2018 ASCO Annual Meeting

CHICAGO – Are today’s myeloma drugs affordable? Two Mayo Clinic researchers agreed that costs are high but not whether the price is offset by the value.

“I don’t think there is any debate here. It’s like debating whether the Earth is flat or not,” S. Vincent Rajkumar, MD, of Mayo Clinic, Rochester, Minn., said during a debate at the annual meeting of the American Society of Clinical Oncology. “These drugs are expensive.”

“I would trust Dr. Rajkumar with my life if I were diagnosed with myeloma,” countered Rafael Fonseca, MD, of Mayo Clinic in Phoenix, Ariz., “But I think he’s wrong on drug economics.”

Dr. Rajkumar said the total lifetime costs to treat all patients diagnosed with multiple myeloma in 2017 were $22.4 billion, a “conservative estimate” that excluded hospital, infusion, laboratory, imaging, physician, nursing, and ancillary costs.

“Every single drug is expensive,” he said, referring to newer approved myeloma therapies that cost up to $192,000/year individually, and up to $590,000/year in triplet or quadruplet combination regimens, according to estimates he included in a related article he wrote for the 2018 ASCO Educational Book.

Of $50 billion spent in 2017 on cancer drugs, 80% of that spending was based on just 35 drugs, of which 6 were myeloma drugs – and myeloma is just 1% of all cancers. “Maybe it’s because of all the progress we’ve made in myeloma, but unless you think none of the other cancers should have the type of progress we have, this is not going to be affordable,” Dr. Rajkumar said.

Drugs approved by the Food and Drug Administration (FDA) in 2017 cost $100,000/year or more, with an average of $150,000/year, according to Dr. Rajkumar. He compared that with the average U.S. annual gross household income of $52,000, saying that the high price of drugs has contributed to compliance problems and medical bankruptcy.

While Dr. Fonseca agreed that drug prices are “skyrocketing,” he challenged the notion that the increases were not affordable in his presentation and an associated ASCO Educational Book article.

In his talk, Dr. Fonseca said the availability of new myeloma drugs has led to “astounding” improvements in overall survival, but today’s best drugs are still not good enough. “We cannot afford to stop innovation and the move forward as we are ever so close to curing a large fraction of myeloma patients,” he said.

The increasing cost of drugs has been offset by societal and health effects, Dr. Fonseca argued.

The war on cancer from 1988 to 2000 added 23 million additional life-years, which has equated to $1.9 trillion in social value for Americans, according to one analysis he cited. In one myeloma-specific study, investigators found myeloma drug costs increased from $36,607 in 2004 to $109,544 in 2009, but those increases were balanced out by $67,900 in health benefits.

Although the financial impact of myeloma on the individual patient can be significant, it’s not bankruptcies, but out-of-pocket costs such as copayments, that have the most direct effect on patients, Dr. Fonseca said. Research shows medical bankruptcies are not associated with drug copayments, he added, but rather other medical expenses, such as hospital and physician bills, along with loss of income and limited savings.

Dr. Rajkumar – unconvinced that myeloma drugs are currently affordable – urged action on several fronts, including value-based pricing or tying the price of a drug to how much value it produces.

The Medicare program has to be able to negotiate prices, he added, and patients should be allowed to reimport cancer drugs from other countries for personal use. He also pushed for more to be done to facilitate the entry of generics and biosimilars into the marketplace.

He also called for a relaxation of FDA regulations to lower drug development costs. “We have so many regulations so that every T is crossed and every I is dotted, to the point that it costs $30,000, $40,000 per patient to do a trial,” he said.

But Dr. Fonseca opposed market interference, saying that price controls would kill innovation.

“The patented drugs of today are the generics of the future, and absent innovation, we won’t have future generics,” he said in his presentation. “Price fixing kills innovation. ... So if we engage in that, today’s best is simply the best there is going to be.”

Dr. Rajkumar reported having no conflicts of interest. Dr. Fonseca reported consulting work with Amgen, Bristol-Myers Squibb, Celgene, Takeda Pharmaceutical, Bayer, Janssen, AbbVie, Pharmacyclics, Sanofi, Kite Pharma, and Juno Therapeutics, and scientific advisory board work with Adaptive Biotechnologies.

CHICAGO – Are today’s myeloma drugs affordable? Two Mayo Clinic researchers agreed that costs are high but not whether the price is offset by the value.

“I don’t think there is any debate here. It’s like debating whether the Earth is flat or not,” S. Vincent Rajkumar, MD, of Mayo Clinic, Rochester, Minn., said during a debate at the annual meeting of the American Society of Clinical Oncology. “These drugs are expensive.”

“I would trust Dr. Rajkumar with my life if I were diagnosed with myeloma,” countered Rafael Fonseca, MD, of Mayo Clinic in Phoenix, Ariz., “But I think he’s wrong on drug economics.”

Dr. Rajkumar said the total lifetime costs to treat all patients diagnosed with multiple myeloma in 2017 were $22.4 billion, a “conservative estimate” that excluded hospital, infusion, laboratory, imaging, physician, nursing, and ancillary costs.

“Every single drug is expensive,” he said, referring to newer approved myeloma therapies that cost up to $192,000/year individually, and up to $590,000/year in triplet or quadruplet combination regimens, according to estimates he included in a related article he wrote for the 2018 ASCO Educational Book.

Of $50 billion spent in 2017 on cancer drugs, 80% of that spending was based on just 35 drugs, of which 6 were myeloma drugs – and myeloma is just 1% of all cancers. “Maybe it’s because of all the progress we’ve made in myeloma, but unless you think none of the other cancers should have the type of progress we have, this is not going to be affordable,” Dr. Rajkumar said.

Drugs approved by the Food and Drug Administration (FDA) in 2017 cost $100,000/year or more, with an average of $150,000/year, according to Dr. Rajkumar. He compared that with the average U.S. annual gross household income of $52,000, saying that the high price of drugs has contributed to compliance problems and medical bankruptcy.

While Dr. Fonseca agreed that drug prices are “skyrocketing,” he challenged the notion that the increases were not affordable in his presentation and an associated ASCO Educational Book article.

In his talk, Dr. Fonseca said the availability of new myeloma drugs has led to “astounding” improvements in overall survival, but today’s best drugs are still not good enough. “We cannot afford to stop innovation and the move forward as we are ever so close to curing a large fraction of myeloma patients,” he said.

The increasing cost of drugs has been offset by societal and health effects, Dr. Fonseca argued.

The war on cancer from 1988 to 2000 added 23 million additional life-years, which has equated to $1.9 trillion in social value for Americans, according to one analysis he cited. In one myeloma-specific study, investigators found myeloma drug costs increased from $36,607 in 2004 to $109,544 in 2009, but those increases were balanced out by $67,900 in health benefits.

Although the financial impact of myeloma on the individual patient can be significant, it’s not bankruptcies, but out-of-pocket costs such as copayments, that have the most direct effect on patients, Dr. Fonseca said. Research shows medical bankruptcies are not associated with drug copayments, he added, but rather other medical expenses, such as hospital and physician bills, along with loss of income and limited savings.

Dr. Rajkumar – unconvinced that myeloma drugs are currently affordable – urged action on several fronts, including value-based pricing or tying the price of a drug to how much value it produces.

The Medicare program has to be able to negotiate prices, he added, and patients should be allowed to reimport cancer drugs from other countries for personal use. He also pushed for more to be done to facilitate the entry of generics and biosimilars into the marketplace.

He also called for a relaxation of FDA regulations to lower drug development costs. “We have so many regulations so that every T is crossed and every I is dotted, to the point that it costs $30,000, $40,000 per patient to do a trial,” he said.

But Dr. Fonseca opposed market interference, saying that price controls would kill innovation.

“The patented drugs of today are the generics of the future, and absent innovation, we won’t have future generics,” he said in his presentation. “Price fixing kills innovation. ... So if we engage in that, today’s best is simply the best there is going to be.”

Dr. Rajkumar reported having no conflicts of interest. Dr. Fonseca reported consulting work with Amgen, Bristol-Myers Squibb, Celgene, Takeda Pharmaceutical, Bayer, Janssen, AbbVie, Pharmacyclics, Sanofi, Kite Pharma, and Juno Therapeutics, and scientific advisory board work with Adaptive Biotechnologies.

CHICAGO – Are today’s myeloma drugs affordable? Two Mayo Clinic researchers agreed that costs are high but not whether the price is offset by the value.

“I don’t think there is any debate here. It’s like debating whether the Earth is flat or not,” S. Vincent Rajkumar, MD, of Mayo Clinic, Rochester, Minn., said during a debate at the annual meeting of the American Society of Clinical Oncology. “These drugs are expensive.”

“I would trust Dr. Rajkumar with my life if I were diagnosed with myeloma,” countered Rafael Fonseca, MD, of Mayo Clinic in Phoenix, Ariz., “But I think he’s wrong on drug economics.”

Dr. Rajkumar said the total lifetime costs to treat all patients diagnosed with multiple myeloma in 2017 were $22.4 billion, a “conservative estimate” that excluded hospital, infusion, laboratory, imaging, physician, nursing, and ancillary costs.

“Every single drug is expensive,” he said, referring to newer approved myeloma therapies that cost up to $192,000/year individually, and up to $590,000/year in triplet or quadruplet combination regimens, according to estimates he included in a related article he wrote for the 2018 ASCO Educational Book.

