2016 ASCO Annual Meeting

CHICAGO – More children treated for high-risk neuroblastoma who received a second autologous stem cell transplant in consolidation after induction chemotherapy were alive after 3 years compared with children getting a single transplant, Dr. Julie R. Park reported at the annual meeting of the American Society of Clinical Oncology.

Neuroblastoma (NB) is the most common extracranial tumor of childhood and arises in the sympathetic nervous system of very young children. Fewer than 50% of children with high-risk NB survive 5 years following today’s multiagent, aggressive therapy. Single autologous hematopoietic stem cell transplant (ASCT) has improved outcomes, and in pilot studies, tandem ASCT appeared tolerable with better efficacy as consolidation therapy for high-risk NB.

The present trial enrolled 665 patients (mean age 3.1 years), who received an induction regimen of six cycles of chemotherapy, with harvest of peripheral blood stem cells after the first two cycles and surgery after five cycles. Patients with adequate stem cell collection, adequate organ function, and no evidence of disease progression were randomized to either standard therapy with a single ASCT with carboplatin, etoposide, melphalan and local radiotherapy (n = 179); or to a double (tandem) ASCT with cyclophosphamide and thiotepa prior to the first ASCT followed 6 weeks later by a dose-modified regimen of carboplatin, etoposide, melphalan and radiotherapy prior to a second ASCT (n = 176). The two transplants were separated by 6-8 weeks.

About 70% of patients in each arm received dinutuximab plus cytokine immunotherapy after their transplants. Dinutuximab is an antibody directed against GD2, an antigen present on neuroblastoma cells. About 38% of patients had high-risk tumors based on the presence of MYCN gene amplification.

The children who were randomized to receive a tandem transplant had a statistically significant, improved event-free survival, with a 3-year event-free survival of 61%, compared to those children receiving a single transplant, with a 3-year event-free survival of 48% (P = .0081), reported Dr. Park, professor of pediatrics at the University of Washington, Seattle.

Three-year overall survival did not differ between the two groups, at 74% for the tandem transplant group and 69% for the single transplant group (P = .185). The study was powered to see a difference in event-free survival, and the study was probably not long enough to detect a difference in overall survival, Dr. Park said.

Anti-GD2 immunotherapy improved both event-free and overall survival for both the tandem and single ASCT groups. At 3 years from the time of the patients’ receiving immunotherapy, event-free survival was 73.7% and 56%, respectively (P = .0033), and overall survival was 83.7% and 74.4% (P = .0322), respectively.

The benefit of tandem transplant occurred without an increase in toxicity or regimen-related mortality. The rates of severe toxicities were similar in the two arms. Two patients receiving a tandem ASCT died, compared with eight receiving a single ASCT.

“This finding will change the way we treat children with high-risk neuroblastoma in North America, which still claims many young lives and is in urgent need of better treatments,” Dr. Park said in a press release.

Dr. Park noted that most NB recurrences happen within 2-3 years from diagnosis and that patients who have not had a recurrence by 3 years have a better chance of long-term survival. Patients in this study will continue to be followed for 10 years.

Dr. Park disclosed ties with Roche. Dr. Hunger reported ties with Merck, Sigma Tau, Jazz Pharmaceuticals, and Spectrum Pharmaceuticals.

CHICAGO – More children treated for high-risk neuroblastoma who received a second autologous stem cell transplant in consolidation after induction chemotherapy were alive after 3 years compared with children getting a single transplant, Dr. Julie R. Park reported at the annual meeting of the American Society of Clinical Oncology.

Neuroblastoma (NB) is the most common extracranial tumor of childhood and arises in the sympathetic nervous system of very young children. Fewer than 50% of children with high-risk NB survive 5 years following today’s multiagent, aggressive therapy. Single autologous hematopoietic stem cell transplant (ASCT) has improved outcomes, and in pilot studies, tandem ASCT appeared tolerable with better efficacy as consolidation therapy for high-risk NB.

The present trial enrolled 665 patients (mean age 3.1 years), who received an induction regimen of six cycles of chemotherapy, with harvest of peripheral blood stem cells after the first two cycles and surgery after five cycles. Patients with adequate stem cell collection, adequate organ function, and no evidence of disease progression were randomized to either standard therapy with a single ASCT with carboplatin, etoposide, melphalan and local radiotherapy (n = 179); or to a double (tandem) ASCT with cyclophosphamide and thiotepa prior to the first ASCT followed 6 weeks later by a dose-modified regimen of carboplatin, etoposide, melphalan and radiotherapy prior to a second ASCT (n = 176). The two transplants were separated by 6-8 weeks.

About 70% of patients in each arm received dinutuximab plus cytokine immunotherapy after their transplants. Dinutuximab is an antibody directed against GD2, an antigen present on neuroblastoma cells. About 38% of patients had high-risk tumors based on the presence of MYCN gene amplification.

The children who were randomized to receive a tandem transplant had a statistically significant, improved event-free survival, with a 3-year event-free survival of 61%, compared to those children receiving a single transplant, with a 3-year event-free survival of 48% (P = .0081), reported Dr. Park, professor of pediatrics at the University of Washington, Seattle.

Three-year overall survival did not differ between the two groups, at 74% for the tandem transplant group and 69% for the single transplant group (P = .185). The study was powered to see a difference in event-free survival, and the study was probably not long enough to detect a difference in overall survival, Dr. Park said.

Anti-GD2 immunotherapy improved both event-free and overall survival for both the tandem and single ASCT groups. At 3 years from the time of the patients’ receiving immunotherapy, event-free survival was 73.7% and 56%, respectively (P = .0033), and overall survival was 83.7% and 74.4% (P = .0322), respectively.

The benefit of tandem transplant occurred without an increase in toxicity or regimen-related mortality. The rates of severe toxicities were similar in the two arms. Two patients receiving a tandem ASCT died, compared with eight receiving a single ASCT.

“This finding will change the way we treat children with high-risk neuroblastoma in North America, which still claims many young lives and is in urgent need of better treatments,” Dr. Park said in a press release.

Dr. Park noted that most NB recurrences happen within 2-3 years from diagnosis and that patients who have not had a recurrence by 3 years have a better chance of long-term survival. Patients in this study will continue to be followed for 10 years.

Dr. Park disclosed ties with Roche. Dr. Hunger reported ties with Merck, Sigma Tau, Jazz Pharmaceuticals, and Spectrum Pharmaceuticals.

CHICAGO – More children treated for high-risk neuroblastoma who received a second autologous stem cell transplant in consolidation after induction chemotherapy were alive after 3 years compared with children getting a single transplant, Dr. Julie R. Park reported at the annual meeting of the American Society of Clinical Oncology.

Neuroblastoma (NB) is the most common extracranial tumor of childhood and arises in the sympathetic nervous system of very young children. Fewer than 50% of children with high-risk NB survive 5 years following today’s multiagent, aggressive therapy. Single autologous hematopoietic stem cell transplant (ASCT) has improved outcomes, and in pilot studies, tandem ASCT appeared tolerable with better efficacy as consolidation therapy for high-risk NB.

The present trial enrolled 665 patients (mean age 3.1 years), who received an induction regimen of six cycles of chemotherapy, with harvest of peripheral blood stem cells after the first two cycles and surgery after five cycles. Patients with adequate stem cell collection, adequate organ function, and no evidence of disease progression were randomized to either standard therapy with a single ASCT with carboplatin, etoposide, melphalan and local radiotherapy (n = 179); or to a double (tandem) ASCT with cyclophosphamide and thiotepa prior to the first ASCT followed 6 weeks later by a dose-modified regimen of carboplatin, etoposide, melphalan and radiotherapy prior to a second ASCT (n = 176). The two transplants were separated by 6-8 weeks.

About 70% of patients in each arm received dinutuximab plus cytokine immunotherapy after their transplants. Dinutuximab is an antibody directed against GD2, an antigen present on neuroblastoma cells. About 38% of patients had high-risk tumors based on the presence of MYCN gene amplification.

The children who were randomized to receive a tandem transplant had a statistically significant, improved event-free survival, with a 3-year event-free survival of 61%, compared to those children receiving a single transplant, with a 3-year event-free survival of 48% (P = .0081), reported Dr. Park, professor of pediatrics at the University of Washington, Seattle.

Three-year overall survival did not differ between the two groups, at 74% for the tandem transplant group and 69% for the single transplant group (P = .185). The study was powered to see a difference in event-free survival, and the study was probably not long enough to detect a difference in overall survival, Dr. Park said.

Anti-GD2 immunotherapy improved both event-free and overall survival for both the tandem and single ASCT groups. At 3 years from the time of the patients’ receiving immunotherapy, event-free survival was 73.7% and 56%, respectively (P = .0033), and overall survival was 83.7% and 74.4% (P = .0322), respectively.

The benefit of tandem transplant occurred without an increase in toxicity or regimen-related mortality. The rates of severe toxicities were similar in the two arms. Two patients receiving a tandem ASCT died, compared with eight receiving a single ASCT.

“This finding will change the way we treat children with high-risk neuroblastoma in North America, which still claims many young lives and is in urgent need of better treatments,” Dr. Park said in a press release.

