecan and measure how much SN-38 gets to the tumor,” he said at a briefing.

The conjugate has good activity in patients who have experienced relapses after multiple prior lines of therapy, and it can be delivered repeatedly over a long course of therapy with toxicities that are manageable, he noted.

The compound was found to have good activity in several solid tumors in a phase I trial, which led to an expanded phase II trial including, as of May 10, 2015, a total of 56 patients with TNBC, 2 of whom had received fewer than three doses of the study drug by the data cutoff, and therefore were not included in the efficacy analysis.

Patients received IMMU-132 intravenously in doses of 8 or 10 mg/kg on days 1 and 8 of each 21-day cycle, which could be repeated until progression or unacceptable toxicity.

Among 54 assessable patients, the overall response rate (percentage change from baseline according to RECIST [Response Evaluation Criteria in Solid Tumors] 1.1 guidelines) was 31.5%, (17 of 54) consisting of 2 confirmed complete responses and 15 partial responses. Additionally, there were 24 cases of stable disease (4 confirmed), 9 of which had a greater than 20% regression of tumor, but had not met the definition of a partial response by the time of the analysis.

The combined clinical benefit rate, a composite of complete and partial responses and stable disease for 6 months or more, was 44%.

Median progression-free survival in an intent to treat analysis was 7 months. Median overall survival had not been reached, with 87% of patients alive at the data cutoff.

Among all patients in the study, including those with TNBC and other tumors, adverse events at the 10 mg/kg dose included diarrhea in 37% (grade 3 or 4 in 6%); Dr. Goldenberg noted that severe diarrhea is one of the common adverse effects of the parent compound irinotecan, earning it a black-box warning. Other common adverse events associated with irinotecan were neutropenia in 26% (grade 3 or 4 in 15%), febrile neutropenia, all grade 3 or 4, in 4%, and anemia in 20% (grade 3/4 in 6%).

“I have to say that for me, SN-38 was a brilliant idea,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md.

He said that the data showing less severe diarrhea with IMMU-132 than with the parent irinotecan are encouraging, because it may allow more patients to benefit from the therapy.

“This is a very active drug, irinotecan. It gets activated to SN-38 through enterohepatic metabolism, and therefore, it has a very difficult toxicity, which is diarrhea. In fact, I’ve had patients who are responding, who have come off the drug because they can’t stand the diarrhea,” he said.

Dr. Helman moderated a briefing in which Dr. Goldenberg presented the data but was not involved in the study.

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Antibody drug conjugate induces responses in heavily pretreated TNBC
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Inside the Article

Vitals

Key clinical point: Conjugating a metabolite of irinotecan to an antibody allows targeted delivery of the otherwise highly toxic drug.

Major finding: The overall response rate in patients with heavily pretreated triple-negative breast cancer was 31%, including two complete responses.

Data source: Phase II open label trial, including a cohort of 56 patients with triple-negative breast cancer.

Disclosures: The study was funded by Immunomedics. Dr. Goldenberg is an officer and chairman of the company. Dr. Bardia and Dr. Helman reported no conflicts of interest.

Immune-related events with checkpoint inhibitors are manageable

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Immune-related events with checkpoint inhibitors are manageable

BOSTON Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.

“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.

There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”

Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.

The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.

Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.

He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.

Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.

Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.

As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.

“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.

PD-1 inhibitors

Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.

In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.

The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.

Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.

Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.

In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.

For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.

 

 

In a second, retrospective study of 83 patients enrolled in clinical trials of pembrolizumab for melanoma, non–small cell lung cancer, prostate cancer, and Merkel cell carcinoma, patients in each of three pembrolizumab dosing groups who developed cutaneous AEs had significantly longer progression-free intervals than patients who did not develop cutaneous AEs.

A similar correlation between cutaneous events with nivolumab and favorable outcomes was seen in a study of pooled data on 148 patients with resected or unresectable metastatic melanoma. The investigators found that both rash and vitiligo correlated significantly with better overall survival.

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BOSTON Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.

“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.

There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”

Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.

The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.

Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.

He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.

Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.

Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.

As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.

“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.

PD-1 inhibitors

Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.

In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.

The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.

Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.

Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.

In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.

For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.

 

 

In a second, retrospective study of 83 patients enrolled in clinical trials of pembrolizumab for melanoma, non–small cell lung cancer, prostate cancer, and Merkel cell carcinoma, patients in each of three pembrolizumab dosing groups who developed cutaneous AEs had significantly longer progression-free intervals than patients who did not develop cutaneous AEs.

A similar correlation between cutaneous events with nivolumab and favorable outcomes was seen in a study of pooled data on 148 patients with resected or unresectable metastatic melanoma. The investigators found that both rash and vitiligo correlated significantly with better overall survival.

BOSTON Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.

“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.

There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”

Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.

The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.

Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.

He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.

Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.

Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.

As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.

“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.

PD-1 inhibitors

Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.

In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.

The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.

Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.

Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.

In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.

For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.

 

 

In a second, retrospective study of 83 patients enrolled in clinical trials of pembrolizumab for melanoma, non–small cell lung cancer, prostate cancer, and Merkel cell carcinoma, patients in each of three pembrolizumab dosing groups who developed cutaneous AEs had significantly longer progression-free intervals than patients who did not develop cutaneous AEs.

A similar correlation between cutaneous events with nivolumab and favorable outcomes was seen in a study of pooled data on 148 patients with resected or unresectable metastatic melanoma. The investigators found that both rash and vitiligo correlated significantly with better overall survival.

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Key clinical point: Inhibitors of CTLA-4 and PD-1/PD-L1 are associated with manageable immune-related adverse events.

Major finding: Cutaneous adverse events with PD-1 inhibitor therapy appear to be predictive of favorable outcomes.

Data source: Review of current knowledge of the immune-related adverse events associated with checkpoint inhibitors.

Disclosures: Dr. Italiano reported no conflicts of interest.

IDH1 mutant inhibitor targets gliomas, chondrosarcomas

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IDH1 mutant inhibitor targets gliomas, chondrosarcomas

BOSTON – An investigational agent targeted against tumors carrying mutant forms of the metabolic protein IDH1 has shown clinical activity against advanced solid tumors, including gliomas and chondrosarcomas, investigators reported.

In a phase I trial in 62 patients with advanced IDH1 mutation-positive solid tumors that had recurred or progressed on a median three prior lines of therapy, 7 of 11 patients with chondrosarcomas treated with AG-120 had stable disease, with five of the responses maintained beyond 6 months, and 10 of 20 patients with glioma had stable disease, with 4 having responses longer than 6 months, reported Dr. Howard A. Burris III, chief medical officer and executive director, drug development program, at the Sarah Cannon Research Institute, Nashville, Tenn.

Dr. Howard A. Burris III

“These tumors don’t respond to any of our systemic therapies, so it’s pretty remarkable that you get patients who don’t have treatment options that do so well for so long. We’ve just not seen that in the past,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who was not involved in the study.

A related compound, AG-221, which inhibits IDH2, has previously been shown to produce durable objective responses in 30%-50% of patients with acute myeloid leukemia. Here at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics, Dr. Burris presented the first clinical results with the IHD1-inhibiting compound in solid tumors.

IDH1 is normally involved in regulation of the Krebs cycle, the central metabolic pathway. IDH1 mutations produce the metabolite 2-hydroxyglutarate (2-HG), which causes genetic and epigenetic dysregulation, leading to oncogenesis via unchecked cell proliferation. AG-120 blocks the accumulation of 2-HG, thereby allowing cells to differentiate and undergo apoptosis as normal, thereby restoring homeostasis.

Dr. Lee J. Helman

IDH1 mutations are found in an estimated 68%-74% of gliomas, 11%-24% of intrahepatic cholangiocarcinomas (IHCC), and in 40%-52% of chondrosarcomas, Dr. Burris said.

Early efficacy promising

He reported early safety and clinical data from a single-arm, dose escalation study of single-agent AG-210 dosed orally once or twice daily in 28-day cycles in one of eight dose levels. The dose escalation phase has been completed and a 500-mg q.i.d. dose has been selected.

There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Serious adverse events, occurring in one patient each (18 of 62 patients) were acute kidney injury, acute respiratory failure, anemia, ataxia, brain herniation, confusional state, cystitis, urinary tract infection, headache, hyponatremia, joint effusion, esophageal varices hemorrhage, partial seizures, seizure, bacteremia, superior vena cava syndrome, vertebral fracture, and urosepsis. There were no deaths judged to be treatment related.

Data on 55 patients were available for the efficacy analysis. Among 11 patients with chondrosarcoma, 7 had stable disease, 2 had progressive disease, and 2 had unknown status. Among 20 patients with IHCC, there was 1 partial response, 11 cases of stable disease, 6 of progressive disease, and 2 unknown. Among patients with glioma, 10 had stable disease, and 10 had progressive disease.

Of four remaining patients (with adenocarcinoma and colitis-associated neuroendocrine, small intestine, and ovarian cancers), one had stable disease, and three had progression.

The patient with IHCC who had a partial response was a 65-year-old woman who had previously been treated with multiple lines of chemotherapy, including combinations of cisplatin and gemcitabine, gemcitabine and oxaliplatin, and cisplatin and docetaxel. Following treatment with AG-120, she had a 98.7% reduction in 2-HG level, and an 81% reduction in Ki-67 staining, indicating marked tumor reduction.

