Safety Concerns Weigh on Carfilzomib in Multiple Myeloma

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.