Of $50 billion spent in 2017 on cancer drugs, 80% of that spending was based on just 35 drugs, of which 6 were myeloma drugs – and myeloma is just 1% of all cancers. “Maybe it’s because of all the progress we’ve made in myeloma, but unless you think none of the other cancers should have the type of progress we have, this is not going to be affordable,” Dr. Rajkumar said.

Drugs approved by the Food and Drug Administration (FDA) in 2017 cost $100,000/year or more, with an average of $150,000/year, according to Dr. Rajkumar. He compared that with the average U.S. annual gross household income of $52,000, saying that the high price of drugs has contributed to compliance problems and medical bankruptcy.

While Dr. Fonseca agreed that drug prices are “skyrocketing,” he challenged the notion that the increases were not affordable in his presentation and an associated ASCO Educational Book article.

In his talk, Dr. Fonseca said the availability of new myeloma drugs has led to “astounding” improvements in overall survival, but today’s best drugs are still not good enough. “We cannot afford to stop innovation and the move forward as we are ever so close to curing a large fraction of myeloma patients,” he said.

The increasing cost of drugs has been offset by societal and health effects, Dr. Fonseca argued.

The war on cancer from 1988 to 2000 added 23 million additional life-years, which has equated to $1.9 trillion in social value for Americans, according to one analysis he cited. In one myeloma-specific study, investigators found myeloma drug costs increased from $36,607 in 2004 to $109,544 in 2009, but those increases were balanced out by $67,900 in health benefits.

Although the financial impact of myeloma on the individual patient can be significant, it’s not bankruptcies, but out-of-pocket costs such as copayments, that have the most direct effect on patients, Dr. Fonseca said. Research shows medical bankruptcies are not associated with drug copayments, he added, but rather other medical expenses, such as hospital and physician bills, along with loss of income and limited savings.

Dr. Rajkumar – unconvinced that myeloma drugs are currently affordable – urged action on several fronts, including value-based pricing or tying the price of a drug to how much value it produces.

The Medicare program has to be able to negotiate prices, he added, and patients should be allowed to reimport cancer drugs from other countries for personal use. He also pushed for more to be done to facilitate the entry of generics and biosimilars into the marketplace.

He also called for a relaxation of FDA regulations to lower drug development costs. “We have so many regulations so that every T is crossed and every I is dotted, to the point that it costs $30,000, $40,000 per patient to do a trial,” he said.

But Dr. Fonseca opposed market interference, saying that price controls would kill innovation.

“The patented drugs of today are the generics of the future, and absent innovation, we won’t have future generics,” he said in his presentation. “Price fixing kills innovation. ... So if we engage in that, today’s best is simply the best there is going to be.”

Dr. Rajkumar reported having no conflicts of interest. Dr. Fonseca reported consulting work with Amgen, Bristol-Myers Squibb, Celgene, Takeda Pharmaceutical, Bayer, Janssen, AbbVie, Pharmacyclics, Sanofi, Kite Pharma, and Juno Therapeutics, and scientific advisory board work with Adaptive Biotechnologies.

CHICAGO – High levels of blood and tissue tumor mutational burden appear to have value as biomarkers for checkpoint inhibition response in patients with non–small cell lung cancer, according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.

The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.

Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.

“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.

The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.

Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.

In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.

The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.

B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.

Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.

The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.

Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.

This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.

Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.

“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”

The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.

Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.

SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.

CHICAGO – High levels of blood and tissue tumor mutational burden appear to have value as biomarkers for checkpoint inhibition response in patients with non–small cell lung cancer, according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.

The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.

Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.

“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.

The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.

Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.

In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.

The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.

B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.

Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.

The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.

Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.

This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.

Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.

“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”

The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.

Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.

SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.

CHICAGO – High levels of blood and tissue tumor mutational burden appear to have value as biomarkers for checkpoint inhibition response in patients with non–small cell lung cancer, according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.

The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.

Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.

“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.

The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.

Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.

In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.

The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.

B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.

Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.

The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.

Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.

This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.

Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.

“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”

The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.

Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.

SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.

CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.

That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.

By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.

Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).

“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”

On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*

But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.

Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.

The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).

“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”

Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.

For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.

Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.

Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.

“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”

While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.

“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.

Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.

*This story was updated 6/25/2018.

CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.

That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.

By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.

Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).

“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”

On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*

But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.

Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.

The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).

“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”

Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.

For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.

Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.

Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.

“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”

While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.

“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.

Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.

*This story was updated 6/25/2018.

CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.

That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.

By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.

Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).

“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”

On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*

But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.

Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.

The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).

“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”

Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.

For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.

Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.

Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.

“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”

While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.

“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.

Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.

*This story was updated 6/25/2018.

©ASCO/Zach Boyden-Holmes 2018

CHICAGO—A specific gene signature might be able to identify patients at risk of CD19 CAR T-cell associated neurotoxicity, according to results of an exploratory analysis presented at the 2018 ASCO Annual Meeting.

The analysis, based on bone marrow samples from patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated with JCAR015 in the ROCKET trial, helped identify a set of neurotoxicity-associated genes that separated patients based on molecular subtype.

“These findings suggest that patient risk stratification by molecular subtype of disease or gene expression signature may play a role in identifying patients at elevated risk of neurotoxicity,” said Jae Park, MD, of Memorial Sloan Kettering Cancer Center, New York, New York, in a presentation of the findings (abstract 7007).

The phase 2 ROCKET study included adult patients with relapsed or refractory morphological (>5% blasts in bone marrow) CD-19 positive disease in first salvage or greater, including post allogeneic hematopoietic stem cell transplantation (HSCT). Prior blinatumomab was allowed.

The tumor gene expression study presented at ASCO was based on sequenced RNA from pre-apheresis bone marrow samples available for 31 patients in the ROCKET study.

Investigators identified a set of 10 genes expressed more frequently in bone marrow samples from patients in ROCKET with low (grade 0-1) neurotoxicity, and 7 that were more frequent in those who had severe (grade 4-5) neurotoxicity.

Looking at B-cell ALL samples in public datasets by molecular subtype, they found genes highly expressed in the low neurotoxicity ROCKET patients were also highly expressed in Philadelphia chromosome-positive (Ph+) and Ph-like subtypes.

Conversely, the genes highly expressed in the severe neurotoxicity patients were also highly expressed in non-Ph-like samples.

A total of 16 ROCKET patients were classified as having Ph-like gene expression and 15 as having non-Ph-like expression.

There were no grade 4-5 neurotoxicity events in the Ph-like patients, while both grade 3+ and grade 4+ neurotoxicity were significantly more prevalent in the non-Ph-like patients, investigators reported.

One of the most differentially expressed genes in the set was CCL17, which was higher in the low-neurotoxicity tumor samples, and likewise highly expressed in Ph-like B-cell ALL, according to the report.

“[CCL17] may serve as an early biomarker for differentiating severe neurotoxicity,” Dr Park said.

These findings are now being validated in the previously mentioned data set, as well as other studies to see if the findings can be replicated, according to Dr Park.

Juno Therapeutics, a Celgene company, shut down the phase 2 ROCKET trial of JCAR015 in 2017 after 2 clinical holds in 2016 and 5 patient deaths. 

©ASCO/Zach Boyden-Holmes 2018

CHICAGO—A specific gene signature might be able to identify patients at risk of CD19 CAR T-cell associated neurotoxicity, according to results of an exploratory analysis presented at the 2018 ASCO Annual Meeting.

The analysis, based on bone marrow samples from patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated with JCAR015 in the ROCKET trial, helped identify a set of neurotoxicity-associated genes that separated patients based on molecular subtype.

“These findings suggest that patient risk stratification by molecular subtype of disease or gene expression signature may play a role in identifying patients at elevated risk of neurotoxicity,” said Jae Park, MD, of Memorial Sloan Kettering Cancer Center, New York, New York, in a presentation of the findings (abstract 7007).

The phase 2 ROCKET study included adult patients with relapsed or refractory morphological (>5% blasts in bone marrow) CD-19 positive disease in first salvage or greater, including post allogeneic hematopoietic stem cell transplantation (HSCT). Prior blinatumomab was allowed.

The tumor gene expression study presented at ASCO was based on sequenced RNA from pre-apheresis bone marrow samples available for 31 patients in the ROCKET study.

Investigators identified a set of 10 genes expressed more frequently in bone marrow samples from patients in ROCKET with low (grade 0-1) neurotoxicity, and 7 that were more frequent in those who had severe (grade 4-5) neurotoxicity.

Looking at B-cell ALL samples in public datasets by molecular subtype, they found genes highly expressed in the low neurotoxicity ROCKET patients were also highly expressed in Philadelphia chromosome-positive (Ph+) and Ph-like subtypes.

Conversely, the genes highly expressed in the severe neurotoxicity patients were also highly expressed in non-Ph-like samples.

A total of 16 ROCKET patients were classified as having Ph-like gene expression and 15 as having non-Ph-like expression.

There were no grade 4-5 neurotoxicity events in the Ph-like patients, while both grade 3+ and grade 4+ neurotoxicity were significantly more prevalent in the non-Ph-like patients, investigators reported.

One of the most differentially expressed genes in the set was CCL17, which was higher in the low-neurotoxicity tumor samples, and likewise highly expressed in Ph-like B-cell ALL, according to the report.

“[CCL17] may serve as an early biomarker for differentiating severe neurotoxicity,” Dr Park said.

These findings are now being validated in the previously mentioned data set, as well as other studies to see if the findings can be replicated, according to Dr Park.