Dr. Park noted that most NB recurrences happen within 2-3 years from diagnosis and that patients who have not had a recurrence by 3 years have a better chance of long-term survival. Patients in this study will continue to be followed for 10 years.

Dr. Park disclosed ties with Roche. Dr. Hunger reported ties with Merck, Sigma Tau, Jazz Pharmaceuticals, and Spectrum Pharmaceuticals.

CHICAGO – Adding daratumumab to the current two-drug standard of care for relapsed or refractory multiple myeloma dramatically improves outcomes, according to results of an interim analysis of the phase III CASTOR trial.

When added to bortezomib and dexamethasone, the anti-CD38 antibody, which has both direct and indirect antimyeloma activity, reduced the risk of progression or death by 61%, with little increase in toxicity, investigators reported in a plenary session and press briefing at the annual meeting of the American Society of Clinical Oncology.

This magnitude of benefit is “unprecedented in randomized studies that compare novel treatments for relapsed, refractory multiple myeloma,” contended lead investigator Dr. Antonio Palumbo, chief of the multiple myeloma unit at the University of Torino, Italy.

“We hope this [daratumumab combination for myeloma] will be the translation of R-CHOP for lymphoma,” he added, referring to the addition of rituximab to an established backbone regimen. “Daratumumab-DVd [bortezomib-dexamethasone] might be considered today a new standard of care for relapsed and refractory multiple myeloma.”

At present, daratumumab is approved by the Food and Drug Administration for use only after patients have received at least three other therapies, Dr. Palumbo said.

“This study will open the opportunity to have a combination approach after diagnosis, therefore, at first relapse,” he commented, while noting that sufficient evidence should be obtained before using a drug for a new indication. “It’s very important to move as fast as we can this combination into the early phases of disease, where there is the major impact, even from a cost-efficacy point of view.”

The CASTOR findings add to evidence suggesting that daratumumab is synergistic with other myeloma therapies, according to invited discussant Dr. Paul G. Richardson, the R.J. Corman Professor of Medicine, Harvard Medical School, Boston, and the clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston.

“What I think is particularly impressive is the effect on the one-prior-line-of-treatment stratum,” he said, where the reduction in risk of progression or death was 69% with the addition of daratumumab.

Findings from the POLLUX trial, soon to be presented at another meeting, show a similar benefit when daratumumab is added to lenalidomide and dexamethasone in this setting, yielding a 63% reduction in the risk of events, according to Dr. Richardson. Additionally, other anti-CD38 antibodies and immune checkpoint inhibitors are being studied in this disease.

“I would first and foremost emphasize that this is not a zero-sum game. We need all of these drugs and all of these combinations to fight this disease,” he maintained, reviewing the many options now available. “But truly, the advent of the monoclonal antibody platform in this setting has resulted in hazard ratios that are unprecedented,” he agreed.

In CASTOR, 498 patients were randomized evenly to eight cycles of bortezomib (Velcade) plus dexamethasone, either alone or with the addition of daratumumab (Darzalex) given concurrently and then as monotherapy after completion of those cycles.

In the interim analysis, conducted at a median follow-up of about 7 months, the trial met its primary endpoint of progression-free survival: the median time to an event had not been reached with the daratumumab three-drug therapy but was 7.2 months with the standard two-drug therapy (hazard ratio, 0.39; P less than .0001). The difference translated to a more than doubling of the 1-year rate of progression-free survival (60.7% vs. 26.9%).

Benefit was generally consistent across patient subgroups stratified by disease characteristics and previous treatments, although greater impact was seen among the subgroups having earlier-stage or less heavily pretreated disease.

On the basis of these interim findings, patients in the standard therapy arm were allowed to cross over to get daratumumab, according to Dr. Palumbo.

The triple regimen was also associated with a higher overall response rate (83% vs. 63%; P less than .0001) as well as deeper responses, with a doubling in rates of both very good partial response (VGPR) or better and complete response (CR) or better.

“More patients do achieve a profound cytoreduction,” Dr. Palumbo said. “The remission duration is almost [tripled] in patients with a CR or VGPR versus patients with a minimal response or partial response.”

Data for overall survival are not yet mature, but at the time of the analysis, there was also a trend toward fewer deaths with daratumumab than without it (hazard ratio, 0.77).

“Daratumumab did not significantly increase any toxicity that was already present with the combination of bortezomib and dexamethasone,” Dr. Palumbo reported.

The three-drug regimen yielded somewhat higher rates of treatment-emergent thrombocytopenia (59% vs. 44%) and sensory peripheral neuropathy (47% vs. 38%). However, “this was mainly due to the fact that the experimental arm was longer exposed to bortezomib in comparison to the control arm that had a higher proportion of early progressions,” he explained. Additionally, the increase in thrombocytopenia did not translate into increased bleeding.

Forty-five percent of patients in the daratumumab arm had an infusion-related reaction, but nearly all reactions were limited to the first infusion.

The rate of discontinuation because of treatment-emergent adverse events was 7% with daratumumab and 9% without it.

Dr. Palumbo disclosed that he has a consulting or advisory role with and receives honoraria and research funding (institutional) from Genmab, Janssen-Cilag, and Takeda. The trial was sponsored by Janssen Research & Development.

CHICAGO – Adding daratumumab to the current two-drug standard of care for relapsed or refractory multiple myeloma dramatically improves outcomes, according to results of an interim analysis of the phase III CASTOR trial.

When added to bortezomib and dexamethasone, the anti-CD38 antibody, which has both direct and indirect antimyeloma activity, reduced the risk of progression or death by 61%, with little increase in toxicity, investigators reported in a plenary session and press briefing at the annual meeting of the American Society of Clinical Oncology.

This magnitude of benefit is “unprecedented in randomized studies that compare novel treatments for relapsed, refractory multiple myeloma,” contended lead investigator Dr. Antonio Palumbo, chief of the multiple myeloma unit at the University of Torino, Italy.

“We hope this [daratumumab combination for myeloma] will be the translation of R-CHOP for lymphoma,” he added, referring to the addition of rituximab to an established backbone regimen. “Daratumumab-DVd [bortezomib-dexamethasone] might be considered today a new standard of care for relapsed and refractory multiple myeloma.”

At present, daratumumab is approved by the Food and Drug Administration for use only after patients have received at least three other therapies, Dr. Palumbo said.

“This study will open the opportunity to have a combination approach after diagnosis, therefore, at first relapse,” he commented, while noting that sufficient evidence should be obtained before using a drug for a new indication. “It’s very important to move as fast as we can this combination into the early phases of disease, where there is the major impact, even from a cost-efficacy point of view.”

The CASTOR findings add to evidence suggesting that daratumumab is synergistic with other myeloma therapies, according to invited discussant Dr. Paul G. Richardson, the R.J. Corman Professor of Medicine, Harvard Medical School, Boston, and the clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston.

“What I think is particularly impressive is the effect on the one-prior-line-of-treatment stratum,” he said, where the reduction in risk of progression or death was 69% with the addition of daratumumab.

Findings from the POLLUX trial, soon to be presented at another meeting, show a similar benefit when daratumumab is added to lenalidomide and dexamethasone in this setting, yielding a 63% reduction in the risk of events, according to Dr. Richardson. Additionally, other anti-CD38 antibodies and immune checkpoint inhibitors are being studied in this disease.

“I would first and foremost emphasize that this is not a zero-sum game. We need all of these drugs and all of these combinations to fight this disease,” he maintained, reviewing the many options now available. “But truly, the advent of the monoclonal antibody platform in this setting has resulted in hazard ratios that are unprecedented,” he agreed.

In CASTOR, 498 patients were randomized evenly to eight cycles of bortezomib (Velcade) plus dexamethasone, either alone or with the addition of daratumumab (Darzalex) given concurrently and then as monotherapy after completion of those cycles.

In the interim analysis, conducted at a median follow-up of about 7 months, the trial met its primary endpoint of progression-free survival: the median time to an event had not been reached with the daratumumab three-drug therapy but was 7.2 months with the standard two-drug therapy (hazard ratio, 0.39; P less than .0001). The difference translated to a more than doubling of the 1-year rate of progression-free survival (60.7% vs. 26.9%).

Benefit was generally consistent across patient subgroups stratified by disease characteristics and previous treatments, although greater impact was seen among the subgroups having earlier-stage or less heavily pretreated disease.

On the basis of these interim findings, patients in the standard therapy arm were allowed to cross over to get daratumumab, according to Dr. Palumbo.

The triple regimen was also associated with a higher overall response rate (83% vs. 63%; P less than .0001) as well as deeper responses, with a doubling in rates of both very good partial response (VGPR) or better and complete response (CR) or better.

“More patients do achieve a profound cytoreduction,” Dr. Palumbo said. “The remission duration is almost [tripled] in patients with a CR or VGPR versus patients with a minimal response or partial response.”

Data for overall survival are not yet mature, but at the time of the analysis, there was also a trend toward fewer deaths with daratumumab than without it (hazard ratio, 0.77).