“This patient in fact was on the trial for more than 9 months. By protocol criteria, she had to come off study for development of a solitary new, small lesion that was felt to be a new metastatic spot, but had no change – no further regrowth of the tumor that had shrunk,” Dr. Burris said in a briefing following his presentation of the data in a plenary session.

In a 38-year-old man with grade II glioma, investigators saw volumetric changes consistent with 2-HG reduction on magnetic resonance spectroscopy, he added.

For the expansion phase, investigators are currently enrolling four cohorts each of 25 patients with low-grade glioma (with at least 6 months of prior scans), IHCC following progression on first-line therapy, high-grade metastatic chondrosarcoma, and patients with other solid tumors with IDH1 mutations. They are also planning a randomized phase II study in patients with IHCC beginning in 2016.

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BOSTON – An investigational agent targeted against tumors carrying mutant forms of the metabolic protein IDH1 has shown clinical activity against advanced solid tumors, including gliomas and chondrosarcomas, investigators reported.

In a phase I trial in 62 patients with advanced IDH1 mutation-positive solid tumors that had recurred or progressed on a median three prior lines of therapy, 7 of 11 patients with chondrosarcomas treated with AG-120 had stable disease, with five of the responses maintained beyond 6 months, and 10 of 20 patients with glioma had stable disease, with 4 having responses longer than 6 months, reported Dr. Howard A. Burris III, chief medical officer and executive director, drug development program, at the Sarah Cannon Research Institute, Nashville, Tenn.

Dr. Howard A. Burris III

“These tumors don’t respond to any of our systemic therapies, so it’s pretty remarkable that you get patients who don’t have treatment options that do so well for so long. We’ve just not seen that in the past,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who was not involved in the study.

A related compound, AG-221, which inhibits IDH2, has previously been shown to produce durable objective responses in 30%-50% of patients with acute myeloid leukemia. Here at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics, Dr. Burris presented the first clinical results with the IHD1-inhibiting compound in solid tumors.

IDH1 is normally involved in regulation of the Krebs cycle, the central metabolic pathway. IDH1 mutations produce the metabolite 2-hydroxyglutarate (2-HG), which causes genetic and epigenetic dysregulation, leading to oncogenesis via unchecked cell proliferation. AG-120 blocks the accumulation of 2-HG, thereby allowing cells to differentiate and undergo apoptosis as normal, thereby restoring homeostasis.

Dr. Lee J. Helman

IDH1 mutations are found in an estimated 68%-74% of gliomas, 11%-24% of intrahepatic cholangiocarcinomas (IHCC), and in 40%-52% of chondrosarcomas, Dr. Burris said.

Early efficacy promising

He reported early safety and clinical data from a single-arm, dose escalation study of single-agent AG-210 dosed orally once or twice daily in 28-day cycles in one of eight dose levels. The dose escalation phase has been completed and a 500-mg q.i.d. dose has been selected.

There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Serious adverse events, occurring in one patient each (18 of 62 patients) were acute kidney injury, acute respiratory failure, anemia, ataxia, brain herniation, confusional state, cystitis, urinary tract infection, headache, hyponatremia, joint effusion, esophageal varices hemorrhage, partial seizures, seizure, bacteremia, superior vena cava syndrome, vertebral fracture, and urosepsis. There were no deaths judged to be treatment related.

Data on 55 patients were available for the efficacy analysis. Among 11 patients with chondrosarcoma, 7 had stable disease, 2 had progressive disease, and 2 had unknown status. Among 20 patients with IHCC, there was 1 partial response, 11 cases of stable disease, 6 of progressive disease, and 2 unknown. Among patients with glioma, 10 had stable disease, and 10 had progressive disease.

Of four remaining patients (with adenocarcinoma and colitis-associated neuroendocrine, small intestine, and ovarian cancers), one had stable disease, and three had progression.

The patient with IHCC who had a partial response was a 65-year-old woman who had previously been treated with multiple lines of chemotherapy, including combinations of cisplatin and gemcitabine, gemcitabine and oxaliplatin, and cisplatin and docetaxel. Following treatment with AG-120, she had a 98.7% reduction in 2-HG level, and an 81% reduction in Ki-67 staining, indicating marked tumor reduction.

“This patient in fact was on the trial for more than 9 months. By protocol criteria, she had to come off study for development of a solitary new, small lesion that was felt to be a new metastatic spot, but had no change – no further regrowth of the tumor that had shrunk,” Dr. Burris said in a briefing following his presentation of the data in a plenary session.

In a 38-year-old man with grade II glioma, investigators saw volumetric changes consistent with 2-HG reduction on magnetic resonance spectroscopy, he added.

For the expansion phase, investigators are currently enrolling four cohorts each of 25 patients with low-grade glioma (with at least 6 months of prior scans), IHCC following progression on first-line therapy, high-grade metastatic chondrosarcoma, and patients with other solid tumors with IDH1 mutations. They are also planning a randomized phase II study in patients with IHCC beginning in 2016.

BOSTON – An investigational agent targeted against tumors carrying mutant forms of the metabolic protein IDH1 has shown clinical activity against advanced solid tumors, including gliomas and chondrosarcomas, investigators reported.

In a phase I trial in 62 patients with advanced IDH1 mutation-positive solid tumors that had recurred or progressed on a median three prior lines of therapy, 7 of 11 patients with chondrosarcomas treated with AG-120 had stable disease, with five of the responses maintained beyond 6 months, and 10 of 20 patients with glioma had stable disease, with 4 having responses longer than 6 months, reported Dr. Howard A. Burris III, chief medical officer and executive director, drug development program, at the Sarah Cannon Research Institute, Nashville, Tenn.

Dr. Howard A. Burris III

“These tumors don’t respond to any of our systemic therapies, so it’s pretty remarkable that you get patients who don’t have treatment options that do so well for so long. We’ve just not seen that in the past,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who was not involved in the study.

A related compound, AG-221, which inhibits IDH2, has previously been shown to produce durable objective responses in 30%-50% of patients with acute myeloid leukemia. Here at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics, Dr. Burris presented the first clinical results with the IHD1-inhibiting compound in solid tumors.

IDH1 is normally involved in regulation of the Krebs cycle, the central metabolic pathway. IDH1 mutations produce the metabolite 2-hydroxyglutarate (2-HG), which causes genetic and epigenetic dysregulation, leading to oncogenesis via unchecked cell proliferation. AG-120 blocks the accumulation of 2-HG, thereby allowing cells to differentiate and undergo apoptosis as normal, thereby restoring homeostasis.

Dr. Lee J. Helman

IDH1 mutations are found in an estimated 68%-74% of gliomas, 11%-24% of intrahepatic cholangiocarcinomas (IHCC), and in 40%-52% of chondrosarcomas, Dr. Burris said.

Early efficacy promising

He reported early safety and clinical data from a single-arm, dose escalation study of single-agent AG-210 dosed orally once or twice daily in 28-day cycles in one of eight dose levels. The dose escalation phase has been completed and a 500-mg q.i.d. dose has been selected.

There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Serious adverse events, occurring in one patient each (18 of 62 patients) were acute kidney injury, acute respiratory failure, anemia, ataxia, brain herniation, confusional state, cystitis, urinary tract infection, headache, hyponatremia, joint effusion, esophageal varices hemorrhage, partial seizures, seizure, bacteremia, superior vena cava syndrome, vertebral fracture, and urosepsis. There were no deaths judged to be treatment related.

Data on 55 patients were available for the efficacy analysis. Among 11 patients with chondrosarcoma, 7 had stable disease, 2 had progressive disease, and 2 had unknown status. Among 20 patients with IHCC, there was 1 partial response, 11 cases of stable disease, 6 of progressive disease, and 2 unknown. Among patients with glioma, 10 had stable disease, and 10 had progressive disease.

Of four remaining patients (with adenocarcinoma and colitis-associated neuroendocrine, small intestine, and ovarian cancers), one had stable disease, and three had progression.

The patient with IHCC who had a partial response was a 65-year-old woman who had previously been treated with multiple lines of chemotherapy, including combinations of cisplatin and gemcitabine, gemcitabine and oxaliplatin, and cisplatin and docetaxel. Following treatment with AG-120, she had a 98.7% reduction in 2-HG level, and an 81% reduction in Ki-67 staining, indicating marked tumor reduction.

“This patient in fact was on the trial for more than 9 months. By protocol criteria, she had to come off study for development of a solitary new, small lesion that was felt to be a new metastatic spot, but had no change – no further regrowth of the tumor that had shrunk,” Dr. Burris said in a briefing following his presentation of the data in a plenary session.

In a 38-year-old man with grade II glioma, investigators saw volumetric changes consistent with 2-HG reduction on magnetic resonance spectroscopy, he added.

For the expansion phase, investigators are currently enrolling four cohorts each of 25 patients with low-grade glioma (with at least 6 months of prior scans), IHCC following progression on first-line therapy, high-grade metastatic chondrosarcoma, and patients with other solid tumors with IDH1 mutations. They are also planning a randomized phase II study in patients with IHCC beginning in 2016.

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Key clinical point: AG-120 is a first-in-class inhibitor of IDH1 mutations that may drive oncogenesis.

Major finding: 10 of 20 patients with gliomas and 7 of 11 with chondrosarcomas had stable disease on AG-120.

Data source: Phase I dose-escalation trial in 62 patients (55 available for efficacy analysis).

Disclosures: The trial is supported by Agios Pharmaceuticals. Dr. Burris and Dr. Helman reported no conflicts of interest.