Juno Therapeutics, a Celgene company, shut down the phase 2 ROCKET trial of JCAR015 in 2017 after 2 clinical holds in 2016 and 5 patient deaths. 

©ASCO/Zach Boyden-Holmes 2018

CHICAGO—A specific gene signature might be able to identify patients at risk of CD19 CAR T-cell associated neurotoxicity, according to results of an exploratory analysis presented at the 2018 ASCO Annual Meeting.

The analysis, based on bone marrow samples from patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated with JCAR015 in the ROCKET trial, helped identify a set of neurotoxicity-associated genes that separated patients based on molecular subtype.

“These findings suggest that patient risk stratification by molecular subtype of disease or gene expression signature may play a role in identifying patients at elevated risk of neurotoxicity,” said Jae Park, MD, of Memorial Sloan Kettering Cancer Center, New York, New York, in a presentation of the findings (abstract 7007).

The phase 2 ROCKET study included adult patients with relapsed or refractory morphological (>5% blasts in bone marrow) CD-19 positive disease in first salvage or greater, including post allogeneic hematopoietic stem cell transplantation (HSCT). Prior blinatumomab was allowed.

The tumor gene expression study presented at ASCO was based on sequenced RNA from pre-apheresis bone marrow samples available for 31 patients in the ROCKET study.

Investigators identified a set of 10 genes expressed more frequently in bone marrow samples from patients in ROCKET with low (grade 0-1) neurotoxicity, and 7 that were more frequent in those who had severe (grade 4-5) neurotoxicity.

Looking at B-cell ALL samples in public datasets by molecular subtype, they found genes highly expressed in the low neurotoxicity ROCKET patients were also highly expressed in Philadelphia chromosome-positive (Ph+) and Ph-like subtypes.

Conversely, the genes highly expressed in the severe neurotoxicity patients were also highly expressed in non-Ph-like samples.

A total of 16 ROCKET patients were classified as having Ph-like gene expression and 15 as having non-Ph-like expression.

There were no grade 4-5 neurotoxicity events in the Ph-like patients, while both grade 3+ and grade 4+ neurotoxicity were significantly more prevalent in the non-Ph-like patients, investigators reported.

One of the most differentially expressed genes in the set was CCL17, which was higher in the low-neurotoxicity tumor samples, and likewise highly expressed in Ph-like B-cell ALL, according to the report.

“[CCL17] may serve as an early biomarker for differentiating severe neurotoxicity,” Dr Park said.

These findings are now being validated in the previously mentioned data set, as well as other studies to see if the findings can be replicated, according to Dr Park.

Juno Therapeutics, a Celgene company, shut down the phase 2 ROCKET trial of JCAR015 in 2017 after 2 clinical holds in 2016 and 5 patient deaths. 

©ASCO/Scott Morgan 2018

CHICAGO—Minimal residual disease (MRD) kinetics confirms the high, durable MRD-negativity with venetoclax plus rituximab in relapsed/refractory chronic lymphocytic leukemia (CLL), according to a further examination of the phase 3 MURANO study.

Undetectable MRD-negativity is associated with extended progression-free survival (PFS) and overall survival in patients receiving chemoimmunotherapy for CLL.

“Attainment of MRD-negativity in relapsed/refractory CLL is also a desired trial endpoint due to the subjectivity of complete response definition regarding pathologic lymph node size,” said Peter Hillmen, MD, of St James’s University Hospital, Leeds, United Kingdom, at the 2018 ASCO Annual Meeting.

Dr Hillmen reported new data on MRD response in cytogenetic and molecular risk groups, MRD sustainability and kinetics, and MRD conversion in the MURANO trial (abstract 7508).

MURANO trial (NCT02005471)

In the trial, venetoclax-rituximab showed superior PFS and peripheral blood and bone marrow MRD-negativity as compared to bendamustine plus rituximab (BR) in relapsed/refractory CLL patients.

Patients were randomized to venetoclax-rituximab for 6 months, followed by single-agent venetoclax for up to 1.5 years, or BR for 6 months. Peripheral blood samples were serially collected and bone marrow was collected at the end of combination treatment or at best response.

MRD findings

The new results show higher concordance in MRD-negativity between bone marrow and peripheral blood in venetoclax-rituximab (45 of 50 patients, 90%) vs BR (3 of 10 patients, 30%) in paired samples.

Focusing on peripheral blood MRD, Dr Hillmen said the best MRD-negativity rates were higher with venetoclax-rituximab (84%) than BR (23%). These results were independent of high-risk factors—such as del 17p, IGVH unmutated, and mutated TP53—only for venetoclax-rituximab treated patients.

“The superior peripheral blood MRD response with venetoclax-rituximab was consistent across subgroups at the end of completion of treatment,” Dr Hillmen said. “Most patients who achieved peripheral blood MRD-negativity on venetoclax-rituximab remained MRD-negative and were progression-free.”

Among 121 of 194 (62%) patients on venetoclax-rituximab who achieved MRD-negativity at the end of combination therapy, 100 (83%) patients maintained MRD-negativity and were progression-free at a median follow-up of 13.8 months. Two patients developed progressive disease and 2 patients died (unrelated to CLL).

Two patients developed Richter’s disease (with one MRD-positive directly before therapy) and 15 (12%) patients converted to confirmed MRD-positive at a median MRD-positive follow-up of 5.6 months.

“High peripheral blood MRD-negativity at the end of combination treatment and concordance with bone marrow MRD with venetoclax-rituximab,” Dr Hillmen said, “confirms the value of peripheral blood MRD for evaluation of treatment benefit in relapsed/refractory CLL patients. The high rate of peripheral blood MRD-negativity at end of combination treatment with venetoclax-rituximab was attained regardless of risk features.”

Some conversion to MRD-positivity occurred only in a small proportion of patients. Most cases were of intermediate level and remained progression-free, he said.

“MRD kinetics indicate that peripheral blood MRD-negativity with venetoclax-rituximab occurs early and is maintained over time with current follow-up,” Dr Hillmen added. The MRD data now provide a framework for designing response adaptive therapy.

The US Food and Drug Administration recently approved venetoclax-rituximab for CLL or small lymphocytic lymphoma for patients with or without del 17p.

Venetoclax is being developed by Genentech and Abbvie. 

©ASCO/Scott Morgan 2018

CHICAGO—Minimal residual disease (MRD) kinetics confirms the high, durable MRD-negativity with venetoclax plus rituximab in relapsed/refractory chronic lymphocytic leukemia (CLL), according to a further examination of the phase 3 MURANO study.

Undetectable MRD-negativity is associated with extended progression-free survival (PFS) and overall survival in patients receiving chemoimmunotherapy for CLL.

“Attainment of MRD-negativity in relapsed/refractory CLL is also a desired trial endpoint due to the subjectivity of complete response definition regarding pathologic lymph node size,” said Peter Hillmen, MD, of St James’s University Hospital, Leeds, United Kingdom, at the 2018 ASCO Annual Meeting.

Dr Hillmen reported new data on MRD response in cytogenetic and molecular risk groups, MRD sustainability and kinetics, and MRD conversion in the MURANO trial (abstract 7508).

MURANO trial (NCT02005471)

In the trial, venetoclax-rituximab showed superior PFS and peripheral blood and bone marrow MRD-negativity as compared to bendamustine plus rituximab (BR) in relapsed/refractory CLL patients.

Patients were randomized to venetoclax-rituximab for 6 months, followed by single-agent venetoclax for up to 1.5 years, or BR for 6 months. Peripheral blood samples were serially collected and bone marrow was collected at the end of combination treatment or at best response.

MRD findings

The new results show higher concordance in MRD-negativity between bone marrow and peripheral blood in venetoclax-rituximab (45 of 50 patients, 90%) vs BR (3 of 10 patients, 30%) in paired samples.

Focusing on peripheral blood MRD, Dr Hillmen said the best MRD-negativity rates were higher with venetoclax-rituximab (84%) than BR (23%). These results were independent of high-risk factors—such as del 17p, IGVH unmutated, and mutated TP53—only for venetoclax-rituximab treated patients.

“The superior peripheral blood MRD response with venetoclax-rituximab was consistent across subgroups at the end of completion of treatment,” Dr Hillmen said. “Most patients who achieved peripheral blood MRD-negativity on venetoclax-rituximab remained MRD-negative and were progression-free.”

Among 121 of 194 (62%) patients on venetoclax-rituximab who achieved MRD-negativity at the end of combination therapy, 100 (83%) patients maintained MRD-negativity and were progression-free at a median follow-up of 13.8 months. Two patients developed progressive disease and 2 patients died (unrelated to CLL).

Two patients developed Richter’s disease (with one MRD-positive directly before therapy) and 15 (12%) patients converted to confirmed MRD-positive at a median MRD-positive follow-up of 5.6 months.

“High peripheral blood MRD-negativity at the end of combination treatment and concordance with bone marrow MRD with venetoclax-rituximab,” Dr Hillmen said, “confirms the value of peripheral blood MRD for evaluation of treatment benefit in relapsed/refractory CLL patients. The high rate of peripheral blood MRD-negativity at end of combination treatment with venetoclax-rituximab was attained regardless of risk features.”

Some conversion to MRD-positivity occurred only in a small proportion of patients. Most cases were of intermediate level and remained progression-free, he said.

“MRD kinetics indicate that peripheral blood MRD-negativity with venetoclax-rituximab occurs early and is maintained over time with current follow-up,” Dr Hillmen added. The MRD data now provide a framework for designing response adaptive therapy.