“Daratumumab did not significantly increase any toxicity that was already present with the combination of bortezomib and dexamethasone,” Dr. Palumbo reported.

The three-drug regimen yielded somewhat higher rates of treatment-emergent thrombocytopenia (59% vs. 44%) and sensory peripheral neuropathy (47% vs. 38%). However, “this was mainly due to the fact that the experimental arm was longer exposed to bortezomib in comparison to the control arm that had a higher proportion of early progressions,” he explained. Additionally, the increase in thrombocytopenia did not translate into increased bleeding.

Forty-five percent of patients in the daratumumab arm had an infusion-related reaction, but nearly all reactions were limited to the first infusion.

The rate of discontinuation because of treatment-emergent adverse events was 7% with daratumumab and 9% without it.

Dr. Palumbo disclosed that he has a consulting or advisory role with and receives honoraria and research funding (institutional) from Genmab, Janssen-Cilag, and Takeda. The trial was sponsored by Janssen Research & Development.

CHICAGO – Adding daratumumab to the current two-drug standard of care for relapsed or refractory multiple myeloma dramatically improves outcomes, according to results of an interim analysis of the phase III CASTOR trial.

When added to bortezomib and dexamethasone, the anti-CD38 antibody, which has both direct and indirect antimyeloma activity, reduced the risk of progression or death by 61%, with little increase in toxicity, investigators reported in a plenary session and press briefing at the annual meeting of the American Society of Clinical Oncology.

This magnitude of benefit is “unprecedented in randomized studies that compare novel treatments for relapsed, refractory multiple myeloma,” contended lead investigator Dr. Antonio Palumbo, chief of the multiple myeloma unit at the University of Torino, Italy.

“We hope this [daratumumab combination for myeloma] will be the translation of R-CHOP for lymphoma,” he added, referring to the addition of rituximab to an established backbone regimen. “Daratumumab-DVd [bortezomib-dexamethasone] might be considered today a new standard of care for relapsed and refractory multiple myeloma.”

At present, daratumumab is approved by the Food and Drug Administration for use only after patients have received at least three other therapies, Dr. Palumbo said.

“This study will open the opportunity to have a combination approach after diagnosis, therefore, at first relapse,” he commented, while noting that sufficient evidence should be obtained before using a drug for a new indication. “It’s very important to move as fast as we can this combination into the early phases of disease, where there is the major impact, even from a cost-efficacy point of view.”

The CASTOR findings add to evidence suggesting that daratumumab is synergistic with other myeloma therapies, according to invited discussant Dr. Paul G. Richardson, the R.J. Corman Professor of Medicine, Harvard Medical School, Boston, and the clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston.

“What I think is particularly impressive is the effect on the one-prior-line-of-treatment stratum,” he said, where the reduction in risk of progression or death was 69% with the addition of daratumumab.

Findings from the POLLUX trial, soon to be presented at another meeting, show a similar benefit when daratumumab is added to lenalidomide and dexamethasone in this setting, yielding a 63% reduction in the risk of events, according to Dr. Richardson. Additionally, other anti-CD38 antibodies and immune checkpoint inhibitors are being studied in this disease.

“I would first and foremost emphasize that this is not a zero-sum game. We need all of these drugs and all of these combinations to fight this disease,” he maintained, reviewing the many options now available. “But truly, the advent of the monoclonal antibody platform in this setting has resulted in hazard ratios that are unprecedented,” he agreed.

In CASTOR, 498 patients were randomized evenly to eight cycles of bortezomib (Velcade) plus dexamethasone, either alone or with the addition of daratumumab (Darzalex) given concurrently and then as monotherapy after completion of those cycles.

In the interim analysis, conducted at a median follow-up of about 7 months, the trial met its primary endpoint of progression-free survival: the median time to an event had not been reached with the daratumumab three-drug therapy but was 7.2 months with the standard two-drug therapy (hazard ratio, 0.39; P less than .0001). The difference translated to a more than doubling of the 1-year rate of progression-free survival (60.7% vs. 26.9%).

Benefit was generally consistent across patient subgroups stratified by disease characteristics and previous treatments, although greater impact was seen among the subgroups having earlier-stage or less heavily pretreated disease.

On the basis of these interim findings, patients in the standard therapy arm were allowed to cross over to get daratumumab, according to Dr. Palumbo.

The triple regimen was also associated with a higher overall response rate (83% vs. 63%; P less than .0001) as well as deeper responses, with a doubling in rates of both very good partial response (VGPR) or better and complete response (CR) or better.

“More patients do achieve a profound cytoreduction,” Dr. Palumbo said. “The remission duration is almost [tripled] in patients with a CR or VGPR versus patients with a minimal response or partial response.”

Data for overall survival are not yet mature, but at the time of the analysis, there was also a trend toward fewer deaths with daratumumab than without it (hazard ratio, 0.77).

“Daratumumab did not significantly increase any toxicity that was already present with the combination of bortezomib and dexamethasone,” Dr. Palumbo reported.

The three-drug regimen yielded somewhat higher rates of treatment-emergent thrombocytopenia (59% vs. 44%) and sensory peripheral neuropathy (47% vs. 38%). However, “this was mainly due to the fact that the experimental arm was longer exposed to bortezomib in comparison to the control arm that had a higher proportion of early progressions,” he explained. Additionally, the increase in thrombocytopenia did not translate into increased bleeding.

Forty-five percent of patients in the daratumumab arm had an infusion-related reaction, but nearly all reactions were limited to the first infusion.

The rate of discontinuation because of treatment-emergent adverse events was 7% with daratumumab and 9% without it.

Dr. Palumbo disclosed that he has a consulting or advisory role with and receives honoraria and research funding (institutional) from Genmab, Janssen-Cilag, and Takeda. The trial was sponsored by Janssen Research & Development.

Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy. 

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . .  is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.

Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy. 

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . .  is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.

Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy. 

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . .  is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.

CHICAGO – Do anthracyclines still have a role in treating breast cancer? What are the implications for resistance of extending adjuvant aromatase inhibitors to 10 years or beyond? How best to treat women with metastatic hormone receptor–positive breast cancer, in light of findings on CDK 4/6 and mTOR inhibitors? Does sequence matter? In the case of HER2-positive disease, can a trastuzumab biosimilar be as effective as trastuzumab? And does a regimen with TDM-1 do more than reduce toxicity?

Dr. William A. Gradishar and Dr. Hope S. Rugo reflect on these questions and more in a video roundtable at the annual meeting of the American Society of Clinical Oncology.

Dr. William A. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago. He had no disclosures to report. Dr. Hope S. Rugo is professor of medicine at the University of California, San Francisco. She disclosed she is on the Speakers’ Bureau for Genomic Health and receives research funding (institutional) from Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, GlaxoSmithKline, Genentech, Celsion, Nektar, and Merck.

[email protected]

On Twitter @NikolaidesLaura

CHICAGO – Do anthracyclines still have a role in treating breast cancer? What are the implications for resistance of extending adjuvant aromatase inhibitors to 10 years or beyond? How best to treat women with metastatic hormone receptor–positive breast cancer, in light of findings on CDK 4/6 and mTOR inhibitors? Does sequence matter? In the case of HER2-positive disease, can a trastuzumab biosimilar be as effective as trastuzumab? And does a regimen with TDM-1 do more than reduce toxicity?

Dr. William A. Gradishar and Dr. Hope S. Rugo reflect on these questions and more in a video roundtable at the annual meeting of the American Society of Clinical Oncology.

Dr. William A. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago. He had no disclosures to report. Dr. Hope S. Rugo is professor of medicine at the University of California, San Francisco. She disclosed she is on the Speakers’ Bureau for Genomic Health and receives research funding (institutional) from Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, GlaxoSmithKline, Genentech, Celsion, Nektar, and Merck.

[email protected]

On Twitter @NikolaidesLaura

CHICAGO – Do anthracyclines still have a role in treating breast cancer? What are the implications for resistance of extending adjuvant aromatase inhibitors to 10 years or beyond? How best to treat women with metastatic hormone receptor–positive breast cancer, in light of findings on CDK 4/6 and mTOR inhibitors? Does sequence matter? In the case of HER2-positive disease, can a trastuzumab biosimilar be as effective as trastuzumab? And does a regimen with TDM-1 do more than reduce toxicity?

Dr. William A. Gradishar and Dr. Hope S. Rugo reflect on these questions and more in a video roundtable at the annual meeting of the American Society of Clinical Oncology.

Dr. William A. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago. He had no disclosures to report. Dr. Hope S. Rugo is professor of medicine at the University of California, San Francisco. She disclosed she is on the Speakers’ Bureau for Genomic Health and receives research funding (institutional) from Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, GlaxoSmithKline, Genentech, Celsion, Nektar, and Merck.

[email protected]

On Twitter @NikolaidesLaura

CHICAGO – Agents that target the HER2, BRAF, Hedgehog, or EGFR pathways show promise in nonindicated tumor types that harbor these molecular alterations, according to early findings from the MyPathway study.