Pan-AKT inhibitor shrinks tumors in patients with AKT1 mutation

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Pan-AKT inhibitor shrinks tumors in patients with AKT1 mutation

BOSTON – A novel pan-AKT inhibitor was associated in a phase 1 trial with tumor shrinkage in a large proportion of patients with solid tumors bearing a mutation in AKT1.

The investigational compound, labeled AZD5363, targets the AKT1 E17K mutation, which occurs in approximately 0.5% to 4% of many different types of solid tumors. In a phase I trial, 33 of 41 assessable patients with tumors bearing the mutation had regression of tumors, reported Dr. David M. Hyman, acting director of experimental therapeutics at Memorial Sloan Kettering Cancer Center in New York.

Dr. David M. Hyman

“We believe this is the first clinical data suggesting that the AKT1 E17K mutations are targetable driver mutations in solid tumors,” he said at a briefing at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Mutations in the PI3K/AKT/mTOR pathway are frequently found in human cancers, and dysregulation of the pathway has been shown to drive tumor growth and survival of malignant cells.

“Although this pathway is among the most commonly activated in all human cancer, it is rarely activated by somatic mutation of AKT itself,” Dr. Hyman said. “When you see AKT mutations, they are almost always of a single allele at the 17 amino acid position, which is the E17K mutation. This is a mutation that has been extensively functionally classified, and behaves as a classic driver oncogene.”

The E17K mutation occurs in approximately 4% of breast cancers, 2% of bladder cancers, 1.5% of colorectal tumors, 1% each of cervical, ovarian, and prostate cancers, and 0.5% of lung adenocarcinomas.

AZD5363 is a catalytic inhibitor of all AKT isoforms 1, 2, and 3. In preclinical studies, it has been shown to inhibit tumor cell proliferation in vitro, and tumor growth in vivo in tumor xenograft models.

Dr. Hyman and colleagues reported on early results from one part of a four-part, phase I study of AZD5363 in adults with advanced solid tumors. Part D of the ongoing study focuses on patients with tumors bearing AKT1 mutations.

At present, 45 patients with E17K mutations have been treated with the agent, including 21 with estrogen receptor (ER)-positive breast cancer, four with triple-negative breast cancer, 14 with gynecological cancers, and eight with other tumor types.

As noted, of 41 patients with sufficient data for assessment, 33 had some degree of tumor regression, and of this group 12 met RECIST (Response Evaluation Criteria in Solid Tumors) parameters for partial responses. Among patients assessable for response, 14 of 18 with ER-positive breast cancer had lesion shrinkage, and five of these patients had partial responses (3 confirmed and 2 unconfirmed).

Among patients with gynecological tumors, 9 of 11 had shrinkage of their target lesion, including 3 with confirmed partial responses. Two of these patients are still on study, with the longest follow-up at the time of data cutoff of 39.2 months

Among patients with 12 other tumor types (apocrine anal, triple-negative breast cancer, colon, lung, prostate, squamous anal, thyroid) 10 patients had demonstrated target lesion shrinkage, one had a confirmed partial response that is ongoing, and two had unconfirmed partial response, one of which is ongoing.

The investigators also used cell-free DNA (cfDNA) analysis to evaluate efficacy of AZD5363 during treatment, and found that declines in AKT1 cfDNA allele fractions were transient among non-responders, whereas declines persisting for 21 days or more correlated with both durable tumor regression and RECIST response (P = .0049).

Dr. Hyman noted that there were also preclinical signs that AZD5363 could lead to reactivation of ER signaling.

“It became a natural question to ask whether patients did better with a combination of ER-directed therapy and AKT-directed therapy,” he said.

To answer this question, the investigators offered sequential therapy to patients with ER-positive breast cancer who had previously had resistance to the ER degrader fulvestrant and who had progressed on AZD5363 monotherapy. Two patients were offered crossover to AZD5363 with fulvestrant, regardless of prior hormonal therapy.

One of the patients had disease progression while on the combination. The second patient, who had received 10 prior lines of therapy and had disease progression before starting on the combination at 120 days on treatment, had significant shrinkage of her breast lesion 6 weeks after starting on the combination, and liver lesions that had previously enhanced on imaging are no longer enhancing, and her cfDNA allele fractions have declined. She remains on the combination after more than 160 days.

“This was very convincing evidence to us of synergy between these two compounds,” he said.

Dr. Jean-Charles Soria, from the Institut Gustave Roussy, Villejuif, France, who moderated the briefing, commented that “although this [mutation] is a rare situation, in the range of 2% to 3%, it’s certainly important, because 2% to 3% of breast cancer patients is a significant number, so this drug has legs,” he said.

 

 

The question yet to be settled, however, is the true duration of response, he added.

The study is sponsored by AstraZeneca. Dr. Hyman disclosed consulting for Atara Biotherapeutics. Dr. Soria reported having no disclosures.

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BOSTON – A novel pan-AKT inhibitor was associated in a phase 1 trial with tumor shrinkage in a large proportion of patients with solid tumors bearing a mutation in AKT1.

The investigational compound, labeled AZD5363, targets the AKT1 E17K mutation, which occurs in approximately 0.5% to 4% of many different types of solid tumors. In a phase I trial, 33 of 41 assessable patients with tumors bearing the mutation had regression of tumors, reported Dr. David M. Hyman, acting director of experimental therapeutics at Memorial Sloan Kettering Cancer Center in New York.

Dr. David M. Hyman

“We believe this is the first clinical data suggesting that the AKT1 E17K mutations are targetable driver mutations in solid tumors,” he said at a briefing at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Mutations in the PI3K/AKT/mTOR pathway are frequently found in human cancers, and dysregulation of the pathway has been shown to drive tumor growth and survival of malignant cells.

“Although this pathway is among the most commonly activated in all human cancer, it is rarely activated by somatic mutation of AKT itself,” Dr. Hyman said. “When you see AKT mutations, they are almost always of a single allele at the 17 amino acid position, which is the E17K mutation. This is a mutation that has been extensively functionally classified, and behaves as a classic driver oncogene.”

The E17K mutation occurs in approximately 4% of breast cancers, 2% of bladder cancers, 1.5% of colorectal tumors, 1% each of cervical, ovarian, and prostate cancers, and 0.5% of lung adenocarcinomas.

AZD5363 is a catalytic inhibitor of all AKT isoforms 1, 2, and 3. In preclinical studies, it has been shown to inhibit tumor cell proliferation in vitro, and tumor growth in vivo in tumor xenograft models.

Dr. Hyman and colleagues reported on early results from one part of a four-part, phase I study of AZD5363 in adults with advanced solid tumors. Part D of the ongoing study focuses on patients with tumors bearing AKT1 mutations.

At present, 45 patients with E17K mutations have been treated with the agent, including 21 with estrogen receptor (ER)-positive breast cancer, four with triple-negative breast cancer, 14 with gynecological cancers, and eight with other tumor types.

As noted, of 41 patients with sufficient data for assessment, 33 had some degree of tumor regression, and of this group 12 met RECIST (Response Evaluation Criteria in Solid Tumors) parameters for partial responses. Among patients assessable for response, 14 of 18 with ER-positive breast cancer had lesion shrinkage, and five of these patients had partial responses (3 confirmed and 2 unconfirmed).

Among patients with gynecological tumors, 9 of 11 had shrinkage of their target lesion, including 3 with confirmed partial responses. Two of these patients are still on study, with the longest follow-up at the time of data cutoff of 39.2 months

Among patients with 12 other tumor types (apocrine anal, triple-negative breast cancer, colon, lung, prostate, squamous anal, thyroid) 10 patients had demonstrated target lesion shrinkage, one had a confirmed partial response that is ongoing, and two had unconfirmed partial response, one of which is ongoing.

The investigators also used cell-free DNA (cfDNA) analysis to evaluate efficacy of AZD5363 during treatment, and found that declines in AKT1 cfDNA allele fractions were transient among non-responders, whereas declines persisting for 21 days or more correlated with both durable tumor regression and RECIST response (P = .0049).

Dr. Hyman noted that there were also preclinical signs that AZD5363 could lead to reactivation of ER signaling.

“It became a natural question to ask whether patients did better with a combination of ER-directed therapy and AKT-directed therapy,” he said.

To answer this question, the investigators offered sequential therapy to patients with ER-positive breast cancer who had previously had resistance to the ER degrader fulvestrant and who had progressed on AZD5363 monotherapy. Two patients were offered crossover to AZD5363 with fulvestrant, regardless of prior hormonal therapy.

One of the patients had disease progression while on the combination. The second patient, who had received 10 prior lines of therapy and had disease progression before starting on the combination at 120 days on treatment, had significant shrinkage of her breast lesion 6 weeks after starting on the combination, and liver lesions that had previously enhanced on imaging are no longer enhancing, and her cfDNA allele fractions have declined. She remains on the combination after more than 160 days.

“This was very convincing evidence to us of synergy between these two compounds,” he said.

Dr. Jean-Charles Soria, from the Institut Gustave Roussy, Villejuif, France, who moderated the briefing, commented that “although this [mutation] is a rare situation, in the range of 2% to 3%, it’s certainly important, because 2% to 3% of breast cancer patients is a significant number, so this drug has legs,” he said.

 

 

The question yet to be settled, however, is the true duration of response, he added.

The study is sponsored by AstraZeneca. Dr. Hyman disclosed consulting for Atara Biotherapeutics. Dr. Soria reported having no disclosures.