The US Food and Drug Administration recently approved venetoclax-rituximab for CLL or small lymphocytic lymphoma for patients with or without del 17p.

Venetoclax is being developed by Genentech and Abbvie. 

©ASCO/Scott Morgan 2018

CHICAGO—Minimal residual disease (MRD) kinetics confirms the high, durable MRD-negativity with venetoclax plus rituximab in relapsed/refractory chronic lymphocytic leukemia (CLL), according to a further examination of the phase 3 MURANO study.

Undetectable MRD-negativity is associated with extended progression-free survival (PFS) and overall survival in patients receiving chemoimmunotherapy for CLL.

“Attainment of MRD-negativity in relapsed/refractory CLL is also a desired trial endpoint due to the subjectivity of complete response definition regarding pathologic lymph node size,” said Peter Hillmen, MD, of St James’s University Hospital, Leeds, United Kingdom, at the 2018 ASCO Annual Meeting.

Dr Hillmen reported new data on MRD response in cytogenetic and molecular risk groups, MRD sustainability and kinetics, and MRD conversion in the MURANO trial (abstract 7508).

MURANO trial (NCT02005471)

In the trial, venetoclax-rituximab showed superior PFS and peripheral blood and bone marrow MRD-negativity as compared to bendamustine plus rituximab (BR) in relapsed/refractory CLL patients.

Patients were randomized to venetoclax-rituximab for 6 months, followed by single-agent venetoclax for up to 1.5 years, or BR for 6 months. Peripheral blood samples were serially collected and bone marrow was collected at the end of combination treatment or at best response.

MRD findings

The new results show higher concordance in MRD-negativity between bone marrow and peripheral blood in venetoclax-rituximab (45 of 50 patients, 90%) vs BR (3 of 10 patients, 30%) in paired samples.

Focusing on peripheral blood MRD, Dr Hillmen said the best MRD-negativity rates were higher with venetoclax-rituximab (84%) than BR (23%). These results were independent of high-risk factors—such as del 17p, IGVH unmutated, and mutated TP53—only for venetoclax-rituximab treated patients.

“The superior peripheral blood MRD response with venetoclax-rituximab was consistent across subgroups at the end of completion of treatment,” Dr Hillmen said. “Most patients who achieved peripheral blood MRD-negativity on venetoclax-rituximab remained MRD-negative and were progression-free.”

Among 121 of 194 (62%) patients on venetoclax-rituximab who achieved MRD-negativity at the end of combination therapy, 100 (83%) patients maintained MRD-negativity and were progression-free at a median follow-up of 13.8 months. Two patients developed progressive disease and 2 patients died (unrelated to CLL).

Two patients developed Richter’s disease (with one MRD-positive directly before therapy) and 15 (12%) patients converted to confirmed MRD-positive at a median MRD-positive follow-up of 5.6 months.

“High peripheral blood MRD-negativity at the end of combination treatment and concordance with bone marrow MRD with venetoclax-rituximab,” Dr Hillmen said, “confirms the value of peripheral blood MRD for evaluation of treatment benefit in relapsed/refractory CLL patients. The high rate of peripheral blood MRD-negativity at end of combination treatment with venetoclax-rituximab was attained regardless of risk features.”

Some conversion to MRD-positivity occurred only in a small proportion of patients. Most cases were of intermediate level and remained progression-free, he said.

“MRD kinetics indicate that peripheral blood MRD-negativity with venetoclax-rituximab occurs early and is maintained over time with current follow-up,” Dr Hillmen added. The MRD data now provide a framework for designing response adaptive therapy.

The US Food and Drug Administration recently approved venetoclax-rituximab for CLL or small lymphocytic lymphoma for patients with or without del 17p.

Venetoclax is being developed by Genentech and Abbvie. 

©ASCO/Rodney White 2018

CHICAGO—Prior exposure to blinatumomab does not appear to affect the successful manufacture of KTE-C19 or its efficacy in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), an investigator reported at the 2018 ASCO Annual Meeting.

The clinical benefit of KTE-C19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, was preserved regardless of whether patients were exposed to blinatumomab, said Bijal D. Shah, MD, of Moffitt Cancer Center in Tampa, Florida.

High rates of complete response and undetectable minimal residual disease (MRD) were independent of exposure to blinatumomab, a CD19/CD3 bispecific T-cell engager.

“We feel the results of these data support KTE-C19 as an effective option for adults with refractory leukemia, regardless of prior exposure to CD19-directed therapy,” Dr Shah reported at the meeting (abstract 7006*).

The current standard of care for adults with relapsed/refractory ALL includes blinatumomab, raising the question of whether prior exposure to this CD19-directed treatment could influence the manufacture or efficacy of KTE-C19.

Sara Cooley, MD, of Masonic Medical Center, University of Minnesota in Minneapolis, said results of this analysis suggest prior blinatumomab should not be a contraindication or concern in the context of KTE-C19.

“This remains to be shown with other CAR T-cell therapies,” she said in a presentation at ASCO on cellular therapy in leukemia.

The analysis by Dr Shah and co-investigators was based on ZUMA-3 (NCT02614066), a phase 1 study including adults with relapsed/refractory ALL who received KTE-C19 at doses of 0.5, 1, or 2 x 10⁶ cells/kg.

They excluded patients in the highest dose cohort, who were required to be blinatumomab naïve, per protocol. That left 23 patients who received 0.5 or 1 x 10⁶ cells/kg, of whom 11 had prior blinatumomab exposure and 12 did not.

Best overall response appeared to be independent of prior blinatumomab treatment, with a CR rate of 72% overall, and 63% and 80% for blinatumomab-exposed and blinatumomab-naïve patients, respectively.

The rate of undetectable MRD was likewise high at 88% in the prior blinatumomab group and 100% in the no-blinatumomab group.

Product characteristics did not vary according to blinatumomab exposure, though there was a trend toward a more differentiated phenotype in those patients who had received prior CD19-directed treatment, he said.

There were no significant differences between groups in the rate of grade 3 or greater cytokine release syndrome. Neurologic events were higher in the blinatumomab-naïve patients, though a higher percentage of those patients received the 1 x 10⁶ cells/kg dose, Dr Shah reported.

Investigators also looked at CAR T levels by treatment.

“We cannot appreciate any significant differences between the blinatumomab-naïve and the blinatumomab-exposed groups,” Dr Shah told ASCO attendees.

The ZUMA-3 trial was sponsored by Kite, a Gilead Company. 

*Data in the abstract differ from the presentation.

©ASCO/Rodney White 2018

CHICAGO—Prior exposure to blinatumomab does not appear to affect the successful manufacture of KTE-C19 or its efficacy in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), an investigator reported at the 2018 ASCO Annual Meeting.

The clinical benefit of KTE-C19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, was preserved regardless of whether patients were exposed to blinatumomab, said Bijal D. Shah, MD, of Moffitt Cancer Center in Tampa, Florida.

High rates of complete response and undetectable minimal residual disease (MRD) were independent of exposure to blinatumomab, a CD19/CD3 bispecific T-cell engager.

“We feel the results of these data support KTE-C19 as an effective option for adults with refractory leukemia, regardless of prior exposure to CD19-directed therapy,” Dr Shah reported at the meeting (abstract 7006*).

The current standard of care for adults with relapsed/refractory ALL includes blinatumomab, raising the question of whether prior exposure to this CD19-directed treatment could influence the manufacture or efficacy of KTE-C19.

Sara Cooley, MD, of Masonic Medical Center, University of Minnesota in Minneapolis, said results of this analysis suggest prior blinatumomab should not be a contraindication or concern in the context of KTE-C19.

“This remains to be shown with other CAR T-cell therapies,” she said in a presentation at ASCO on cellular therapy in leukemia.

The analysis by Dr Shah and co-investigators was based on ZUMA-3 (NCT02614066), a phase 1 study including adults with relapsed/refractory ALL who received KTE-C19 at doses of 0.5, 1, or 2 x 10⁶ cells/kg.

They excluded patients in the highest dose cohort, who were required to be blinatumomab naïve, per protocol. That left 23 patients who received 0.5 or 1 x 10⁶ cells/kg, of whom 11 had prior blinatumomab exposure and 12 did not.

Best overall response appeared to be independent of prior blinatumomab treatment, with a CR rate of 72% overall, and 63% and 80% for blinatumomab-exposed and blinatumomab-naïve patients, respectively.

The rate of undetectable MRD was likewise high at 88% in the prior blinatumomab group and 100% in the no-blinatumomab group.

Product characteristics did not vary according to blinatumomab exposure, though there was a trend toward a more differentiated phenotype in those patients who had received prior CD19-directed treatment, he said.

There were no significant differences between groups in the rate of grade 3 or greater cytokine release syndrome. Neurologic events were higher in the blinatumomab-naïve patients, though a higher percentage of those patients received the 1 x 10⁶ cells/kg dose, Dr Shah reported.

Investigators also looked at CAR T levels by treatment.

“We cannot appreciate any significant differences between the blinatumomab-naïve and the blinatumomab-exposed groups,” Dr Shah told ASCO attendees.

The ZUMA-3 trial was sponsored by Kite, a Gilead Company. 

*Data in the abstract differ from the presentation.

©ASCO/Rodney White 2018

CHICAGO—Prior exposure to blinatumomab does not appear to affect the successful manufacture of KTE-C19 or its efficacy in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), an investigator reported at the 2018 ASCO Annual Meeting.