Of 129 patients enrolled in the multicenter, open-label, phase IIa study, 29 had a major response, defined as tumor shrinkage of at least 30%, to such treatment. One of those patients had a complete response, and 28 had a partial response. An additional 40 patients had stable disease on treatment. Fourteen of the 29 patients progressed after a median of 6 months’ follow-up, and 15 responses were ongoing at up to 11 months, Dr. John D. Hainsworth reported at the annual meeting of the American Society of Clinical Oncology.

©Gio_tto/Thinkstock.com

No new safety signals were observed, said Dr. Hainsworth of Sarah Cannon Research Institute in Nashville, Tenn.

Treatments evaluated in MyPathway included:

• Trastuzumab + pertuzumab, which targets the HER2 pathway and is currently indicated for breast cancer.

• Vemurafenib, which targets the BRAF pathway and is currently indicated for melanoma.

• Vismodegib, which targets the Hedgehog pathway and is currently indicated for basal cell carcinoma of the skin.

• Erlotinib, which targets the EGFR pathway and is indicated for non–small-cell lung cancer.

Responses have been seen with all four of the treatments, but the best responses were seen among patients with HER2 and BRAF abnormalities.

Among 61 cancers with HER2 amplification/overexpression, trastuzumab + pertuzumab provided a benefit for colorectal, bladder, biliary, non–small-cell lung, pancreas, and head/neck cancers.

Of 20 colorectal tumors, 7 (35%) showed complete or partial response, and 3 (15%) remained stable for at least 120 days (clinical benefit rate, 50%). Complete/partial responses and stable disease, respectively, were also seen in three and two of eight bladder tumors (clinical benefit rate, 63%), in three and three of six biliary tumors (clinical benefit rate, 100%), in two and zero of seven non–small-cell lung tumors (clinical benefit rate, 29%), one and zero of six pancreas tumors (clinical benefit rate, 17%), and one and zero of three head and neck tumors (34%). One of 11 other types of tumors showed disease stability at 120 days (clinical benefit rate, 9%). The overall clinical benefit rate in the study was 43%, Dr. Hainsworth said.

Among 33 cancers with the BRAF mutation, vemurafenib showed activity for non–small-cell lung, ovary, unknown primary, colorectal, pancreas, and head/neck tumors. Of 15 non–small-cell lung tumors, 3 (20%) showed complete or partial responses and 2 (13%) remained stable for at least 120 days (clinical benefit rate, 33%). Complete/partial responses and stable disease, respectively, were also seen in one and two of four ovary tumors (clinical benefit rate, 75%), and complete or partial responses were seen in one each of three unknown primary tumors, two colorectal tumors, two pancreas tumors, and one head/neck tumor (clinical benefit rates of 33%, 50%, 50%, and 100%, respectively). No benefit was seen with tumors at other sites (total clinical benefit rate, 36%), Dr. Hainsworth said.

“Of interest in this group [of patients with BRAF mutations], seven of the eight responses were in V600E mutations, and as you know, that’s the mutation that’s been specifically correlated with high response to BRAF inhibition in melanoma where this treatment is now approved,” he said, adding that the response rate in those patients was 38%.

Based on these early results, enrollment of patients with HER2 abnormalities and colorectal, bladder, or biliary cancer, and of patients with BRAF mutations and lung cancer, will be expanded, he said.

Subjects enrolled in MyPathway have advanced cancer showing abnormalities in any of the pathways of interest. The first 129 received a mean of three prior therapies, and in the 29 who responded, 12 different types of cancer responded to the targeted treatment.

“An increasing number of targeted agents for advanced cancer are in use now based on the presence of molecular abnormalities in the cancer. … We’ve known that the same mutations that are in those cancers are found in a wide variety of other cancers, although at a lower incidence, and it’s been difficult to test how effective these same treatments are for the other cancers due to the difficulty in identifying the patient population,” he said, explaining that an increase in comprehensive genomic profiling in recent years has allowed for identification of more and more of these mutations in other cancers.

“I think we’ve shown now that this trial design is feasible, where patients are selected on the basis of molecular abnormalities in their cancers rather than on their primary tumor type or primary site, and certainly offers opportunities for patients with these molecular abnormalities,” Dr. Hainsworth concluded.

Thus far, MyPathway has enrolled more than 200 patients, and is designed to accrue up to 500, with adjustment of treatment groups based on response rates. Emerging new regimens that target these pathways, such as the MEK inhibitor cobemetinib, will also be added, as will new agents targeting additional molecular abnormalities.

The study design, using this “tumor-agnostic approach,” mirrors that of the ASCO-led TAPUR trial, according to ASCO spokesperson Dr. Sumanta Kumar Pal.

The findings of these and other precision medicine trials may ultimately shift the longstanding cancer treatment paradigm, Dr. Pal said.

MyPathway received funding from Genentech. Dr. Hainsworth reported that his institution has received research funding from Astellas Pharma, AstraZeneca, Celgene, Genentech, Johnson & Johnson, Lilly, and Novartis.

[email protected]

CHICAGO – Agents that target the HER2, BRAF, Hedgehog, or EGFR pathways show promise in nonindicated tumor types that harbor these molecular alterations, according to early findings from the MyPathway study.

Of 129 patients enrolled in the multicenter, open-label, phase IIa study, 29 had a major response, defined as tumor shrinkage of at least 30%, to such treatment. One of those patients had a complete response, and 28 had a partial response. An additional 40 patients had stable disease on treatment. Fourteen of the 29 patients progressed after a median of 6 months’ follow-up, and 15 responses were ongoing at up to 11 months, Dr. John D. Hainsworth reported at the annual meeting of the American Society of Clinical Oncology.

©Gio_tto/Thinkstock.com

No new safety signals were observed, said Dr. Hainsworth of Sarah Cannon Research Institute in Nashville, Tenn.

Treatments evaluated in MyPathway included:

• Trastuzumab + pertuzumab, which targets the HER2 pathway and is currently indicated for breast cancer.

• Vemurafenib, which targets the BRAF pathway and is currently indicated for melanoma.

• Vismodegib, which targets the Hedgehog pathway and is currently indicated for basal cell carcinoma of the skin.

• Erlotinib, which targets the EGFR pathway and is indicated for non–small-cell lung cancer.

Responses have been seen with all four of the treatments, but the best responses were seen among patients with HER2 and BRAF abnormalities.

Among 61 cancers with HER2 amplification/overexpression, trastuzumab + pertuzumab provided a benefit for colorectal, bladder, biliary, non–small-cell lung, pancreas, and head/neck cancers.

Of 20 colorectal tumors, 7 (35%) showed complete or partial response, and 3 (15%) remained stable for at least 120 days (clinical benefit rate, 50%). Complete/partial responses and stable disease, respectively, were also seen in three and two of eight bladder tumors (clinical benefit rate, 63%), in three and three of six biliary tumors (clinical benefit rate, 100%), in two and zero of seven non–small-cell lung tumors (clinical benefit rate, 29%), one and zero of six pancreas tumors (clinical benefit rate, 17%), and one and zero of three head and neck tumors (34%). One of 11 other types of tumors showed disease stability at 120 days (clinical benefit rate, 9%). The overall clinical benefit rate in the study was 43%, Dr. Hainsworth said.

Among 33 cancers with the BRAF mutation, vemurafenib showed activity for non–small-cell lung, ovary, unknown primary, colorectal, pancreas, and head/neck tumors. Of 15 non–small-cell lung tumors, 3 (20%) showed complete or partial responses and 2 (13%) remained stable for at least 120 days (clinical benefit rate, 33%). Complete/partial responses and stable disease, respectively, were also seen in one and two of four ovary tumors (clinical benefit rate, 75%), and complete or partial responses were seen in one each of three unknown primary tumors, two colorectal tumors, two pancreas tumors, and one head/neck tumor (clinical benefit rates of 33%, 50%, 50%, and 100%, respectively). No benefit was seen with tumors at other sites (total clinical benefit rate, 36%), Dr. Hainsworth said.

“Of interest in this group [of patients with BRAF mutations], seven of the eight responses were in V600E mutations, and as you know, that’s the mutation that’s been specifically correlated with high response to BRAF inhibition in melanoma where this treatment is now approved,” he said, adding that the response rate in those patients was 38%.

Based on these early results, enrollment of patients with HER2 abnormalities and colorectal, bladder, or biliary cancer, and of patients with BRAF mutations and lung cancer, will be expanded, he said.

Subjects enrolled in MyPathway have advanced cancer showing abnormalities in any of the pathways of interest. The first 129 received a mean of three prior therapies, and in the 29 who responded, 12 different types of cancer responded to the targeted treatment.

“An increasing number of targeted agents for advanced cancer are in use now based on the presence of molecular abnormalities in the cancer. … We’ve known that the same mutations that are in those cancers are found in a wide variety of other cancers, although at a lower incidence, and it’s been difficult to test how effective these same treatments are for the other cancers due to the difficulty in identifying the patient population,” he said, explaining that an increase in comprehensive genomic profiling in recent years has allowed for identification of more and more of these mutations in other cancers.