BOSTON – A novel pan-AKT inhibitor was associated in a phase 1 trial with tumor shrinkage in a large proportion of patients with solid tumors bearing a mutation in AKT1.

The investigational compound, labeled AZD5363, targets the AKT1 E17K mutation, which occurs in approximately 0.5% to 4% of many different types of solid tumors. In a phase I trial, 33 of 41 assessable patients with tumors bearing the mutation had regression of tumors, reported Dr. David M. Hyman, acting director of experimental therapeutics at Memorial Sloan Kettering Cancer Center in New York.

Dr. David M. Hyman

“We believe this is the first clinical data suggesting that the AKT1 E17K mutations are targetable driver mutations in solid tumors,” he said at a briefing at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Mutations in the PI3K/AKT/mTOR pathway are frequently found in human cancers, and dysregulation of the pathway has been shown to drive tumor growth and survival of malignant cells.

“Although this pathway is among the most commonly activated in all human cancer, it is rarely activated by somatic mutation of AKT itself,” Dr. Hyman said. “When you see AKT mutations, they are almost always of a single allele at the 17 amino acid position, which is the E17K mutation. This is a mutation that has been extensively functionally classified, and behaves as a classic driver oncogene.”

The E17K mutation occurs in approximately 4% of breast cancers, 2% of bladder cancers, 1.5% of colorectal tumors, 1% each of cervical, ovarian, and prostate cancers, and 0.5% of lung adenocarcinomas.

AZD5363 is a catalytic inhibitor of all AKT isoforms 1, 2, and 3. In preclinical studies, it has been shown to inhibit tumor cell proliferation in vitro, and tumor growth in vivo in tumor xenograft models.

Dr. Hyman and colleagues reported on early results from one part of a four-part, phase I study of AZD5363 in adults with advanced solid tumors. Part D of the ongoing study focuses on patients with tumors bearing AKT1 mutations.

At present, 45 patients with E17K mutations have been treated with the agent, including 21 with estrogen receptor (ER)-positive breast cancer, four with triple-negative breast cancer, 14 with gynecological cancers, and eight with other tumor types.

As noted, of 41 patients with sufficient data for assessment, 33 had some degree of tumor regression, and of this group 12 met RECIST (Response Evaluation Criteria in Solid Tumors) parameters for partial responses. Among patients assessable for response, 14 of 18 with ER-positive breast cancer had lesion shrinkage, and five of these patients had partial responses (3 confirmed and 2 unconfirmed).

Among patients with gynecological tumors, 9 of 11 had shrinkage of their target lesion, including 3 with confirmed partial responses. Two of these patients are still on study, with the longest follow-up at the time of data cutoff of 39.2 months

Among patients with 12 other tumor types (apocrine anal, triple-negative breast cancer, colon, lung, prostate, squamous anal, thyroid) 10 patients had demonstrated target lesion shrinkage, one had a confirmed partial response that is ongoing, and two had unconfirmed partial response, one of which is ongoing.

The investigators also used cell-free DNA (cfDNA) analysis to evaluate efficacy of AZD5363 during treatment, and found that declines in AKT1 cfDNA allele fractions were transient among non-responders, whereas declines persisting for 21 days or more correlated with both durable tumor regression and RECIST response (P = .0049).

Dr. Hyman noted that there were also preclinical signs that AZD5363 could lead to reactivation of ER signaling.

“It became a natural question to ask whether patients did better with a combination of ER-directed therapy and AKT-directed therapy,” he said.

To answer this question, the investigators offered sequential therapy to patients with ER-positive breast cancer who had previously had resistance to the ER degrader fulvestrant and who had progressed on AZD5363 monotherapy. Two patients were offered crossover to AZD5363 with fulvestrant, regardless of prior hormonal therapy.

One of the patients had disease progression while on the combination. The second patient, who had received 10 prior lines of therapy and had disease progression before starting on the combination at 120 days on treatment, had significant shrinkage of her breast lesion 6 weeks after starting on the combination, and liver lesions that had previously enhanced on imaging are no longer enhancing, and her cfDNA allele fractions have declined. She remains on the combination after more than 160 days.

“This was very convincing evidence to us of synergy between these two compounds,” he said.

Dr. Jean-Charles Soria, from the Institut Gustave Roussy, Villejuif, France, who moderated the briefing, commented that “although this [mutation] is a rare situation, in the range of 2% to 3%, it’s certainly important, because 2% to 3% of breast cancer patients is a significant number, so this drug has legs,” he said.

 

 

The question yet to be settled, however, is the true duration of response, he added.

The study is sponsored by AstraZeneca. Dr. Hyman disclosed consulting for Atara Biotherapeutics. Dr. Soria reported having no disclosures.

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Pan-AKT inhibitor shrinks tumors in patients with AKT1 mutation
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Key clinical point: A novel pan-AKT inhibitor shrinks tumors in patients harboring a mutation in AKT1.

Major finding: Among patients assessable for response, 33 of 41 had tumor regression on AZD5363 monotherapy.

Data source: Phase I study in 45 patients with solid tumors carrying the AKT1 E17K mutation.

Disclosures: The study is sponsored by AstraZeneca. Dr. Hyman disclosed consulting for Atara Biotherapeutics. Dr. Soria reported having no disclosures.

Experimental LOXO-101 induces regression in several hard-to-treat cancers

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Experimental LOXO-101 induces regression in several hard-to-treat cancers

BOSTON – An experimental agent that targets the byproducts of gene fusions has shown surprising clinical activity against notoriously treatment-refractory cancers in early results from a phase I trial.

“I think that’s what remarkable about this is that we have all these different histologies and many different fusions, but all seem to be having some kind of [response] to this molecule,” said lead investigator Dr. David S. Hong, deputy chair and associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston.

Dr. David S. Hong

The molecule, LOXO-101 is a selective inhibitor of abnormal TRKA, TRKAB, and TRKC kinases that arise from gene fusions. TRK fusions have been implicated in tumor development in preclinical studies, he reported at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

One patient, a 41-year-old woman with undifferentiated soft tissue sarcoma of the groin that had metastasized to her lungs had rapid and “substantial” tumor and lung-nodule regression that radiographically fell just shy of a complete response, Dr. Hong said.

The drug also induced robust partial responses in a 55-year-old man with a gastrointestinal stromal tumor (GIST) for whom five prior targeted agents had failed, and a 33-year-old man with mammary analogue secretory carcinoma of the salivary gland (MASC) that had progressed on chemotherapy with docetaxel, carboplatin, and 5-fluorauracil.

A fourth patient, a man (age unspecified) who had papillary thyroid cancer with palpable lymphadenopathy, had no palpable nodes at 1-month follow-up, and appears to be responding to the drug, Dr. Hong added.

Dr. Lee C. Helman

“This is really a dramatic example, I think, of a targeted therapy that is not histology specific, and this is another area in oncology where it’s new, and we’re just feeling our way,” commented Dr. Lee C. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who moderated the briefing where Dr. Hong presented the data.

Tumor promoters

The TRK family of proteins consists of separate tyrosine kinases that, when functioning normally, are important for the development of peripheral central nervous system processes such as pain and thermoregulation, Dr. Hong explained.

“The NTRK 1, 2, and 3 genes which encode for the TRK proteins are subject to these gene rearrangements and fusions, and the resulting TRK gene fusions may become erroneously expressed, and the kinase domain constitutively activated,” he said.

Gene fusions resulting in constitutively active TRKA, B, and C kinases can occur in the range of about 2%-25% in a wide variety of tumors, including adenocarcinomas of the lung, gliomas, thyroid tumors, head and neck cancers, sarcomas, and other types. These fusions have also been detected in more than 75% of MASC tumors, secretory breast carcinomas, and infantile (congenital) fibrosarcoma.

LOXO-101 is an orally delivered small molecule that was rationally designed to target the TRK fusions while largely leaving other kinases alone. In preclinical studies, the compound showed potent tumor growth inhibition and regression in mice bearing NTRK fusions.

The phase I trial is a dose-finding study including a total of 24 patients with various treatment-refractory advanced or metastatic solid tumors. Patients were enrolled regardless of fusional status.

Well tolerated

At the selected dose of 100 mg twice daily, patients appeared to tolerate the drug very well, with few off-target adverse events, Dr. Hong said. The most common side effect was mild dizziness. Grade 3 or 4 adverse events occurring at all doses levels include fatigue (one patient), anemia (two), abdominal pain (one), increased alkaline phosphatase (one), increased aspartate aminotransferase, delirium, and syncope (two each).

A total of six of the 24 patients had TRK fusions in their tumors, and three of these patients were available for assessment as of Oct. 20, 2015.

Dr. Hong and colleagues previously reportedon the case of the 41-year old woman with sarcoma. She was found to have a fusion of LMNA (a gene that encodes for nuclear membrane proteins) with NTRK1. She was started on the 100-mg b.i.d. dose of LOX-101 and had rapid resolution of dyspnea and hypoxemia. She had a confirmed partial response, and a CT scan showed that her multiple pulmonary nodules had regressed, with just a single, small disease site remaining at most recent follow-up. This patient continues on treatment and has been followed for more than 8 months.

The man with GIST had experienced disease progression while on therapy with imatinib, sunitinib, sorafenib, nilotinib, and regorafenib. He was treated in the 150-mg b.i.d. dose cohort, had a confirmed partial response, and remains on study after 4-plus months.