The clinical benefit of KTE-C19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, was preserved regardless of whether patients were exposed to blinatumomab, said Bijal D. Shah, MD, of Moffitt Cancer Center in Tampa, Florida.

High rates of complete response and undetectable minimal residual disease (MRD) were independent of exposure to blinatumomab, a CD19/CD3 bispecific T-cell engager.

“We feel the results of these data support KTE-C19 as an effective option for adults with refractory leukemia, regardless of prior exposure to CD19-directed therapy,” Dr Shah reported at the meeting (abstract 7006*).

The current standard of care for adults with relapsed/refractory ALL includes blinatumomab, raising the question of whether prior exposure to this CD19-directed treatment could influence the manufacture or efficacy of KTE-C19.

Sara Cooley, MD, of Masonic Medical Center, University of Minnesota in Minneapolis, said results of this analysis suggest prior blinatumomab should not be a contraindication or concern in the context of KTE-C19.

“This remains to be shown with other CAR T-cell therapies,” she said in a presentation at ASCO on cellular therapy in leukemia.

The analysis by Dr Shah and co-investigators was based on ZUMA-3 (NCT02614066), a phase 1 study including adults with relapsed/refractory ALL who received KTE-C19 at doses of 0.5, 1, or 2 x 10⁶ cells/kg.

They excluded patients in the highest dose cohort, who were required to be blinatumomab naïve, per protocol. That left 23 patients who received 0.5 or 1 x 10⁶ cells/kg, of whom 11 had prior blinatumomab exposure and 12 did not.

Best overall response appeared to be independent of prior blinatumomab treatment, with a CR rate of 72% overall, and 63% and 80% for blinatumomab-exposed and blinatumomab-naïve patients, respectively.

The rate of undetectable MRD was likewise high at 88% in the prior blinatumomab group and 100% in the no-blinatumomab group.

Product characteristics did not vary according to blinatumomab exposure, though there was a trend toward a more differentiated phenotype in those patients who had received prior CD19-directed treatment, he said.

There were no significant differences between groups in the rate of grade 3 or greater cytokine release syndrome. Neurologic events were higher in the blinatumomab-naïve patients, though a higher percentage of those patients received the 1 x 10⁶ cells/kg dose, Dr Shah reported.

Investigators also looked at CAR T levels by treatment.

“We cannot appreciate any significant differences between the blinatumomab-naïve and the blinatumomab-exposed groups,” Dr Shah told ASCO attendees.

The ZUMA-3 trial was sponsored by Kite, a Gilead Company. 

*Data in the abstract differ from the presentation.

Micrograph showing Hodgkin lymphoma

CHICAGO—Interim PET scans can identify a subset of Hodgkin lymphoma (HL) patients with a better outcome suitable for de-escalation treatment after upfront BEACOPP without impairing disease control, according to final results of the AHL2011-LYSA study.

BEACOPP, compared to ABVD, improves progression-free survival (PFS) but not overall survival (OS) and is associated with a higher risk of myelodysplasia, acute leukemia, and infertility.

Investigators evaluated whether some patients might be able to reduce treatment intensity without compromising the effectiveness of their therapy.

Olivier Casasnovas, MD, of CHU Le Bocage Service d'Hématologie Clinique, Dijon, France,  presented the final analysis at the 2018 ASCO Annual Meeting (abstract 7503).

AHL2011-LYSA study (NCT01358747)

The randomized phase 3 study compared an early PET-driven treatment de-escalation to a non-PET-monitored strategy in patients with advanced-stage HL.

The study included 823 previously untreated patients, median age 30 years (range 16 – 60), with stage III, IV, or high-risk IIB HL.

The PET-driven strategy consisted of 2 BEACOPP* cycles (PET2), followed by 4 cycles of ABVD** for PET2-negative patients, and 4 cycles of BEACOPP for PET2-positive patients.

The experimental PET-driven strategy (410 patients) was randomly compared to a standard treatment delivering 6 cycles of BEACOPP (413 patients). PFS was the primary endpoint with a hypothesis of non-inferiority of the PET-driven arm compared to the standard arm.

Patients characteristics were well balanced between the arms, Dr Casasnovas said. PET2-positivity rate was similar in both arms (experimental 13%, standard 12%).

Based on PET2 results, 346 (84%) patients received 4 cycles of ABVD and 51 (12%) patients received 4 additional cycles of BEACOPP in the experimental arm.

Results

With a median follow-up of 50 months, the 5-year PFS was similar in the standard (86.2%) and the PET-driven arms (85.7%). The 5-year PFS for PET 2-negative/PET 4-negative patients was 90.9%, for PET 2-positive/PET4-negative patients was 75.4%, and for PET 4-positive patients was 46.5%.

The 5-year OS was similar in both arms (96.4% experimental, 95.2% standard).

The treatment toxicity was significantly higher in patients receiving 6 cycles of BEACOPP as compared to those who received 2 cycles of BEACOPP plus 4 cycles of ABVD.

Those who received more cycles of BEACOPP had more frequent grade 3 or higher adverse events than those with fewer cycles, including anemia (11% vs 2%), leukopenia (85% vs 74%), thrombocytopenia (44% vs 15%), and sepsis (7% vs 3%), as well as in serious adverse events (45% vs 28%).

“After 4 cycles of chemotherapy, it [PET positivity] identifies a subset of patients with a particularly poor outcome,” Dr Casasnovas said, “encouraging researchers to develop new treatment options in these patients.”

“PET performed after 2 cycles of BEACOPP escalation can be safely used to guide subsequent treatment,” he concluded.

“This approach allows clinicians to reduce the treatment-related immediate toxicity in most patients,” he added, “and provides similar patient outcomes compared to standard BEACOPP escalation treatment.” 

* Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone

**Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine

Micrograph showing Hodgkin lymphoma

CHICAGO—Interim PET scans can identify a subset of Hodgkin lymphoma (HL) patients with a better outcome suitable for de-escalation treatment after upfront BEACOPP without impairing disease control, according to final results of the AHL2011-LYSA study.

BEACOPP, compared to ABVD, improves progression-free survival (PFS) but not overall survival (OS) and is associated with a higher risk of myelodysplasia, acute leukemia, and infertility.

Investigators evaluated whether some patients might be able to reduce treatment intensity without compromising the effectiveness of their therapy.

Olivier Casasnovas, MD, of CHU Le Bocage Service d'Hématologie Clinique, Dijon, France,  presented the final analysis at the 2018 ASCO Annual Meeting (abstract 7503).

AHL2011-LYSA study (NCT01358747)

The randomized phase 3 study compared an early PET-driven treatment de-escalation to a non-PET-monitored strategy in patients with advanced-stage HL.

The study included 823 previously untreated patients, median age 30 years (range 16 – 60), with stage III, IV, or high-risk IIB HL.

The PET-driven strategy consisted of 2 BEACOPP* cycles (PET2), followed by 4 cycles of ABVD** for PET2-negative patients, and 4 cycles of BEACOPP for PET2-positive patients.

The experimental PET-driven strategy (410 patients) was randomly compared to a standard treatment delivering 6 cycles of BEACOPP (413 patients). PFS was the primary endpoint with a hypothesis of non-inferiority of the PET-driven arm compared to the standard arm.

Patients characteristics were well balanced between the arms, Dr Casasnovas said. PET2-positivity rate was similar in both arms (experimental 13%, standard 12%).

Based on PET2 results, 346 (84%) patients received 4 cycles of ABVD and 51 (12%) patients received 4 additional cycles of BEACOPP in the experimental arm.

Results

With a median follow-up of 50 months, the 5-year PFS was similar in the standard (86.2%) and the PET-driven arms (85.7%). The 5-year PFS for PET 2-negative/PET 4-negative patients was 90.9%, for PET 2-positive/PET4-negative patients was 75.4%, and for PET 4-positive patients was 46.5%.

The 5-year OS was similar in both arms (96.4% experimental, 95.2% standard).

The treatment toxicity was significantly higher in patients receiving 6 cycles of BEACOPP as compared to those who received 2 cycles of BEACOPP plus 4 cycles of ABVD.

Those who received more cycles of BEACOPP had more frequent grade 3 or higher adverse events than those with fewer cycles, including anemia (11% vs 2%), leukopenia (85% vs 74%), thrombocytopenia (44% vs 15%), and sepsis (7% vs 3%), as well as in serious adverse events (45% vs 28%).

“After 4 cycles of chemotherapy, it [PET positivity] identifies a subset of patients with a particularly poor outcome,” Dr Casasnovas said, “encouraging researchers to develop new treatment options in these patients.”

“PET performed after 2 cycles of BEACOPP escalation can be safely used to guide subsequent treatment,” he concluded.

“This approach allows clinicians to reduce the treatment-related immediate toxicity in most patients,” he added, “and provides similar patient outcomes compared to standard BEACOPP escalation treatment.” 

* Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone

**Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine

Micrograph showing Hodgkin lymphoma

CHICAGO—Interim PET scans can identify a subset of Hodgkin lymphoma (HL) patients with a better outcome suitable for de-escalation treatment after upfront BEACOPP without impairing disease control, according to final results of the AHL2011-LYSA study.

BEACOPP, compared to ABVD, improves progression-free survival (PFS) but not overall survival (OS) and is associated with a higher risk of myelodysplasia, acute leukemia, and infertility.

Investigators evaluated whether some patients might be able to reduce treatment intensity without compromising the effectiveness of their therapy.