“I think we’ve shown now that this trial design is feasible, where patients are selected on the basis of molecular abnormalities in their cancers rather than on their primary tumor type or primary site, and certainly offers opportunities for patients with these molecular abnormalities,” Dr. Hainsworth concluded.

Thus far, MyPathway has enrolled more than 200 patients, and is designed to accrue up to 500, with adjustment of treatment groups based on response rates. Emerging new regimens that target these pathways, such as the MEK inhibitor cobemetinib, will also be added, as will new agents targeting additional molecular abnormalities.

The study design, using this “tumor-agnostic approach,” mirrors that of the ASCO-led TAPUR trial, according to ASCO spokesperson Dr. Sumanta Kumar Pal.

The findings of these and other precision medicine trials may ultimately shift the longstanding cancer treatment paradigm, Dr. Pal said.

MyPathway received funding from Genentech. Dr. Hainsworth reported that his institution has received research funding from Astellas Pharma, AstraZeneca, Celgene, Genentech, Johnson & Johnson, Lilly, and Novartis.

[email protected]

CHICAGO – Agents that target the HER2, BRAF, Hedgehog, or EGFR pathways show promise in nonindicated tumor types that harbor these molecular alterations, according to early findings from the MyPathway study.

Of 129 patients enrolled in the multicenter, open-label, phase IIa study, 29 had a major response, defined as tumor shrinkage of at least 30%, to such treatment. One of those patients had a complete response, and 28 had a partial response. An additional 40 patients had stable disease on treatment. Fourteen of the 29 patients progressed after a median of 6 months’ follow-up, and 15 responses were ongoing at up to 11 months, Dr. John D. Hainsworth reported at the annual meeting of the American Society of Clinical Oncology.

©Gio_tto/Thinkstock.com

No new safety signals were observed, said Dr. Hainsworth of Sarah Cannon Research Institute in Nashville, Tenn.

Treatments evaluated in MyPathway included:

• Trastuzumab + pertuzumab, which targets the HER2 pathway and is currently indicated for breast cancer.

• Vemurafenib, which targets the BRAF pathway and is currently indicated for melanoma.

• Vismodegib, which targets the Hedgehog pathway and is currently indicated for basal cell carcinoma of the skin.

• Erlotinib, which targets the EGFR pathway and is indicated for non–small-cell lung cancer.

Responses have been seen with all four of the treatments, but the best responses were seen among patients with HER2 and BRAF abnormalities.

Among 61 cancers with HER2 amplification/overexpression, trastuzumab + pertuzumab provided a benefit for colorectal, bladder, biliary, non–small-cell lung, pancreas, and head/neck cancers.

Of 20 colorectal tumors, 7 (35%) showed complete or partial response, and 3 (15%) remained stable for at least 120 days (clinical benefit rate, 50%). Complete/partial responses and stable disease, respectively, were also seen in three and two of eight bladder tumors (clinical benefit rate, 63%), in three and three of six biliary tumors (clinical benefit rate, 100%), in two and zero of seven non–small-cell lung tumors (clinical benefit rate, 29%), one and zero of six pancreas tumors (clinical benefit rate, 17%), and one and zero of three head and neck tumors (34%). One of 11 other types of tumors showed disease stability at 120 days (clinical benefit rate, 9%). The overall clinical benefit rate in the study was 43%, Dr. Hainsworth said.

Among 33 cancers with the BRAF mutation, vemurafenib showed activity for non–small-cell lung, ovary, unknown primary, colorectal, pancreas, and head/neck tumors. Of 15 non–small-cell lung tumors, 3 (20%) showed complete or partial responses and 2 (13%) remained stable for at least 120 days (clinical benefit rate, 33%). Complete/partial responses and stable disease, respectively, were also seen in one and two of four ovary tumors (clinical benefit rate, 75%), and complete or partial responses were seen in one each of three unknown primary tumors, two colorectal tumors, two pancreas tumors, and one head/neck tumor (clinical benefit rates of 33%, 50%, 50%, and 100%, respectively). No benefit was seen with tumors at other sites (total clinical benefit rate, 36%), Dr. Hainsworth said.

“Of interest in this group [of patients with BRAF mutations], seven of the eight responses were in V600E mutations, and as you know, that’s the mutation that’s been specifically correlated with high response to BRAF inhibition in melanoma where this treatment is now approved,” he said, adding that the response rate in those patients was 38%.

Based on these early results, enrollment of patients with HER2 abnormalities and colorectal, bladder, or biliary cancer, and of patients with BRAF mutations and lung cancer, will be expanded, he said.

Subjects enrolled in MyPathway have advanced cancer showing abnormalities in any of the pathways of interest. The first 129 received a mean of three prior therapies, and in the 29 who responded, 12 different types of cancer responded to the targeted treatment.

“An increasing number of targeted agents for advanced cancer are in use now based on the presence of molecular abnormalities in the cancer. … We’ve known that the same mutations that are in those cancers are found in a wide variety of other cancers, although at a lower incidence, and it’s been difficult to test how effective these same treatments are for the other cancers due to the difficulty in identifying the patient population,” he said, explaining that an increase in comprehensive genomic profiling in recent years has allowed for identification of more and more of these mutations in other cancers.

“I think we’ve shown now that this trial design is feasible, where patients are selected on the basis of molecular abnormalities in their cancers rather than on their primary tumor type or primary site, and certainly offers opportunities for patients with these molecular abnormalities,” Dr. Hainsworth concluded.

Thus far, MyPathway has enrolled more than 200 patients, and is designed to accrue up to 500, with adjustment of treatment groups based on response rates. Emerging new regimens that target these pathways, such as the MEK inhibitor cobemetinib, will also be added, as will new agents targeting additional molecular abnormalities.

The study design, using this “tumor-agnostic approach,” mirrors that of the ASCO-led TAPUR trial, according to ASCO spokesperson Dr. Sumanta Kumar Pal.

The findings of these and other precision medicine trials may ultimately shift the longstanding cancer treatment paradigm, Dr. Pal said.

MyPathway received funding from Genentech. Dr. Hainsworth reported that his institution has received research funding from Astellas Pharma, AstraZeneca, Celgene, Genentech, Johnson & Johnson, Lilly, and Novartis.

[email protected]

CHICAGO – Adding the cytokine IL-2 to front-line therapy with the anti-GD2 antibody ch14.18/CHO provided no additional survival benefit and only added to toxicity in the treatment of pediatric patients with high-risk neuroblastoma (NB), Dr. Ruth Ladenstein reported at the annual meeting of the American Society of Clinical Oncology.

A form of the antibody (dinutuximab) is approved for use in combination with granulocyte-macrophage colony stimulating factor, IL-2, and 13-cis-retinoic acid (RA) to treat high risk NB. A previous study (N Engl J Med. 2010;363:1324-34) showed that a combination of ch14.18 and the cytokines improved event free survival to 66% at 2 years, but the role of cytokines in this context remained unclear. Dr. Ladenstein and associates therefore performed a phase III trial that randomized patients to the antibody with or without subcutaneous (sc) IL-2.

High-risk NB was defined as patients with International Neuroblastoma Staging System stage 4 disease 1 year old or older, stage 4 less than 1 year old with MYCN amplification, or stage 2,3 patients up to age 21 years with MYCN amplification. Patients underwent a rapid induction therapy, followed by peripheral stem cell harvest, local control with complete tumor resection, myeloablative therapy with peripheral stem cell transplant, local control with radiotherapy, and then ch14.18 anti-GD2 monoclonal immunotherapy with RA, with or without sc IL-2.

Inclusion criteria were a complete response or partial response with three or fewer skeletal metastatic spots and no positive bone marrow biopsies on two aspirates. Randomization occurred between day 60 and 90 post stem cell infusion. RA was given on days 1-14 post randomization. For the arm receiving IL-2, it was given as 5 daily injections of 6 x 106 IU/m² per day over 8 hours on days 15-19. IL-2 was repeated on days 22-26. Both groups also received the ch14.18 antibody on days 22-26. All patients received high-dose morphine for pain management.

For event free survival (EFS), the primary endpoint of the trial, “if we look at 3 years, we see with antibody alone it’s 57%. With IL-2, it’s 60%. It’s completely clear that there’s no superiority for the IL-2 arm,” said Dr. Ladenstein, professor of pediatrics at the Children’s Cancer Research Institute, Austria.

At 5 years, the EFS was no different for the two treatment arms, at 51% for antibody alone and 56% for antibody plus IL-2 (P = .561). There were 199/200 patients in the antibody-alone arm with follow-up after randomization and 203/206 in the antibody plus IL-2 arm. The same was true for the secondary endpoint of overall survival, with 66% survival with antibody-alone and 58% in the antibody plus IL-2 at 5 years.

The EFS for patients with a complete response prior to immunotherapy was 66% at 3 years and was 50% for patients with less than a complete response, a significant difference (P = .003) in favor of those with a complete response. IL-2 administration had no effect on the EFS of the patients with a complete response if it was given with the immunotherapy. Similarly, IL-2 made no difference for patients who had had a very good partial response or a partial response prior to immunotherapy. For complete, very good partial, or partial responses prior to immunotherapy, the overall response to immunotherapy was 51%.