 

 

The third patient, the 33-year-old man with MASC, was assigned to the 100-mg b.i.d. dose. He too had a partial response, with radiologic evidence of substantial tumor shrinkage, and a persistent, tumor-related cough that disappeared after about 10 days of treatment, and remains on study after more than 3 months of follow-up.

The investigators have begun accruing patients for a phase II “basket” trial in adult patients with advanced or metastatic solid tumors displaying TRK fusions, including non–small cell lung cancers, thyroid tumors, sarcomas, colorectal cancer, salivary gland cancers, primary central nervous system cancers, and all other solid tumors.

Dr. Hong said that the results indicate the importance of tumor profiling for the majority of patients, especially those whose disease is refractory to standard therapies.

The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.

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BOSTON – An experimental agent that targets the byproducts of gene fusions has shown surprising clinical activity against notoriously treatment-refractory cancers in early results from a phase I trial.

“I think that’s what remarkable about this is that we have all these different histologies and many different fusions, but all seem to be having some kind of [response] to this molecule,” said lead investigator Dr. David S. Hong, deputy chair and associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston.

Dr. David S. Hong

The molecule, LOXO-101 is a selective inhibitor of abnormal TRKA, TRKAB, and TRKC kinases that arise from gene fusions. TRK fusions have been implicated in tumor development in preclinical studies, he reported at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

One patient, a 41-year-old woman with undifferentiated soft tissue sarcoma of the groin that had metastasized to her lungs had rapid and “substantial” tumor and lung-nodule regression that radiographically fell just shy of a complete response, Dr. Hong said.

The drug also induced robust partial responses in a 55-year-old man with a gastrointestinal stromal tumor (GIST) for whom five prior targeted agents had failed, and a 33-year-old man with mammary analogue secretory carcinoma of the salivary gland (MASC) that had progressed on chemotherapy with docetaxel, carboplatin, and 5-fluorauracil.

A fourth patient, a man (age unspecified) who had papillary thyroid cancer with palpable lymphadenopathy, had no palpable nodes at 1-month follow-up, and appears to be responding to the drug, Dr. Hong added.

Dr. Lee C. Helman

“This is really a dramatic example, I think, of a targeted therapy that is not histology specific, and this is another area in oncology where it’s new, and we’re just feeling our way,” commented Dr. Lee C. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who moderated the briefing where Dr. Hong presented the data.

Tumor promoters

The TRK family of proteins consists of separate tyrosine kinases that, when functioning normally, are important for the development of peripheral central nervous system processes such as pain and thermoregulation, Dr. Hong explained.

“The NTRK 1, 2, and 3 genes which encode for the TRK proteins are subject to these gene rearrangements and fusions, and the resulting TRK gene fusions may become erroneously expressed, and the kinase domain constitutively activated,” he said.

Gene fusions resulting in constitutively active TRKA, B, and C kinases can occur in the range of about 2%-25% in a wide variety of tumors, including adenocarcinomas of the lung, gliomas, thyroid tumors, head and neck cancers, sarcomas, and other types. These fusions have also been detected in more than 75% of MASC tumors, secretory breast carcinomas, and infantile (congenital) fibrosarcoma.

LOXO-101 is an orally delivered small molecule that was rationally designed to target the TRK fusions while largely leaving other kinases alone. In preclinical studies, the compound showed potent tumor growth inhibition and regression in mice bearing NTRK fusions.

The phase I trial is a dose-finding study including a total of 24 patients with various treatment-refractory advanced or metastatic solid tumors. Patients were enrolled regardless of fusional status.

Well tolerated

At the selected dose of 100 mg twice daily, patients appeared to tolerate the drug very well, with few off-target adverse events, Dr. Hong said. The most common side effect was mild dizziness. Grade 3 or 4 adverse events occurring at all doses levels include fatigue (one patient), anemia (two), abdominal pain (one), increased alkaline phosphatase (one), increased aspartate aminotransferase, delirium, and syncope (two each).

A total of six of the 24 patients had TRK fusions in their tumors, and three of these patients were available for assessment as of Oct. 20, 2015.

Dr. Hong and colleagues previously reportedon the case of the 41-year old woman with sarcoma. She was found to have a fusion of LMNA (a gene that encodes for nuclear membrane proteins) with NTRK1. She was started on the 100-mg b.i.d. dose of LOX-101 and had rapid resolution of dyspnea and hypoxemia. She had a confirmed partial response, and a CT scan showed that her multiple pulmonary nodules had regressed, with just a single, small disease site remaining at most recent follow-up. This patient continues on treatment and has been followed for more than 8 months.

The man with GIST had experienced disease progression while on therapy with imatinib, sunitinib, sorafenib, nilotinib, and regorafenib. He was treated in the 150-mg b.i.d. dose cohort, had a confirmed partial response, and remains on study after 4-plus months.

 

 

The third patient, the 33-year-old man with MASC, was assigned to the 100-mg b.i.d. dose. He too had a partial response, with radiologic evidence of substantial tumor shrinkage, and a persistent, tumor-related cough that disappeared after about 10 days of treatment, and remains on study after more than 3 months of follow-up.

The investigators have begun accruing patients for a phase II “basket” trial in adult patients with advanced or metastatic solid tumors displaying TRK fusions, including non–small cell lung cancers, thyroid tumors, sarcomas, colorectal cancer, salivary gland cancers, primary central nervous system cancers, and all other solid tumors.

Dr. Hong said that the results indicate the importance of tumor profiling for the majority of patients, especially those whose disease is refractory to standard therapies.

The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.

BOSTON – An experimental agent that targets the byproducts of gene fusions has shown surprising clinical activity against notoriously treatment-refractory cancers in early results from a phase I trial.

“I think that’s what remarkable about this is that we have all these different histologies and many different fusions, but all seem to be having some kind of [response] to this molecule,” said lead investigator Dr. David S. Hong, deputy chair and associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston.

Dr. David S. Hong

The molecule, LOXO-101 is a selective inhibitor of abnormal TRKA, TRKAB, and TRKC kinases that arise from gene fusions. TRK fusions have been implicated in tumor development in preclinical studies, he reported at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

One patient, a 41-year-old woman with undifferentiated soft tissue sarcoma of the groin that had metastasized to her lungs had rapid and “substantial” tumor and lung-nodule regression that radiographically fell just shy of a complete response, Dr. Hong said.

The drug also induced robust partial responses in a 55-year-old man with a gastrointestinal stromal tumor (GIST) for whom five prior targeted agents had failed, and a 33-year-old man with mammary analogue secretory carcinoma of the salivary gland (MASC) that had progressed on chemotherapy with docetaxel, carboplatin, and 5-fluorauracil.

A fourth patient, a man (age unspecified) who had papillary thyroid cancer with palpable lymphadenopathy, had no palpable nodes at 1-month follow-up, and appears to be responding to the drug, Dr. Hong added.

Dr. Lee C. Helman

“This is really a dramatic example, I think, of a targeted therapy that is not histology specific, and this is another area in oncology where it’s new, and we’re just feeling our way,” commented Dr. Lee C. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who moderated the briefing where Dr. Hong presented the data.

Tumor promoters

The TRK family of proteins consists of separate tyrosine kinases that, when functioning normally, are important for the development of peripheral central nervous system processes such as pain and thermoregulation, Dr. Hong explained.

“The NTRK 1, 2, and 3 genes which encode for the TRK proteins are subject to these gene rearrangements and fusions, and the resulting TRK gene fusions may become erroneously expressed, and the kinase domain constitutively activated,” he said.

Gene fusions resulting in constitutively active TRKA, B, and C kinases can occur in the range of about 2%-25% in a wide variety of tumors, including adenocarcinomas of the lung, gliomas, thyroid tumors, head and neck cancers, sarcomas, and other types. These fusions have also been detected in more than 75% of MASC tumors, secretory breast carcinomas, and infantile (congenital) fibrosarcoma.

LOXO-101 is an orally delivered small molecule that was rationally designed to target the TRK fusions while largely leaving other kinases alone. In preclinical studies, the compound showed potent tumor growth inhibition and regression in mice bearing NTRK fusions.

The phase I trial is a dose-finding study including a total of 24 patients with various treatment-refractory advanced or metastatic solid tumors. Patients were enrolled regardless of fusional status.

Well tolerated

At the selected dose of 100 mg twice daily, patients appeared to tolerate the drug very well, with few off-target adverse events, Dr. Hong said. The most common side effect was mild dizziness. Grade 3 or 4 adverse events occurring at all doses levels include fatigue (one patient), anemia (two), abdominal pain (one), increased alkaline phosphatase (one), increased aspartate aminotransferase, delirium, and syncope (two each).

A total of six of the 24 patients had TRK fusions in their tumors, and three of these patients were available for assessment as of Oct. 20, 2015.

Dr. Hong and colleagues previously reportedon the case of the 41-year old woman with sarcoma. She was found to have a fusion of LMNA (a gene that encodes for nuclear membrane proteins) with NTRK1. She was started on the 100-mg b.i.d. dose of LOX-101 and had rapid resolution of dyspnea and hypoxemia. She had a confirmed partial response, and a CT scan showed that her multiple pulmonary nodules had regressed, with just a single, small disease site remaining at most recent follow-up. This patient continues on treatment and has been followed for more than 8 months.

The man with GIST had experienced disease progression while on therapy with imatinib, sunitinib, sorafenib, nilotinib, and regorafenib. He was treated in the 150-mg b.i.d. dose cohort, had a confirmed partial response, and remains on study after 4-plus months.