Olivier Casasnovas, MD, of CHU Le Bocage Service d'Hématologie Clinique, Dijon, France,  presented the final analysis at the 2018 ASCO Annual Meeting (abstract 7503).

AHL2011-LYSA study (NCT01358747)

The randomized phase 3 study compared an early PET-driven treatment de-escalation to a non-PET-monitored strategy in patients with advanced-stage HL.

The study included 823 previously untreated patients, median age 30 years (range 16 – 60), with stage III, IV, or high-risk IIB HL.

The PET-driven strategy consisted of 2 BEACOPP* cycles (PET2), followed by 4 cycles of ABVD** for PET2-negative patients, and 4 cycles of BEACOPP for PET2-positive patients.

The experimental PET-driven strategy (410 patients) was randomly compared to a standard treatment delivering 6 cycles of BEACOPP (413 patients). PFS was the primary endpoint with a hypothesis of non-inferiority of the PET-driven arm compared to the standard arm.

Patients characteristics were well balanced between the arms, Dr Casasnovas said. PET2-positivity rate was similar in both arms (experimental 13%, standard 12%).

Based on PET2 results, 346 (84%) patients received 4 cycles of ABVD and 51 (12%) patients received 4 additional cycles of BEACOPP in the experimental arm.

Results

With a median follow-up of 50 months, the 5-year PFS was similar in the standard (86.2%) and the PET-driven arms (85.7%). The 5-year PFS for PET 2-negative/PET 4-negative patients was 90.9%, for PET 2-positive/PET4-negative patients was 75.4%, and for PET 4-positive patients was 46.5%.

The 5-year OS was similar in both arms (96.4% experimental, 95.2% standard).

The treatment toxicity was significantly higher in patients receiving 6 cycles of BEACOPP as compared to those who received 2 cycles of BEACOPP plus 4 cycles of ABVD.

Those who received more cycles of BEACOPP had more frequent grade 3 or higher adverse events than those with fewer cycles, including anemia (11% vs 2%), leukopenia (85% vs 74%), thrombocytopenia (44% vs 15%), and sepsis (7% vs 3%), as well as in serious adverse events (45% vs 28%).

“After 4 cycles of chemotherapy, it [PET positivity] identifies a subset of patients with a particularly poor outcome,” Dr Casasnovas said, “encouraging researchers to develop new treatment options in these patients.”

“PET performed after 2 cycles of BEACOPP escalation can be safely used to guide subsequent treatment,” he concluded.

“This approach allows clinicians to reduce the treatment-related immediate toxicity in most patients,” he added, “and provides similar patient outcomes compared to standard BEACOPP escalation treatment.” 

* Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone

**Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine

©ASCO/Scott Morgan 2018

CHICAGO—The investigational drug ivosidenib, an inhibitor of the mutant IDH1 enzyme, achieved complete remission (CR) rates of 32% and an overall response rate of 42% in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML) and IDH1 mutation, according to investigators.

In addition, overall survival (OS) in patients who achieved CR more than doubled compared with those in the overall study population.

Fewer patients with CR had febrile neutropenia and infectious complications, and 25% of patients with CR were able to clear the IDH1 clone.

 Duration of response was 6.5 months with the investigational drug.

Investigators reported the grade 3/4 toxicities could be managed with supportive care, were not fatal, and some patients still achieved responses.

IDH1 mutation, first identified almost 10 years ago with the sequencing of the first AML cancer genome, is a recurrent mutation in over 10% of patients with AML.

Mutated IDH1, reported in several malignancies, results in impaired cellular differentiation.  Ivosidenib is a first-in-class oral therapy designed to inhibit the mutant IDH1 enzyme.

Phase 1 study (NCT02074839)

The phase 1 dose-escalation and dose expansion study specifically enrolled patients with R/RAML with mutated IDH1.

Daniel A. Pollyea, MD, of the Colorado University School of Medicine in Aurora, reported the data from 2 of the dose expansion cohorts as well as 35 patients from the dose escalation cohort at the 2018 ASCO Annual Meeting (abstract 7000).

All patients received ivosidenib 500 mg daily.

CR/CRh (CR with partial hematologic recovery; defined as morphologic remission with recovery of neutrophils to at least 500/mm3 and recovery of platelets to at least 50,000/µL) was the primary efficacy endpoint.

Of 179 patients in the primary efficacy cohort, 10% were still receiving treatment at the time of the presentation.

While most patients discontinued due to disease progression, 10% came off therapy for stem cell transplantation. Median duration of treatment was 4 months.

Patients were a median 67 years of age. Approximately 1/3 had secondary AML.

Patients had received a median of 2 prior therapies and approximately 1/4 had relapsed after transplantation.

Fifty-nine percent were refractory to induction or reinduction therapy.

Toxicity

Dr Pollyea considered adverse events to be as expected for a relapsed/refractory AML population.

However, he called out 3 for special mention—leukocytosis, ECG QT prolongation, and IDH differentiation syndrome—none of which was fatal.

Eight percent of patients had grade 3 or 4 leukocytosis, some of which were mechanistically induced from treatment.

About 10% of patients had grade 3 or 4 QT prolongation.

And grade 3 or 4 differentiation syndrome was reported for approximately 5% of patients.

In 19 patients with any grade differentiation syndrome, CR was reported for 5 patients. The message: patients experiencing this adverse event can be managed with supportive care, continue treatment, and still respond.

All adverse events were managed with supportive care measures, including concomitant medications, and ivosidenib dose modifications as required.

CR/CRh was 32% for the efficacy cohort; median time to response was 2 months and median time of response was 8.2 months. CR rate was 24%. Investigator-reported International Working Group categorized ORR was 42%.

The median OS was 9 months for the entire cohort and 18.8 months for patients who achieved CR/CRh.

Dr Pollyea reported that transfusion independence—defined as no need for transfusion for 56 days—was achieved in all CR patients, 75% of CRh patients, and even in a proportion of nonresponders.

Investigtors observed febrile neutropenia and grade 3 or 4 infectious complications in fewer patients who achieved CR/CRh.

Of note was the observation that 23% of patients who achieved CR/CRh were able to clear the mutant IDH1 clone. Patients who did not respond still harbored the IDH1 clone, Dr Pollyea reported.

These results reported at ASCO are an update from those simultaneously published in NEJM.

The study was supported by Agios Pharmaceuticals.

Ivosidenib is being evaluated alone and in combination in other clinical trials. 

©ASCO/Scott Morgan 2018

CHICAGO—The investigational drug ivosidenib, an inhibitor of the mutant IDH1 enzyme, achieved complete remission (CR) rates of 32% and an overall response rate of 42% in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML) and IDH1 mutation, according to investigators.

In addition, overall survival (OS) in patients who achieved CR more than doubled compared with those in the overall study population.

Fewer patients with CR had febrile neutropenia and infectious complications, and 25% of patients with CR were able to clear the IDH1 clone.

 Duration of response was 6.5 months with the investigational drug.

Investigators reported the grade 3/4 toxicities could be managed with supportive care, were not fatal, and some patients still achieved responses.

IDH1 mutation, first identified almost 10 years ago with the sequencing of the first AML cancer genome, is a recurrent mutation in over 10% of patients with AML.

Mutated IDH1, reported in several malignancies, results in impaired cellular differentiation.  Ivosidenib is a first-in-class oral therapy designed to inhibit the mutant IDH1 enzyme.

Phase 1 study (NCT02074839)

The phase 1 dose-escalation and dose expansion study specifically enrolled patients with R/RAML with mutated IDH1.

Daniel A. Pollyea, MD, of the Colorado University School of Medicine in Aurora, reported the data from 2 of the dose expansion cohorts as well as 35 patients from the dose escalation cohort at the 2018 ASCO Annual Meeting (abstract 7000).

All patients received ivosidenib 500 mg daily.

CR/CRh (CR with partial hematologic recovery; defined as morphologic remission with recovery of neutrophils to at least 500/mm3 and recovery of platelets to at least 50,000/µL) was the primary efficacy endpoint.

Of 179 patients in the primary efficacy cohort, 10% were still receiving treatment at the time of the presentation.

While most patients discontinued due to disease progression, 10% came off therapy for stem cell transplantation. Median duration of treatment was 4 months.

Patients were a median 67 years of age. Approximately 1/3 had secondary AML.

Patients had received a median of 2 prior therapies and approximately 1/4 had relapsed after transplantation.

Fifty-nine percent were refractory to induction or reinduction therapy.

Toxicity

Dr Pollyea considered adverse events to be as expected for a relapsed/refractory AML population.

However, he called out 3 for special mention—leukocytosis, ECG QT prolongation, and IDH differentiation syndrome—none of which was fatal.

Eight percent of patients had grade 3 or 4 leukocytosis, some of which were mechanistically induced from treatment.

About 10% of patients had grade 3 or 4 QT prolongation.

And grade 3 or 4 differentiation syndrome was reported for approximately 5% of patients.

In 19 patients with any grade differentiation syndrome, CR was reported for 5 patients. The message: patients experiencing this adverse event can be managed with supportive care, continue treatment, and still respond.

All adverse events were managed with supportive care measures, including concomitant medications, and ivosidenib dose modifications as required.

CR/CRh was 32% for the efficacy cohort; median time to response was 2 months and median time of response was 8.2 months. CR rate was 24%. Investigator-reported International Working Group categorized ORR was 42%.