“However, feasibility is a concern, particularly in the IL-2 arm. Only 61% of the cycles were completed whereas it was 85% in the antibody-only arm, and the interruptions are definitely related mainly to the IL-2 component,” Dr. Ladenstein said.

Toxicity was higher for those patients receiving IL-2 compared to those getting antibody alone: Lansky performance status of 30% or less was 41% vs. 17%, early termination of therapy was 39% vs. 15%, and Common Terminology Criteria grade 3/4 fever was 41% vs. 14%, respectively (all P less than .001). There were also significantly more grade 3/4 allergic reactions and incidences of capillary leak, as well as diarrhea, hypotension, central nervous toxicity, and pain with IL-2.

The outcomes were favorable with antibody immunotherapy alone, but the higher toxicity with IL-2 shows that “a less toxic treatment schedule therefore is needed for this late treatment phase,” Dr. Ladenstein said.

Commenting on the trial, Dr. Barbara Hero of University Children’s Hospital in Cologne, Germany, asked whether cytokines are a useful part of the regimen “because we know the cytokines add quite a lot of toxicity to the regimens.” Even if they are potentially useful, researchers still do not know which cytokines, route of administration, and at what doses and timing would be best. Also, it is not known if a different induction regimen or antibody treatment could make a difference in using cytokines.

Another question is whether cytokines may be of benefit in patients with a higher tumor burden, e.g., more than three skeletal spots, used as the eligibility cut-off in this trial, Dr. Hero said.

CHICAGO – Adding the cytokine IL-2 to front-line therapy with the anti-GD2 antibody ch14.18/CHO provided no additional survival benefit and only added to toxicity in the treatment of pediatric patients with high-risk neuroblastoma (NB), Dr. Ruth Ladenstein reported at the annual meeting of the American Society of Clinical Oncology.

A form of the antibody (dinutuximab) is approved for use in combination with granulocyte-macrophage colony stimulating factor, IL-2, and 13-cis-retinoic acid (RA) to treat high risk NB. A previous study (N Engl J Med. 2010;363:1324-34) showed that a combination of ch14.18 and the cytokines improved event free survival to 66% at 2 years, but the role of cytokines in this context remained unclear. Dr. Ladenstein and associates therefore performed a phase III trial that randomized patients to the antibody with or without subcutaneous (sc) IL-2.

High-risk NB was defined as patients with International Neuroblastoma Staging System stage 4 disease 1 year old or older, stage 4 less than 1 year old with MYCN amplification, or stage 2,3 patients up to age 21 years with MYCN amplification. Patients underwent a rapid induction therapy, followed by peripheral stem cell harvest, local control with complete tumor resection, myeloablative therapy with peripheral stem cell transplant, local control with radiotherapy, and then ch14.18 anti-GD2 monoclonal immunotherapy with RA, with or without sc IL-2.

Inclusion criteria were a complete response or partial response with three or fewer skeletal metastatic spots and no positive bone marrow biopsies on two aspirates. Randomization occurred between day 60 and 90 post stem cell infusion. RA was given on days 1-14 post randomization. For the arm receiving IL-2, it was given as 5 daily injections of 6 x 106 IU/m² per day over 8 hours on days 15-19. IL-2 was repeated on days 22-26. Both groups also received the ch14.18 antibody on days 22-26. All patients received high-dose morphine for pain management.

For event free survival (EFS), the primary endpoint of the trial, “if we look at 3 years, we see with antibody alone it’s 57%. With IL-2, it’s 60%. It’s completely clear that there’s no superiority for the IL-2 arm,” said Dr. Ladenstein, professor of pediatrics at the Children’s Cancer Research Institute, Austria.

At 5 years, the EFS was no different for the two treatment arms, at 51% for antibody alone and 56% for antibody plus IL-2 (P = .561). There were 199/200 patients in the antibody-alone arm with follow-up after randomization and 203/206 in the antibody plus IL-2 arm. The same was true for the secondary endpoint of overall survival, with 66% survival with antibody-alone and 58% in the antibody plus IL-2 at 5 years.

The EFS for patients with a complete response prior to immunotherapy was 66% at 3 years and was 50% for patients with less than a complete response, a significant difference (P = .003) in favor of those with a complete response. IL-2 administration had no effect on the EFS of the patients with a complete response if it was given with the immunotherapy. Similarly, IL-2 made no difference for patients who had had a very good partial response or a partial response prior to immunotherapy. For complete, very good partial, or partial responses prior to immunotherapy, the overall response to immunotherapy was 51%.

“However, feasibility is a concern, particularly in the IL-2 arm. Only 61% of the cycles were completed whereas it was 85% in the antibody-only arm, and the interruptions are definitely related mainly to the IL-2 component,” Dr. Ladenstein said.

Toxicity was higher for those patients receiving IL-2 compared to those getting antibody alone: Lansky performance status of 30% or less was 41% vs. 17%, early termination of therapy was 39% vs. 15%, and Common Terminology Criteria grade 3/4 fever was 41% vs. 14%, respectively (all P less than .001). There were also significantly more grade 3/4 allergic reactions and incidences of capillary leak, as well as diarrhea, hypotension, central nervous toxicity, and pain with IL-2.

The outcomes were favorable with antibody immunotherapy alone, but the higher toxicity with IL-2 shows that “a less toxic treatment schedule therefore is needed for this late treatment phase,” Dr. Ladenstein said.

Commenting on the trial, Dr. Barbara Hero of University Children’s Hospital in Cologne, Germany, asked whether cytokines are a useful part of the regimen “because we know the cytokines add quite a lot of toxicity to the regimens.” Even if they are potentially useful, researchers still do not know which cytokines, route of administration, and at what doses and timing would be best. Also, it is not known if a different induction regimen or antibody treatment could make a difference in using cytokines.

Another question is whether cytokines may be of benefit in patients with a higher tumor burden, e.g., more than three skeletal spots, used as the eligibility cut-off in this trial, Dr. Hero said.

CHICAGO – Adding the cytokine IL-2 to front-line therapy with the anti-GD2 antibody ch14.18/CHO provided no additional survival benefit and only added to toxicity in the treatment of pediatric patients with high-risk neuroblastoma (NB), Dr. Ruth Ladenstein reported at the annual meeting of the American Society of Clinical Oncology.

A form of the antibody (dinutuximab) is approved for use in combination with granulocyte-macrophage colony stimulating factor, IL-2, and 13-cis-retinoic acid (RA) to treat high risk NB. A previous study (N Engl J Med. 2010;363:1324-34) showed that a combination of ch14.18 and the cytokines improved event free survival to 66% at 2 years, but the role of cytokines in this context remained unclear. Dr. Ladenstein and associates therefore performed a phase III trial that randomized patients to the antibody with or without subcutaneous (sc) IL-2.

High-risk NB was defined as patients with International Neuroblastoma Staging System stage 4 disease 1 year old or older, stage 4 less than 1 year old with MYCN amplification, or stage 2,3 patients up to age 21 years with MYCN amplification. Patients underwent a rapid induction therapy, followed by peripheral stem cell harvest, local control with complete tumor resection, myeloablative therapy with peripheral stem cell transplant, local control with radiotherapy, and then ch14.18 anti-GD2 monoclonal immunotherapy with RA, with or without sc IL-2.

Inclusion criteria were a complete response or partial response with three or fewer skeletal metastatic spots and no positive bone marrow biopsies on two aspirates. Randomization occurred between day 60 and 90 post stem cell infusion. RA was given on days 1-14 post randomization. For the arm receiving IL-2, it was given as 5 daily injections of 6 x 106 IU/m² per day over 8 hours on days 15-19. IL-2 was repeated on days 22-26. Both groups also received the ch14.18 antibody on days 22-26. All patients received high-dose morphine for pain management.

For event free survival (EFS), the primary endpoint of the trial, “if we look at 3 years, we see with antibody alone it’s 57%. With IL-2, it’s 60%. It’s completely clear that there’s no superiority for the IL-2 arm,” said Dr. Ladenstein, professor of pediatrics at the Children’s Cancer Research Institute, Austria.

At 5 years, the EFS was no different for the two treatment arms, at 51% for antibody alone and 56% for antibody plus IL-2 (P = .561). There were 199/200 patients in the antibody-alone arm with follow-up after randomization and 203/206 in the antibody plus IL-2 arm. The same was true for the secondary endpoint of overall survival, with 66% survival with antibody-alone and 58% in the antibody plus IL-2 at 5 years.

The EFS for patients with a complete response prior to immunotherapy was 66% at 3 years and was 50% for patients with less than a complete response, a significant difference (P = .003) in favor of those with a complete response. IL-2 administration had no effect on the EFS of the patients with a complete response if it was given with the immunotherapy. Similarly, IL-2 made no difference for patients who had had a very good partial response or a partial response prior to immunotherapy. For complete, very good partial, or partial responses prior to immunotherapy, the overall response to immunotherapy was 51%.