 

 

The third patient, the 33-year-old man with MASC, was assigned to the 100-mg b.i.d. dose. He too had a partial response, with radiologic evidence of substantial tumor shrinkage, and a persistent, tumor-related cough that disappeared after about 10 days of treatment, and remains on study after more than 3 months of follow-up.

The investigators have begun accruing patients for a phase II “basket” trial in adult patients with advanced or metastatic solid tumors displaying TRK fusions, including non–small cell lung cancers, thyroid tumors, sarcomas, colorectal cancer, salivary gland cancers, primary central nervous system cancers, and all other solid tumors.

Dr. Hong said that the results indicate the importance of tumor profiling for the majority of patients, especially those whose disease is refractory to standard therapies.

The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.

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Key clinical point:Inhibition of TRK gene fusion products is a novel strategy for treating cancer.

Major finding: Three of three patients evaluable for response had near-complete responses.

Data source: Phase I dose-finding study in 24 patients, with and without TRK gene fusions.

Disclosures: The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.

Novel EGFR-TKI clears leptomeningeal disease in phase I study

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Novel EGFR-TKI clears leptomeningeal disease in phase I study

BOSTON – An experimental small-molecule tyrosine kinase inhibitor targeted to the epidermal growth factor receptor showed encouraging clinical activity in patients with heavily pretreated non–small cell lung cancer and leptomeningeal disease, one of the most devastating complications of advanced cancer, investigators report.

Dr. Dan Ho Lee

Of eight patients evaluable for response in a phase I, open label study of the compound, labeled AZD9291, one had confirmed clearance of malignant cells from cerebrospinal fluid (CSF), and four others had suspected but unconfirmed clearance of cancer from CSF, reported Dr. Dan Ho Lee of the University of Ulsan College of Medicine, Seoul, South Korea.

In addition, six patients had investigator-rated improvements in brain imaging, and three of seven with abnormal neurologic exams at baseline had significant improvement of symptoms, Dr. Lee said at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Leptomeningeal disease involvement is the nightmare every single clinician taking care of lung cancer patients with EGFR [epidermal growth factor receptor] mutations does not want to face, because that’s a death sentence,” commented Dr. Jean-Charles Soria of the Institut Gustave Roussy, Villejuif, France.

“Having a drug that is delivering in 8 out of 12 patients responding clinically by improvement in their neurological exam, radiologically by MRI, and cytologically by CSF is really transformational for that group of patients,” he said, at a briefing where Dr. Lee presented the data, prior to his presentation in an oral session.

AZD9291 is a tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including T790M resistance mutations, in both preclinical and clinical studies, the compound appeared capable of crossing the blood-brain barrier, making it a candidate for clinical trials in patients with leptomeningeal metastases.

Dr. Jean-Charles Soria

Dr. Lee noted that in patients with EGFR-mutant non–small cell lung cancer (NSCLC), there appears to be an increased risk for CNS involvement, particularly among patients who had received a first-generation EGFR-targeted TKI. Patients with EGFR-mutant NSCLC and leptomeningeal metastases have an expected overall survival of 7-14 months, he said.

As previously reported, in a multicenter clinical trial of AZD9291 (N Engl J Med. 2015 Apr 30. doi: 10.1056/NEJMoa1411817) 123 of 239 patients (51%) who could be evaluated for response had either a partial or complete response. In the subset of patients with known EGFR T790M mutations, the objective response rate was even higher at 61%. In contrast, the objective response rate was 21% in the subset of 61 patients who did not have known EGFR T790M mutations, the investigators said.

Dr. Lee reported here on a cohort of patients with EGFR-mutant NSCLC with leptomeningeal metastases in the BLOOM study. The patients were treated with AZD9291 in a once-daily, 160 mg oral dose.

A total of four men and nine women were enrolled in the cohort. All patients had NSCLC with a sensitizing EGFR mutation, and five were confirmed to have the T790M mutation. The patients had received a median of three prior lines of therapy, including chemotherapy and anti-EGFR TKI. In all, 12 patients were planned for the efficacy analysis, but three withdrew, one at week 6 due to dysphagia, one at week 1 due to aspiration pneumonia, and one at week 3 due to extracranial disease progression.

Of the remaining nine patients, eight had sufficient data to report on all preliminary outcomes, and one had partial data available.

The authors found that, as noted before, three of the eight patients had investigator-rated improvement over baseline in neurologic exams, and of the five patients with normal baseline neurology, four had no change at the most recent follow-up (26 weeks).

Also as noted, one patient had confirmed clearance of cancer from the CSF, and a total of five (including this patient) had negative cytology at their most recent visit. In addition, six of seven patients who had baseline and follow-up brain MRI studies showed improvement at the most recent scan, Dr. Lee said.

The safety profile was similar to that seen with other EGFR-TKIs, with diarrhea and rash, none worse than grade 2, being the most frequent adverse event. There were four grade 3 or greater adverse events, occurring once each in four patients: anemia, hyponatremia, aspiration pneumonia, and neutropenia, the last of which resolved after a 3-day interruption and resumption of the drug at half the original dose (80 mg) daily.

Dr. Soria noted that while the data look very promising, the real test of AZD9291 will come with longer follow-up showing whether the response is durable.

The study was funded by AstraZeneca. Dr. Lee is an advisory board member of Bristol-Myers Squibb, Korea, Boehringer Ingelheim Korea, and Pfizer Korea, and has received lecture fees from AstraZeneca, Ely Lilly, Merck Sharp & Dohme, and Roche. Dr. Soria reported having no disclosures.

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BOSTON – An experimental small-molecule tyrosine kinase inhibitor targeted to the epidermal growth factor receptor showed encouraging clinical activity in patients with heavily pretreated non–small cell lung cancer and leptomeningeal disease, one of the most devastating complications of advanced cancer, investigators report.

Dr. Dan Ho Lee

Of eight patients evaluable for response in a phase I, open label study of the compound, labeled AZD9291, one had confirmed clearance of malignant cells from cerebrospinal fluid (CSF), and four others had suspected but unconfirmed clearance of cancer from CSF, reported Dr. Dan Ho Lee of the University of Ulsan College of Medicine, Seoul, South Korea.

In addition, six patients had investigator-rated improvements in brain imaging, and three of seven with abnormal neurologic exams at baseline had significant improvement of symptoms, Dr. Lee said at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Leptomeningeal disease involvement is the nightmare every single clinician taking care of lung cancer patients with EGFR [epidermal growth factor receptor] mutations does not want to face, because that’s a death sentence,” commented Dr. Jean-Charles Soria of the Institut Gustave Roussy, Villejuif, France.

“Having a drug that is delivering in 8 out of 12 patients responding clinically by improvement in their neurological exam, radiologically by MRI, and cytologically by CSF is really transformational for that group of patients,” he said, at a briefing where Dr. Lee presented the data, prior to his presentation in an oral session.

AZD9291 is a tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including T790M resistance mutations, in both preclinical and clinical studies, the compound appeared capable of crossing the blood-brain barrier, making it a candidate for clinical trials in patients with leptomeningeal metastases.

Dr. Jean-Charles Soria

Dr. Lee noted that in patients with EGFR-mutant non–small cell lung cancer (NSCLC), there appears to be an increased risk for CNS involvement, particularly among patients who had received a first-generation EGFR-targeted TKI. Patients with EGFR-mutant NSCLC and leptomeningeal metastases have an expected overall survival of 7-14 months, he said.

As previously reported, in a multicenter clinical trial of AZD9291 (N Engl J Med. 2015 Apr 30. doi: 10.1056/NEJMoa1411817) 123 of 239 patients (51%) who could be evaluated for response had either a partial or complete response. In the subset of patients with known EGFR T790M mutations, the objective response rate was even higher at 61%. In contrast, the objective response rate was 21% in the subset of 61 patients who did not have known EGFR T790M mutations, the investigators said.

Dr. Lee reported here on a cohort of patients with EGFR-mutant NSCLC with leptomeningeal metastases in the BLOOM study. The patients were treated with AZD9291 in a once-daily, 160 mg oral dose.

A total of four men and nine women were enrolled in the cohort. All patients had NSCLC with a sensitizing EGFR mutation, and five were confirmed to have the T790M mutation. The patients had received a median of three prior lines of therapy, including chemotherapy and anti-EGFR TKI. In all, 12 patients were planned for the efficacy analysis, but three withdrew, one at week 6 due to dysphagia, one at week 1 due to aspiration pneumonia, and one at week 3 due to extracranial disease progression.

Of the remaining nine patients, eight had sufficient data to report on all preliminary outcomes, and one had partial data available.

The authors found that, as noted before, three of the eight patients had investigator-rated improvement over baseline in neurologic exams, and of the five patients with normal baseline neurology, four had no change at the most recent follow-up (26 weeks).

Also as noted, one patient had confirmed clearance of cancer from the CSF, and a total of five (including this patient) had negative cytology at their most recent visit. In addition, six of seven patients who had baseline and follow-up brain MRI studies showed improvement at the most recent scan, Dr. Lee said.

The safety profile was similar to that seen with other EGFR-TKIs, with diarrhea and rash, none worse than grade 2, being the most frequent adverse event. There were four grade 3 or greater adverse events, occurring once each in four patients: anemia, hyponatremia, aspiration pneumonia, and neutropenia, the last of which resolved after a 3-day interruption and resumption of the drug at half the original dose (80 mg) daily.