The median OS was 9 months for the entire cohort and 18.8 months for patients who achieved CR/CRh.

Dr Pollyea reported that transfusion independence—defined as no need for transfusion for 56 days—was achieved in all CR patients, 75% of CRh patients, and even in a proportion of nonresponders.

Investigtors observed febrile neutropenia and grade 3 or 4 infectious complications in fewer patients who achieved CR/CRh.

Of note was the observation that 23% of patients who achieved CR/CRh were able to clear the mutant IDH1 clone. Patients who did not respond still harbored the IDH1 clone, Dr Pollyea reported.

These results reported at ASCO are an update from those simultaneously published in NEJM.

The study was supported by Agios Pharmaceuticals.

Ivosidenib is being evaluated alone and in combination in other clinical trials. 

©ASCO/Scott Morgan 2018

CHICAGO—The investigational drug ivosidenib, an inhibitor of the mutant IDH1 enzyme, achieved complete remission (CR) rates of 32% and an overall response rate of 42% in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML) and IDH1 mutation, according to investigators.

In addition, overall survival (OS) in patients who achieved CR more than doubled compared with those in the overall study population.

Fewer patients with CR had febrile neutropenia and infectious complications, and 25% of patients with CR were able to clear the IDH1 clone.

 Duration of response was 6.5 months with the investigational drug.

Investigators reported the grade 3/4 toxicities could be managed with supportive care, were not fatal, and some patients still achieved responses.

IDH1 mutation, first identified almost 10 years ago with the sequencing of the first AML cancer genome, is a recurrent mutation in over 10% of patients with AML.

Mutated IDH1, reported in several malignancies, results in impaired cellular differentiation.  Ivosidenib is a first-in-class oral therapy designed to inhibit the mutant IDH1 enzyme.

Phase 1 study (NCT02074839)

The phase 1 dose-escalation and dose expansion study specifically enrolled patients with R/RAML with mutated IDH1.

Daniel A. Pollyea, MD, of the Colorado University School of Medicine in Aurora, reported the data from 2 of the dose expansion cohorts as well as 35 patients from the dose escalation cohort at the 2018 ASCO Annual Meeting (abstract 7000).

All patients received ivosidenib 500 mg daily.

CR/CRh (CR with partial hematologic recovery; defined as morphologic remission with recovery of neutrophils to at least 500/mm3 and recovery of platelets to at least 50,000/µL) was the primary efficacy endpoint.

Of 179 patients in the primary efficacy cohort, 10% were still receiving treatment at the time of the presentation.

While most patients discontinued due to disease progression, 10% came off therapy for stem cell transplantation. Median duration of treatment was 4 months.

Patients were a median 67 years of age. Approximately 1/3 had secondary AML.

Patients had received a median of 2 prior therapies and approximately 1/4 had relapsed after transplantation.

Fifty-nine percent were refractory to induction or reinduction therapy.

Toxicity

Dr Pollyea considered adverse events to be as expected for a relapsed/refractory AML population.

However, he called out 3 for special mention—leukocytosis, ECG QT prolongation, and IDH differentiation syndrome—none of which was fatal.

Eight percent of patients had grade 3 or 4 leukocytosis, some of which were mechanistically induced from treatment.

About 10% of patients had grade 3 or 4 QT prolongation.

And grade 3 or 4 differentiation syndrome was reported for approximately 5% of patients.

In 19 patients with any grade differentiation syndrome, CR was reported for 5 patients. The message: patients experiencing this adverse event can be managed with supportive care, continue treatment, and still respond.

All adverse events were managed with supportive care measures, including concomitant medications, and ivosidenib dose modifications as required.

CR/CRh was 32% for the efficacy cohort; median time to response was 2 months and median time of response was 8.2 months. CR rate was 24%. Investigator-reported International Working Group categorized ORR was 42%.

The median OS was 9 months for the entire cohort and 18.8 months for patients who achieved CR/CRh.

Dr Pollyea reported that transfusion independence—defined as no need for transfusion for 56 days—was achieved in all CR patients, 75% of CRh patients, and even in a proportion of nonresponders.

Investigtors observed febrile neutropenia and grade 3 or 4 infectious complications in fewer patients who achieved CR/CRh.

Of note was the observation that 23% of patients who achieved CR/CRh were able to clear the mutant IDH1 clone. Patients who did not respond still harbored the IDH1 clone, Dr Pollyea reported.

These results reported at ASCO are an update from those simultaneously published in NEJM.

The study was supported by Agios Pharmaceuticals.

Ivosidenib is being evaluated alone and in combination in other clinical trials. 

CHICAGO – Preoperative chemotherapy improves outcomes in patients with resectable or borderline resectable pancreatic cancer, preliminary findings from the phase 3 PREOPANC-1 trial suggest.

Overall survival in 127 patients randomized to immediate surgery followed by adjuvant chemotherapy was 13.7 months vs. 17.1 months in 119 patients randomized to receive preoperative chemoradiotherapy and postoperative adjuvant chemotherapy, Geertjan van Tienhoven, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The difference did not quite reach statistical significance, but final analysis requires an additional 26 events, Dr. van Tienhoven of Academic Medical Center, Amsterdam explained in a video interview at the meeting.

Other differences between the groups, which included disease-free survival, local control, and metastasis-free survival, did differ significantly in favor of preoperative chemotherapy, he said.

Of note, 72% and 62% of patients in the immediate surgery and preoperative chemoradiotherapy groups, respectively, underwent resection and a greater proportion of patients in the latter group achieved microscopically complete resection, he said (63% vs. 31%).

Should these results hold up in the final analysis, particularly if the difference in overall survival reaches statistical significance, “then this is a proof of principle and practice-changing trial,” Dr. van Tienhoven said.

Dr. van Tienhoven reported having no disclosures.

SOURCE: van Tienhoven et al. ASCO 2108, Abstract LBA4002.

CHICAGO – Preoperative chemotherapy improves outcomes in patients with resectable or borderline resectable pancreatic cancer, preliminary findings from the phase 3 PREOPANC-1 trial suggest.

Overall survival in 127 patients randomized to immediate surgery followed by adjuvant chemotherapy was 13.7 months vs. 17.1 months in 119 patients randomized to receive preoperative chemoradiotherapy and postoperative adjuvant chemotherapy, Geertjan van Tienhoven, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The difference did not quite reach statistical significance, but final analysis requires an additional 26 events, Dr. van Tienhoven of Academic Medical Center, Amsterdam explained in a video interview at the meeting.

Other differences between the groups, which included disease-free survival, local control, and metastasis-free survival, did differ significantly in favor of preoperative chemotherapy, he said.

Of note, 72% and 62% of patients in the immediate surgery and preoperative chemoradiotherapy groups, respectively, underwent resection and a greater proportion of patients in the latter group achieved microscopically complete resection, he said (63% vs. 31%).

Should these results hold up in the final analysis, particularly if the difference in overall survival reaches statistical significance, “then this is a proof of principle and practice-changing trial,” Dr. van Tienhoven said.

Dr. van Tienhoven reported having no disclosures.

SOURCE: van Tienhoven et al. ASCO 2108, Abstract LBA4002.

CHICAGO – Preoperative chemotherapy improves outcomes in patients with resectable or borderline resectable pancreatic cancer, preliminary findings from the phase 3 PREOPANC-1 trial suggest.

Overall survival in 127 patients randomized to immediate surgery followed by adjuvant chemotherapy was 13.7 months vs. 17.1 months in 119 patients randomized to receive preoperative chemoradiotherapy and postoperative adjuvant chemotherapy, Geertjan van Tienhoven, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The difference did not quite reach statistical significance, but final analysis requires an additional 26 events, Dr. van Tienhoven of Academic Medical Center, Amsterdam explained in a video interview at the meeting.

Other differences between the groups, which included disease-free survival, local control, and metastasis-free survival, did differ significantly in favor of preoperative chemotherapy, he said.

Of note, 72% and 62% of patients in the immediate surgery and preoperative chemoradiotherapy groups, respectively, underwent resection and a greater proportion of patients in the latter group achieved microscopically complete resection, he said (63% vs. 31%).

Should these results hold up in the final analysis, particularly if the difference in overall survival reaches statistical significance, “then this is a proof of principle and practice-changing trial,” Dr. van Tienhoven said.

Dr. van Tienhoven reported having no disclosures.

SOURCE: van Tienhoven et al. ASCO 2108, Abstract LBA4002.

Photo by © ASCO/Zach Boyden-Holmes 2018

CHICAGO—Ibrutinib combined with venetoclax is showing promising clinical activity in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to investigators for the CAPTIVATE study.

In the first 30 patients, 77% of treatment-naïve patients had undetected minimal residual disease (MRD; <10^-4 cells) in the blood and 86% showed a similar response in the bone marrow.

The overall response rate (ORR) was 100% in 11 evaluable patients. The investigators reported this initial data at the 2018 Annual Meeting of the American Society of Clinical Oncology (abstract 7502).

“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” said William G. Wierda, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, who presented the findings at ASCO.

Ibrutinib, a Bruton-kinase inhibitor, has already been approved for the treatment of CLL and venetoclax, a Bcl-2 inhibitor, is currently used to treat relapsed del 17p CLL.

Venetoclax in combination with rituximab was recently approved by the US Food and Drug Administration to treat patients with CLL or small lymphocytic lymphoma whether or not patients have del 17p.

With complementary mechanisms of action and preclinical studies suggesting synergy with the combination, CAPTIVATE was designed to test the efficacy of the oral combination given for 12 cycles.