“However, feasibility is a concern, particularly in the IL-2 arm. Only 61% of the cycles were completed whereas it was 85% in the antibody-only arm, and the interruptions are definitely related mainly to the IL-2 component,” Dr. Ladenstein said.

Toxicity was higher for those patients receiving IL-2 compared to those getting antibody alone: Lansky performance status of 30% or less was 41% vs. 17%, early termination of therapy was 39% vs. 15%, and Common Terminology Criteria grade 3/4 fever was 41% vs. 14%, respectively (all P less than .001). There were also significantly more grade 3/4 allergic reactions and incidences of capillary leak, as well as diarrhea, hypotension, central nervous toxicity, and pain with IL-2.

The outcomes were favorable with antibody immunotherapy alone, but the higher toxicity with IL-2 shows that “a less toxic treatment schedule therefore is needed for this late treatment phase,” Dr. Ladenstein said.

Commenting on the trial, Dr. Barbara Hero of University Children’s Hospital in Cologne, Germany, asked whether cytokines are a useful part of the regimen “because we know the cytokines add quite a lot of toxicity to the regimens.” Even if they are potentially useful, researchers still do not know which cytokines, route of administration, and at what doses and timing would be best. Also, it is not known if a different induction regimen or antibody treatment could make a difference in using cytokines.

Another question is whether cytokines may be of benefit in patients with a higher tumor burden, e.g., more than three skeletal spots, used as the eligibility cut-off in this trial, Dr. Hero said.

CHICAGO – After 2 years of maintenance immunotherapy with rituximab, elderly patients with chronic lymphocytic leukemia had better rates of progression-free survival than did patients in an observation group, based on results of the CLL 2007 SA trial from the French FILO (French Innovative Leukemia Organisation) Group.

The two groups did not significantly differ in overall survival, however, with 92.6% estimated 3-year overall survival in the rituximab group and 87.2% in the observation group. Further, the patients given rituximab had more adverse events, based on data presented by Dr. Caroline Dartigeas of the University Hospital in Tours, France, at the annual meeting of the American Society of Clinical Oncology.

Mary Jo Dales/Frontline Medical News

Given the cost and risk for events with rituximab, the findings raise the question of whether there are any meaningful benefits for maintenance rituximab after induction therapy, Dr. Jonathan W. Friedberg of the University of Rochester, N.Y., who was the discussant of the paper, remarked after the presentation. He asked whether there is any evidence that patients feel better if they’re in remission and, thus, their quality of life is improved.

The study included fit, treatment-naive patients aged 65 years and older with B-cell CLL who lacked del17p. Median patient age was 71.3 years, and two-thirds of the patients were men.

Patients received four cycles of induction therapy with fludarabine, cyclophosphamide, and rituximab on a shortened schedule chosen to reduce the risk of cumulative toxicity. At randomization, patients were stratified for immunoglobulin heavy chain variable (IGHV) status (54.8% of patients had unmutated status) and del11q (21.3% of patients had the deletion). Patients who had complete (25.7% of patients) or partial (62.8% of patients) responses were randomly allocated to either maintenance rituximab (202 patients given 500 mg/m² twice per month for 2 years) or to observation (207 patients). Median follow-up from randomization was 43.6 months.

Median progression-free survival in the rituximab arm was 59.3 months (95% confidence interval, 49.6; not reached), compared with 49 months (95% CI, 40.9-60.5) in the observation group (hazard ratio, 0.597; 95% CI, 0.437-0.814; P = .0011), corresponding to 3-year progression-free survival of 83% and 64.2% in each arm, respectively.

Mary Jo Dales/Frontline Medical News

Estimated overall survival at 3 years was 92.6% with rituximab maintenance and 87.2% in the observation group. Rituximab maintenance significantly improved progression-free survival in patients with and without del11q and in those with unmutated IGHV.

Serious adverse events for hematologic toxicity were seen in 6.9% of rituximab-treated patients and 1.9% of patients in the observation group (P = .027). Serious adverse events for infectious toxicity occurred in 18.8% of rituximab-treated patients and 10.1% of the observation group (P = .036). There were 69 deaths post randomization: 32 in the rituximab-treated group and 37 in the observation group. Secondary cancers, excluding basal cell carcinomas of the skin, occurred in 15.3% of the rituximab arm, including five cases of myelodysplastic syndrome, and in 11.1% of the observation group, including three cases of myelodysplastic syndrome.

Dr. Dartigeas is a consultant to Gilead Sciences and has provided expert testimony for Roche/Genentech. Genentech and Biogen jointly market rituximab (Rituxan).

[email protected]

On Twitter @maryjodales

CHICAGO – After 2 years of maintenance immunotherapy with rituximab, elderly patients with chronic lymphocytic leukemia had better rates of progression-free survival than did patients in an observation group, based on results of the CLL 2007 SA trial from the French FILO (French Innovative Leukemia Organisation) Group.

The two groups did not significantly differ in overall survival, however, with 92.6% estimated 3-year overall survival in the rituximab group and 87.2% in the observation group. Further, the patients given rituximab had more adverse events, based on data presented by Dr. Caroline Dartigeas of the University Hospital in Tours, France, at the annual meeting of the American Society of Clinical Oncology.

Mary Jo Dales/Frontline Medical News

Given the cost and risk for events with rituximab, the findings raise the question of whether there are any meaningful benefits for maintenance rituximab after induction therapy, Dr. Jonathan W. Friedberg of the University of Rochester, N.Y., who was the discussant of the paper, remarked after the presentation. He asked whether there is any evidence that patients feel better if they’re in remission and, thus, their quality of life is improved.

The study included fit, treatment-naive patients aged 65 years and older with B-cell CLL who lacked del17p. Median patient age was 71.3 years, and two-thirds of the patients were men.

Patients received four cycles of induction therapy with fludarabine, cyclophosphamide, and rituximab on a shortened schedule chosen to reduce the risk of cumulative toxicity. At randomization, patients were stratified for immunoglobulin heavy chain variable (IGHV) status (54.8% of patients had unmutated status) and del11q (21.3% of patients had the deletion). Patients who had complete (25.7% of patients) or partial (62.8% of patients) responses were randomly allocated to either maintenance rituximab (202 patients given 500 mg/m² twice per month for 2 years) or to observation (207 patients). Median follow-up from randomization was 43.6 months.

Median progression-free survival in the rituximab arm was 59.3 months (95% confidence interval, 49.6; not reached), compared with 49 months (95% CI, 40.9-60.5) in the observation group (hazard ratio, 0.597; 95% CI, 0.437-0.814; P = .0011), corresponding to 3-year progression-free survival of 83% and 64.2% in each arm, respectively.

Mary Jo Dales/Frontline Medical News

Estimated overall survival at 3 years was 92.6% with rituximab maintenance and 87.2% in the observation group. Rituximab maintenance significantly improved progression-free survival in patients with and without del11q and in those with unmutated IGHV.

Serious adverse events for hematologic toxicity were seen in 6.9% of rituximab-treated patients and 1.9% of patients in the observation group (P = .027). Serious adverse events for infectious toxicity occurred in 18.8% of rituximab-treated patients and 10.1% of the observation group (P = .036). There were 69 deaths post randomization: 32 in the rituximab-treated group and 37 in the observation group. Secondary cancers, excluding basal cell carcinomas of the skin, occurred in 15.3% of the rituximab arm, including five cases of myelodysplastic syndrome, and in 11.1% of the observation group, including three cases of myelodysplastic syndrome.

Dr. Dartigeas is a consultant to Gilead Sciences and has provided expert testimony for Roche/Genentech. Genentech and Biogen jointly market rituximab (Rituxan).

[email protected]

On Twitter @maryjodales

CHICAGO – After 2 years of maintenance immunotherapy with rituximab, elderly patients with chronic lymphocytic leukemia had better rates of progression-free survival than did patients in an observation group, based on results of the CLL 2007 SA trial from the French FILO (French Innovative Leukemia Organisation) Group.

The two groups did not significantly differ in overall survival, however, with 92.6% estimated 3-year overall survival in the rituximab group and 87.2% in the observation group. Further, the patients given rituximab had more adverse events, based on data presented by Dr. Caroline Dartigeas of the University Hospital in Tours, France, at the annual meeting of the American Society of Clinical Oncology.

Mary Jo Dales/Frontline Medical News

Given the cost and risk for events with rituximab, the findings raise the question of whether there are any meaningful benefits for maintenance rituximab after induction therapy, Dr. Jonathan W. Friedberg of the University of Rochester, N.Y., who was the discussant of the paper, remarked after the presentation. He asked whether there is any evidence that patients feel better if they’re in remission and, thus, their quality of life is improved.

The study included fit, treatment-naive patients aged 65 years and older with B-cell CLL who lacked del17p. Median patient age was 71.3 years, and two-thirds of the patients were men.

Patients received four cycles of induction therapy with fludarabine, cyclophosphamide, and rituximab on a shortened schedule chosen to reduce the risk of cumulative toxicity. At randomization, patients were stratified for immunoglobulin heavy chain variable (IGHV) status (54.8% of patients had unmutated status) and del11q (21.3% of patients had the deletion). Patients who had complete (25.7% of patients) or partial (62.8% of patients) responses were randomly allocated to either maintenance rituximab (202 patients given 500 mg/m² twice per month for 2 years) or to observation (207 patients). Median follow-up from randomization was 43.6 months.