Dr. Soria noted that while the data look very promising, the real test of AZD9291 will come with longer follow-up showing whether the response is durable.

The study was funded by AstraZeneca. Dr. Lee is an advisory board member of Bristol-Myers Squibb, Korea, Boehringer Ingelheim Korea, and Pfizer Korea, and has received lecture fees from AstraZeneca, Ely Lilly, Merck Sharp & Dohme, and Roche. Dr. Soria reported having no disclosures.

BOSTON – An experimental small-molecule tyrosine kinase inhibitor targeted to the epidermal growth factor receptor showed encouraging clinical activity in patients with heavily pretreated non–small cell lung cancer and leptomeningeal disease, one of the most devastating complications of advanced cancer, investigators report.

Dr. Dan Ho Lee

Of eight patients evaluable for response in a phase I, open label study of the compound, labeled AZD9291, one had confirmed clearance of malignant cells from cerebrospinal fluid (CSF), and four others had suspected but unconfirmed clearance of cancer from CSF, reported Dr. Dan Ho Lee of the University of Ulsan College of Medicine, Seoul, South Korea.

In addition, six patients had investigator-rated improvements in brain imaging, and three of seven with abnormal neurologic exams at baseline had significant improvement of symptoms, Dr. Lee said at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Leptomeningeal disease involvement is the nightmare every single clinician taking care of lung cancer patients with EGFR [epidermal growth factor receptor] mutations does not want to face, because that’s a death sentence,” commented Dr. Jean-Charles Soria of the Institut Gustave Roussy, Villejuif, France.

“Having a drug that is delivering in 8 out of 12 patients responding clinically by improvement in their neurological exam, radiologically by MRI, and cytologically by CSF is really transformational for that group of patients,” he said, at a briefing where Dr. Lee presented the data, prior to his presentation in an oral session.

AZD9291 is a tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including T790M resistance mutations, in both preclinical and clinical studies, the compound appeared capable of crossing the blood-brain barrier, making it a candidate for clinical trials in patients with leptomeningeal metastases.

Dr. Jean-Charles Soria

Dr. Lee noted that in patients with EGFR-mutant non–small cell lung cancer (NSCLC), there appears to be an increased risk for CNS involvement, particularly among patients who had received a first-generation EGFR-targeted TKI. Patients with EGFR-mutant NSCLC and leptomeningeal metastases have an expected overall survival of 7-14 months, he said.

As previously reported, in a multicenter clinical trial of AZD9291 (N Engl J Med. 2015 Apr 30. doi: 10.1056/NEJMoa1411817) 123 of 239 patients (51%) who could be evaluated for response had either a partial or complete response. In the subset of patients with known EGFR T790M mutations, the objective response rate was even higher at 61%. In contrast, the objective response rate was 21% in the subset of 61 patients who did not have known EGFR T790M mutations, the investigators said.

Dr. Lee reported here on a cohort of patients with EGFR-mutant NSCLC with leptomeningeal metastases in the BLOOM study. The patients were treated with AZD9291 in a once-daily, 160 mg oral dose.

A total of four men and nine women were enrolled in the cohort. All patients had NSCLC with a sensitizing EGFR mutation, and five were confirmed to have the T790M mutation. The patients had received a median of three prior lines of therapy, including chemotherapy and anti-EGFR TKI. In all, 12 patients were planned for the efficacy analysis, but three withdrew, one at week 6 due to dysphagia, one at week 1 due to aspiration pneumonia, and one at week 3 due to extracranial disease progression.

Of the remaining nine patients, eight had sufficient data to report on all preliminary outcomes, and one had partial data available.

The authors found that, as noted before, three of the eight patients had investigator-rated improvement over baseline in neurologic exams, and of the five patients with normal baseline neurology, four had no change at the most recent follow-up (26 weeks).

Also as noted, one patient had confirmed clearance of cancer from the CSF, and a total of five (including this patient) had negative cytology at their most recent visit. In addition, six of seven patients who had baseline and follow-up brain MRI studies showed improvement at the most recent scan, Dr. Lee said.

The safety profile was similar to that seen with other EGFR-TKIs, with diarrhea and rash, none worse than grade 2, being the most frequent adverse event. There were four grade 3 or greater adverse events, occurring once each in four patients: anemia, hyponatremia, aspiration pneumonia, and neutropenia, the last of which resolved after a 3-day interruption and resumption of the drug at half the original dose (80 mg) daily.

Dr. Soria noted that while the data look very promising, the real test of AZD9291 will come with longer follow-up showing whether the response is durable.

The study was funded by AstraZeneca. Dr. Lee is an advisory board member of Bristol-Myers Squibb, Korea, Boehringer Ingelheim Korea, and Pfizer Korea, and has received lecture fees from AstraZeneca, Ely Lilly, Merck Sharp & Dohme, and Roche. Dr. Soria reported having no disclosures.

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Key clinical point: A tyrosine kinase inhibitor targeted to mutant EGFR showed good activity against leptomeningeal metastases in patients with NSCLC.

Major finding: Five patients had no evidence of metastases in cerebrospinal fluid at their most recent follow-up.

Data source: Phase I, open, single-agent trial in 13 patients with EGFR-mutated non–small cell lung cancer.

Disclosures: The study was funded by AstraZeneca. Dr. Lee is an advisory board member of Bristol-Myers Squibb, Korea, Boehringer Ingelheim Korea, and Pfizer Korea, and has received lecture fees from AstraZeneca, Ely Lilly, Merck Sharp & Dohme, and Roche. Dr. Soria reported having no disclosures.

Transcription factor loss linked to worse colorectal cancer outcomes

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Transcription factor loss linked to worse colorectal cancer outcomes

BOSTON– Colorectal cancers arising in the hindgut are more likely to have loss or mutation of the transcription factor SMAD4 than are tumors arising in the proximal two-thirds of the colon, and that loss is associated with significantly worse patient outcomes, investigators reported.

A study of data on nearly 600 patients with colorectal cancer in the Cancer Genome Atlas (TCGA) database showed that loss of SMAD4, which codes for a cell-signaling protein in the transforming growth factor beta pathway, was detected in 87% of tumors originating in the hindgut (including the splenic flexure, descending colon, sigmoid colon, and rectum), compared with 50% of tumors arising in the midgut (small intestine, ascending colon, and transverse colon), reported Dr. Jesse Joshua Smith from Memorial Sloan Kettering Cancer Center, New York.

Dr. Jesse Joshua Smith

In a separate analysis of 388 patients with colorectal cancer treated at Dr. Smith’s center, loss of SMAD4 in patients with cancers in the hindgut was associated with significantly shorter recurrence-free survival: 47 months, compared with 231 months for patients with hindgut cancers that retained SMAD4.

“These data indicate that embryologic origin related to SMAD4 status in colorectal cancer may be important in patient outcomes, and could potentially inform individualized treatment options for patients,” Dr. Smith said at the AACR/NCI)/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Previous studies have suggested that alteration (mutation or loss) of SMAD4 may be more common in cancers of the rectum and other portions of the hindgut, he said.

A recent analysis of 113 patients with locally advanced rectal cancer treated at Memorial Sloan showed that 66% of the tumors evaluated by the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutational Profile of Actionable Targets) platform had SMAD4 copy number losses, he noted.

The investigators hypothesized that SMAD4 loss is more common in hindgut vs. midgut tumors. To test that, they looked at TCGA data on 595 patients with colorectal cancer to determine copy number loss and diploid status, and compared SMAD4 copy number loss to the mutational status of genes encoding for adenomatous polyposis coli (APC) and tumor protein p53 (TP53), as well as mismatch repair status and KRAS amplification.

They found that SMAD4 copy number loss was significantly more common in hindgut tumors (295 vs. 44 diploid, P < .0001) than in midgut tumors (127 vs. 129 diploid, P = nonsignificant). In addition, mutations in both APC and TP53 were significantly associated with SMAD4 copy number loss – and when adjusting for mismatch repair status, SMDA4 copy number loss remained significantly associated with tumors originating in the hindgut and with TP53 mutations.

Similarly, immunohistochemical analysis showed that SMAD4 staining was lower in hindgut vs. midgut tumors, and lower levels of staining were associated with more advanced tumor and nodal stage (P < .05).

As noted, SMAD4 copy number loss in patients with hindgut-derived tumors was associated with worse recurrence-free survival, compared with similar patients with retained SMAD4: median, 47 months, compared with 231 months.

A similar pattern was seen among patients with hindgut tumors with SMAD4 loss but no mutations in DNA mismatch repair genes, with respective median recurrence-free survival of 36 months vs. not yet reached at 140 months.

Dr. Smith and his colleagues plan to enroll 100 additional patients and prospectively collect tumor samples to help determine whether there is an association between embryologic origins of tumors according to SMAD4 status and poor treatment response. They also hope to determine whether there is a similar association in tumors that metastasize to the liver or the lungs.

There is evidence from mouse models to suggest that loss of SMAD4 may confer to tumors resistance to therapeutic regimens based on 5-fluorouracil, Dr. Smith said.

In an interview, he noted that there are also preliminary data to suggest that when SMAD4 is lost or mutated, other pathways, such as the vascular endothelial growth factor (VEGF) pathway, may be upregulated, suggesting that this subset of patients might respond to a VEGF inhibitor.