Study design

 CAPTIVATE (NCT02910583) is an ongoing phase 2 study that enrolled 164 patients with treatment-naïve CLL. Patients first received 3 cycles of ibrutinib monotherapy at the standard dose. This was intended to debulk the disease and reduce risk for venetoclax-associated tumor lysis syndrome (TLS).

Venetoclax 400 mg was initiated at cycle 4. After 12 cycles of the combination, patients with confirmed MRD negativity were randomized to receive ibrutinib with a placebo or to continue with the combination therapy.

In this initial report, Dr Wierda highlighted safety data for all 164 enrolled patients and efficacy data for the first 30 patients who had 6 cycles of combination therapy (MRD assessment cohort).

Dr Wierda also reported bone marrow data for the first 14 patients, who received a total of 12 cycles of the combination and represent the safety run-in cohort.

Ibrutinib and venetoclax show promising activity

 Median age of patients was 58 years; about 2/3 of patients had unmutated IGHV and 1/3 had a creatine clearance of <80 mL/min.

Of 164 patients, 95% remain on therapy, with discontinuations reported for adverse events; one patient had disease progression to Richter’s transformation.

For the MRD evaluation, all 30 patients had 6 months of combination therapy and continue on treatment.

As expected, lead-in with ibrutinib monotherapy debulked the disease.

Investigators observed a reduction in the proportion of patients at high risk for TLS (24% to 3%) and an increase in the proportion of patients at low risk for TLS (12% to 29%).

A similar picture emerged for debulking of lymph node disease. No patient developed clinical TLS.

Other adverse events were consistent with the safety profile of single-agent ibrutinib and venetoclax. No new safety signals were seen.

After 6 cycles of the combination, blood MRD negativity was reported in 77% of the patients in the MRD assessment cohort.

In the safety-run in cohort of 14 patients, blood MRD negativity was reported in 86% of patients after 12 cycles and 93% of patients after 15 cycles of the combination. In these patients, bone marrow MRD negativity was achieved in 86%.

After 12 cycles of combination therapy, the objective response rate was 100% for 11 of the 14 evaluable patients from the safety run-in cohort: 6 patients showed complete remission (CR) or CR with incomplete blood count recovery (CRi) for a CR/CRi of 55%. All patients had confirmed undetectable MRD.

Investigators considered these responses promising and an assessment of the full treatment plan and durability of response are awaited.

The study was sponsored by Pharmacyclics. 

Photo by © ASCO/Zach Boyden-Holmes 2018

CHICAGO—Ibrutinib combined with venetoclax is showing promising clinical activity in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to investigators for the CAPTIVATE study.

In the first 30 patients, 77% of treatment-naïve patients had undetected minimal residual disease (MRD; <10^-4 cells) in the blood and 86% showed a similar response in the bone marrow.

The overall response rate (ORR) was 100% in 11 evaluable patients. The investigators reported this initial data at the 2018 Annual Meeting of the American Society of Clinical Oncology (abstract 7502).

“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” said William G. Wierda, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, who presented the findings at ASCO.

Ibrutinib, a Bruton-kinase inhibitor, has already been approved for the treatment of CLL and venetoclax, a Bcl-2 inhibitor, is currently used to treat relapsed del 17p CLL.

Venetoclax in combination with rituximab was recently approved by the US Food and Drug Administration to treat patients with CLL or small lymphocytic lymphoma whether or not patients have del 17p.

With complementary mechanisms of action and preclinical studies suggesting synergy with the combination, CAPTIVATE was designed to test the efficacy of the oral combination given for 12 cycles.

Study design

 CAPTIVATE (NCT02910583) is an ongoing phase 2 study that enrolled 164 patients with treatment-naïve CLL. Patients first received 3 cycles of ibrutinib monotherapy at the standard dose. This was intended to debulk the disease and reduce risk for venetoclax-associated tumor lysis syndrome (TLS).

Venetoclax 400 mg was initiated at cycle 4. After 12 cycles of the combination, patients with confirmed MRD negativity were randomized to receive ibrutinib with a placebo or to continue with the combination therapy.

In this initial report, Dr Wierda highlighted safety data for all 164 enrolled patients and efficacy data for the first 30 patients who had 6 cycles of combination therapy (MRD assessment cohort).

Dr Wierda also reported bone marrow data for the first 14 patients, who received a total of 12 cycles of the combination and represent the safety run-in cohort.

Ibrutinib and venetoclax show promising activity

 Median age of patients was 58 years; about 2/3 of patients had unmutated IGHV and 1/3 had a creatine clearance of <80 mL/min.

Of 164 patients, 95% remain on therapy, with discontinuations reported for adverse events; one patient had disease progression to Richter’s transformation.

For the MRD evaluation, all 30 patients had 6 months of combination therapy and continue on treatment.

As expected, lead-in with ibrutinib monotherapy debulked the disease.

Investigators observed a reduction in the proportion of patients at high risk for TLS (24% to 3%) and an increase in the proportion of patients at low risk for TLS (12% to 29%).

A similar picture emerged for debulking of lymph node disease. No patient developed clinical TLS.

Other adverse events were consistent with the safety profile of single-agent ibrutinib and venetoclax. No new safety signals were seen.

After 6 cycles of the combination, blood MRD negativity was reported in 77% of the patients in the MRD assessment cohort.

In the safety-run in cohort of 14 patients, blood MRD negativity was reported in 86% of patients after 12 cycles and 93% of patients after 15 cycles of the combination. In these patients, bone marrow MRD negativity was achieved in 86%.

After 12 cycles of combination therapy, the objective response rate was 100% for 11 of the 14 evaluable patients from the safety run-in cohort: 6 patients showed complete remission (CR) or CR with incomplete blood count recovery (CRi) for a CR/CRi of 55%. All patients had confirmed undetectable MRD.

Investigators considered these responses promising and an assessment of the full treatment plan and durability of response are awaited.

The study was sponsored by Pharmacyclics. 

Photo by © ASCO/Zach Boyden-Holmes 2018

CHICAGO—Ibrutinib combined with venetoclax is showing promising clinical activity in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to investigators for the CAPTIVATE study.

In the first 30 patients, 77% of treatment-naïve patients had undetected minimal residual disease (MRD; <10^-4 cells) in the blood and 86% showed a similar response in the bone marrow.

The overall response rate (ORR) was 100% in 11 evaluable patients. The investigators reported this initial data at the 2018 Annual Meeting of the American Society of Clinical Oncology (abstract 7502).

“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” said William G. Wierda, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, who presented the findings at ASCO.

Ibrutinib, a Bruton-kinase inhibitor, has already been approved for the treatment of CLL and venetoclax, a Bcl-2 inhibitor, is currently used to treat relapsed del 17p CLL.

Venetoclax in combination with rituximab was recently approved by the US Food and Drug Administration to treat patients with CLL or small lymphocytic lymphoma whether or not patients have del 17p.

With complementary mechanisms of action and preclinical studies suggesting synergy with the combination, CAPTIVATE was designed to test the efficacy of the oral combination given for 12 cycles.

Study design

 CAPTIVATE (NCT02910583) is an ongoing phase 2 study that enrolled 164 patients with treatment-naïve CLL. Patients first received 3 cycles of ibrutinib monotherapy at the standard dose. This was intended to debulk the disease and reduce risk for venetoclax-associated tumor lysis syndrome (TLS).

Venetoclax 400 mg was initiated at cycle 4. After 12 cycles of the combination, patients with confirmed MRD negativity were randomized to receive ibrutinib with a placebo or to continue with the combination therapy.

In this initial report, Dr Wierda highlighted safety data for all 164 enrolled patients and efficacy data for the first 30 patients who had 6 cycles of combination therapy (MRD assessment cohort).

Dr Wierda also reported bone marrow data for the first 14 patients, who received a total of 12 cycles of the combination and represent the safety run-in cohort.

Ibrutinib and venetoclax show promising activity

 Median age of patients was 58 years; about 2/3 of patients had unmutated IGHV and 1/3 had a creatine clearance of <80 mL/min.

Of 164 patients, 95% remain on therapy, with discontinuations reported for adverse events; one patient had disease progression to Richter’s transformation.

For the MRD evaluation, all 30 patients had 6 months of combination therapy and continue on treatment.

As expected, lead-in with ibrutinib monotherapy debulked the disease.

Investigators observed a reduction in the proportion of patients at high risk for TLS (24% to 3%) and an increase in the proportion of patients at low risk for TLS (12% to 29%).

A similar picture emerged for debulking of lymph node disease. No patient developed clinical TLS.

Other adverse events were consistent with the safety profile of single-agent ibrutinib and venetoclax. No new safety signals were seen.

After 6 cycles of the combination, blood MRD negativity was reported in 77% of the patients in the MRD assessment cohort.

In the safety-run in cohort of 14 patients, blood MRD negativity was reported in 86% of patients after 12 cycles and 93% of patients after 15 cycles of the combination. In these patients, bone marrow MRD negativity was achieved in 86%.

After 12 cycles of combination therapy, the objective response rate was 100% for 11 of the 14 evaluable patients from the safety run-in cohort: 6 patients showed complete remission (CR) or CR with incomplete blood count recovery (CRi) for a CR/CRi of 55%. All patients had confirmed undetectable MRD.

Investigators considered these responses promising and an assessment of the full treatment plan and durability of response are awaited.

The study was sponsored by Pharmacyclics.