Dr. Levi Garraway

The findings suggest that in addition to considering somatic mutations in the development of colorectal cancer, investigators may wish to explore whether lineage-dependent mechanisms or embryologic origin play a role in disease severity, observed Dr. Levi A. Garraway, of the Dana-Farber Cancer Institute, Boston, who was not involved in the study.

Dr. Garraway moderated the briefing at which Dr. Smith presented his data.

The Howard Hughes Medical Institute supported the study. Dr. Smith and Dr. Garraway reported no relevant disclosures.

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BOSTON– Colorectal cancers arising in the hindgut are more likely to have loss or mutation of the transcription factor SMAD4 than are tumors arising in the proximal two-thirds of the colon, and that loss is associated with significantly worse patient outcomes, investigators reported.

A study of data on nearly 600 patients with colorectal cancer in the Cancer Genome Atlas (TCGA) database showed that loss of SMAD4, which codes for a cell-signaling protein in the transforming growth factor beta pathway, was detected in 87% of tumors originating in the hindgut (including the splenic flexure, descending colon, sigmoid colon, and rectum), compared with 50% of tumors arising in the midgut (small intestine, ascending colon, and transverse colon), reported Dr. Jesse Joshua Smith from Memorial Sloan Kettering Cancer Center, New York.

Dr. Jesse Joshua Smith

In a separate analysis of 388 patients with colorectal cancer treated at Dr. Smith’s center, loss of SMAD4 in patients with cancers in the hindgut was associated with significantly shorter recurrence-free survival: 47 months, compared with 231 months for patients with hindgut cancers that retained SMAD4.

“These data indicate that embryologic origin related to SMAD4 status in colorectal cancer may be important in patient outcomes, and could potentially inform individualized treatment options for patients,” Dr. Smith said at the AACR/NCI)/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Previous studies have suggested that alteration (mutation or loss) of SMAD4 may be more common in cancers of the rectum and other portions of the hindgut, he said.

A recent analysis of 113 patients with locally advanced rectal cancer treated at Memorial Sloan showed that 66% of the tumors evaluated by the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutational Profile of Actionable Targets) platform had SMAD4 copy number losses, he noted.

The investigators hypothesized that SMAD4 loss is more common in hindgut vs. midgut tumors. To test that, they looked at TCGA data on 595 patients with colorectal cancer to determine copy number loss and diploid status, and compared SMAD4 copy number loss to the mutational status of genes encoding for adenomatous polyposis coli (APC) and tumor protein p53 (TP53), as well as mismatch repair status and KRAS amplification.

They found that SMAD4 copy number loss was significantly more common in hindgut tumors (295 vs. 44 diploid, P < .0001) than in midgut tumors (127 vs. 129 diploid, P = nonsignificant). In addition, mutations in both APC and TP53 were significantly associated with SMAD4 copy number loss – and when adjusting for mismatch repair status, SMDA4 copy number loss remained significantly associated with tumors originating in the hindgut and with TP53 mutations.

Similarly, immunohistochemical analysis showed that SMAD4 staining was lower in hindgut vs. midgut tumors, and lower levels of staining were associated with more advanced tumor and nodal stage (P < .05).

As noted, SMAD4 copy number loss in patients with hindgut-derived tumors was associated with worse recurrence-free survival, compared with similar patients with retained SMAD4: median, 47 months, compared with 231 months.

A similar pattern was seen among patients with hindgut tumors with SMAD4 loss but no mutations in DNA mismatch repair genes, with respective median recurrence-free survival of 36 months vs. not yet reached at 140 months.

Dr. Smith and his colleagues plan to enroll 100 additional patients and prospectively collect tumor samples to help determine whether there is an association between embryologic origins of tumors according to SMAD4 status and poor treatment response. They also hope to determine whether there is a similar association in tumors that metastasize to the liver or the lungs.

There is evidence from mouse models to suggest that loss of SMAD4 may confer to tumors resistance to therapeutic regimens based on 5-fluorouracil, Dr. Smith said.

In an interview, he noted that there are also preliminary data to suggest that when SMAD4 is lost or mutated, other pathways, such as the vascular endothelial growth factor (VEGF) pathway, may be upregulated, suggesting that this subset of patients might respond to a VEGF inhibitor.

Dr. Levi Garraway

The findings suggest that in addition to considering somatic mutations in the development of colorectal cancer, investigators may wish to explore whether lineage-dependent mechanisms or embryologic origin play a role in disease severity, observed Dr. Levi A. Garraway, of the Dana-Farber Cancer Institute, Boston, who was not involved in the study.

Dr. Garraway moderated the briefing at which Dr. Smith presented his data.

The Howard Hughes Medical Institute supported the study. Dr. Smith and Dr. Garraway reported no relevant disclosures.

BOSTON– Colorectal cancers arising in the hindgut are more likely to have loss or mutation of the transcription factor SMAD4 than are tumors arising in the proximal two-thirds of the colon, and that loss is associated with significantly worse patient outcomes, investigators reported.

A study of data on nearly 600 patients with colorectal cancer in the Cancer Genome Atlas (TCGA) database showed that loss of SMAD4, which codes for a cell-signaling protein in the transforming growth factor beta pathway, was detected in 87% of tumors originating in the hindgut (including the splenic flexure, descending colon, sigmoid colon, and rectum), compared with 50% of tumors arising in the midgut (small intestine, ascending colon, and transverse colon), reported Dr. Jesse Joshua Smith from Memorial Sloan Kettering Cancer Center, New York.

Dr. Jesse Joshua Smith

In a separate analysis of 388 patients with colorectal cancer treated at Dr. Smith’s center, loss of SMAD4 in patients with cancers in the hindgut was associated with significantly shorter recurrence-free survival: 47 months, compared with 231 months for patients with hindgut cancers that retained SMAD4.

“These data indicate that embryologic origin related to SMAD4 status in colorectal cancer may be important in patient outcomes, and could potentially inform individualized treatment options for patients,” Dr. Smith said at the AACR/NCI)/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Previous studies have suggested that alteration (mutation or loss) of SMAD4 may be more common in cancers of the rectum and other portions of the hindgut, he said.

A recent analysis of 113 patients with locally advanced rectal cancer treated at Memorial Sloan showed that 66% of the tumors evaluated by the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutational Profile of Actionable Targets) platform had SMAD4 copy number losses, he noted.

The investigators hypothesized that SMAD4 loss is more common in hindgut vs. midgut tumors. To test that, they looked at TCGA data on 595 patients with colorectal cancer to determine copy number loss and diploid status, and compared SMAD4 copy number loss to the mutational status of genes encoding for adenomatous polyposis coli (APC) and tumor protein p53 (TP53), as well as mismatch repair status and KRAS amplification.

They found that SMAD4 copy number loss was significantly more common in hindgut tumors (295 vs. 44 diploid, P < .0001) than in midgut tumors (127 vs. 129 diploid, P = nonsignificant). In addition, mutations in both APC and TP53 were significantly associated with SMAD4 copy number loss – and when adjusting for mismatch repair status, SMDA4 copy number loss remained significantly associated with tumors originating in the hindgut and with TP53 mutations.

Similarly, immunohistochemical analysis showed that SMAD4 staining was lower in hindgut vs. midgut tumors, and lower levels of staining were associated with more advanced tumor and nodal stage (P < .05).

As noted, SMAD4 copy number loss in patients with hindgut-derived tumors was associated with worse recurrence-free survival, compared with similar patients with retained SMAD4: median, 47 months, compared with 231 months.

A similar pattern was seen among patients with hindgut tumors with SMAD4 loss but no mutations in DNA mismatch repair genes, with respective median recurrence-free survival of 36 months vs. not yet reached at 140 months.

Dr. Smith and his colleagues plan to enroll 100 additional patients and prospectively collect tumor samples to help determine whether there is an association between embryologic origins of tumors according to SMAD4 status and poor treatment response. They also hope to determine whether there is a similar association in tumors that metastasize to the liver or the lungs.

There is evidence from mouse models to suggest that loss of SMAD4 may confer to tumors resistance to therapeutic regimens based on 5-fluorouracil, Dr. Smith said.

In an interview, he noted that there are also preliminary data to suggest that when SMAD4 is lost or mutated, other pathways, such as the vascular endothelial growth factor (VEGF) pathway, may be upregulated, suggesting that this subset of patients might respond to a VEGF inhibitor.

Dr. Levi Garraway

The findings suggest that in addition to considering somatic mutations in the development of colorectal cancer, investigators may wish to explore whether lineage-dependent mechanisms or embryologic origin play a role in disease severity, observed Dr. Levi A. Garraway, of the Dana-Farber Cancer Institute, Boston, who was not involved in the study.

Dr. Garraway moderated the briefing at which Dr. Smith presented his data.

The Howard Hughes Medical Institute supported the study. Dr. Smith and Dr. Garraway reported no relevant disclosures.

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Transcription factor loss linked to worse colorectal cancer outcomes
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Key clinical point: In colorectal cancer arising in the hindgut, loss of SMAD4 is associated with worse recurrence-free survival.

Major finding: Loss of SMAD4 in patients with cancers in the hindgut was associated with a median of 47 months recurrence-free survival, compared with 231 months for patients with hindgut cancers that retained SMAD4.

Data source: Analysis of genomic registry data on 595 patients, and of 388 patients with colorectal cancer in a case series.

Disclosures: The Howard Hughes Medical Institute supported the study. Dr. Smith and Dr. Garraway reported no relevant disclosures.