Median progression-free survival in the rituximab arm was 59.3 months (95% confidence interval, 49.6; not reached), compared with 49 months (95% CI, 40.9-60.5) in the observation group (hazard ratio, 0.597; 95% CI, 0.437-0.814; P = .0011), corresponding to 3-year progression-free survival of 83% and 64.2% in each arm, respectively.

Mary Jo Dales/Frontline Medical News

Estimated overall survival at 3 years was 92.6% with rituximab maintenance and 87.2% in the observation group. Rituximab maintenance significantly improved progression-free survival in patients with and without del11q and in those with unmutated IGHV.

Serious adverse events for hematologic toxicity were seen in 6.9% of rituximab-treated patients and 1.9% of patients in the observation group (P = .027). Serious adverse events for infectious toxicity occurred in 18.8% of rituximab-treated patients and 10.1% of the observation group (P = .036). There were 69 deaths post randomization: 32 in the rituximab-treated group and 37 in the observation group. Secondary cancers, excluding basal cell carcinomas of the skin, occurred in 15.3% of the rituximab arm, including five cases of myelodysplastic syndrome, and in 11.1% of the observation group, including three cases of myelodysplastic syndrome.

Dr. Dartigeas is a consultant to Gilead Sciences and has provided expert testimony for Roche/Genentech. Genentech and Biogen jointly market rituximab (Rituxan).

[email protected]

On Twitter @maryjodales

ASCO Annual Meeting 2016

© ASCO/Matt Herp

CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.

Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.

“And it is very unlikely that this outcome will change if the study continues,” she added.

Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.

She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.

So the investigators conducted the trial, which took place in 292 sites in 12 countries.

The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.

They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.

They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.

The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.

One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.

The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.

Investigators performed the first interim analysis after 27 events occurred.

Patient characteristics

Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.

About half (51%) the patients were in group B, 39% in C1, and 10% in C3.

Toxicity

There were 6 deaths due to toxicity, 3 in each arm.

Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.

She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”

Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).

Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.

The control arm had 17 lymphoma events, while the rituximab arm had 3.

Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm.  And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.

One second malignancy, melanoma, occurred in the rituximab arm.

Dr Minard-Colin noted that all events occurred in the first year after randomization

Efficacy

Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.

However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.

The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.

This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.

And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.

Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).

So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”

Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.

Data analyses will be conducted annually hereafter.

ASCO Annual Meeting 2016

© ASCO/Matt Herp

CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.

Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.

“And it is very unlikely that this outcome will change if the study continues,” she added.

Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.

She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.

So the investigators conducted the trial, which took place in 292 sites in 12 countries.

The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.

They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.

They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.

The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.

One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.

The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.

Investigators performed the first interim analysis after 27 events occurred.

Patient characteristics

Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.

About half (51%) the patients were in group B, 39% in C1, and 10% in C3.

Toxicity

There were 6 deaths due to toxicity, 3 in each arm.

Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.

She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”

Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).

Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.

The control arm had 17 lymphoma events, while the rituximab arm had 3.

Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm.  And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.

One second malignancy, melanoma, occurred in the rituximab arm.

Dr Minard-Colin noted that all events occurred in the first year after randomization

Efficacy

Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.

However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.

The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.

This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.

And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.

Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).

So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”

Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.

Data analyses will be conducted annually hereafter.

ASCO Annual Meeting 2016

© ASCO/Matt Herp

CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.

Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.

“And it is very unlikely that this outcome will change if the study continues,” she added.

Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.

She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.

So the investigators conducted the trial, which took place in 292 sites in 12 countries.

The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.

They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.

They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.

The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.

One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.

The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.

Investigators performed the first interim analysis after 27 events occurred.

Patient characteristics

Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.

About half (51%) the patients were in group B, 39% in C1, and 10% in C3.

Toxicity

There were 6 deaths due to toxicity, 3 in each arm.

Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.

She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”

Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).

Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.

The control arm had 17 lymphoma events, while the rituximab arm had 3.

Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm.  And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.

One second malignancy, melanoma, occurred in the rituximab arm.

Dr Minard-Colin noted that all events occurred in the first year after randomization

Efficacy

Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.

However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.

The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.

This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.

And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.

Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).

So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”

Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.

Data analyses will be conducted annually hereafter.

CHICAGO – Liquid biopsy, the testing of the blood for circulating tumor DNA (ctDNA), identified cancer mutations useful as biomarkers in 85% of all advanced cancer cases in the largest-ever genomic analysis performed using such technology.

In nearly half of those (49%), the biomarkers were associated with an approved targeted drug, Philip C. Mack, Ph.D., reported at the annual meeting of the American Society of Clinical Oncology.

The patterns of genetic changes detected in the 17,628 blood specimens analyzed for the study using a highly sensitive next-generation sequencing technique closely mirrored those identified using traditional tumor biopsies, suggesting that liquid biopsy provides a non-invasive alternative to tissue biopsy in certain cases, Dr. Mack, professor and director of molecular pharmacology at the University of California, Davis Comprehensive Cancer Center, said during a press briefing at the meeting.

Overall, taking into account FDA-approved drugs and eligibility for clinical trials, the ctDNA testing revealed a possible treatment option for 63.6% of the 15,191 patients who provided samples.

Further, the commercially available liquid biopsy assay used in the study (Guardant360) identified the presence of resistance alterations that could guide new therapy in patients with tumors that acquire resistance to an effective treatment, he said, noting that these resistance mutations are not typically present at the time of initial tissue-biopsy.

Of the patients included in the study, 37% had lung cancer, 14% had breast cancer, 10% had colorectal cancer, and 39% had other cancers. A comparison of genomic changes in ctDNA in 398 patients with available tumor tissue genetic test results showed that when ctDNA was positive for key abnormalities associated with tumor growth, the same mutations were reported in tissue 94% to 100% of the time.

©Zffoto/Thinkstock

Most of the ctDNA alterations were found at very low levels – with half occurring at a frequency below 0.4% of the total DNA in circulation; even at such low levels, the accuracy of the liquid biopsy assay remained high, Dr. Mack noted.

The ctDNA findings also compared well with those from publicly available population-scale sequencing projects, most notably the Cancer Genome Atlas, he said.

Alterations observed at ctDNA fractions as low as 0.06% responded to treatment, which highlights the importance of assay sensitivity.

Interest in comprehensive tumor genetic profiling to guide patients toward appropriate targeted therapies based on the molecular makeup of their tumors has been increasing, and the current findings underscore its potential value. Advantages of plasma testing include ease of use in any clinic setting, avoidance of biopsy-related complications, ability to monitor changes in disease over time, potential identification of mutations in metastatic lesions not observed in the original tumor biopsy (as genetic changes driving tumor growth often differ in different parts of the tumor), and the opportunity to identify treatment-induced resistance mechanisms, Dr. Mack said.

Additionally, liquid biopsy could be particularly helpful in cases involving tumors for which a traditional biopsy is difficult to obtain.

In fact, the clinical utility of liquid biopsy was evident among 362 lung cancer cases in the study. Tissue was insufficient for traditional biopsy in 63% of the cases, and ctDNA testing identified key genetic mutations at frequencies consistent with their prevalence in the published literature. Thus, ctDNA provided these patients with their only source of an actionable target, Dr. Mack noted.

As for whether liquid biopsy could or should replace tissue biopsy, he explained that it should be viewed more as an additional tool.

“I think there is always going to be a role for tissue-based biopsy,” he said, explaining that a tissue biopsy allows the pathologist to assess the morphological features of the cancer to diagnose it and determine what the tumor type is and where it originated. “That will always be required.”

Leftover tissue should be used for mutational testing, and this is the gold standard. It is in cases when the tissue is of insufficient quality or quantity to allow a broader array of testing that liquid biopsy can provide a complementary source of information, he said.

Further, while it would be ideal to have biopsies of any progressing lesion in a patient who initially had a great response to treatment, that is not feasible, he said.

“So probably, the biggest role for plasma analysis will be occurring down the road as patients are progressing on therapies, as their tumors are evolving, as a way to monitor progression of those cancers,” he said.

Dr. Sumanta Kumar Pal, an ASCO spokesperson and a panel member at the press briefing, noted that “the data that Dr. Mack reported provides key insights into the feasibility of the so-called liquid biopsy.”

“We’re increasingly using genomic data from day-to-day in our clinics to guide therapies,” he said, reiterating that tests such as this provide a useful alternative to tissue-based testing, particularly for the many patients in clinics who have tumors that are challenging to access, such as tumors on bone or near the brain.

“The authors have demonstrated not only the feasibility of the test in detecting alterations, but that the results are often potentially actionable as well ... As oncologists obtain this assay, it’s important to keep in mind trials such as the ASCO-led TAPUR study. TAPUR can potentially link patients with selected genomic alterations to relevant therapies that would otherwise be challenging to access,” he said.

Dr. Pal also noted that there are several other blood-based genomic tests emerging, and it will be important to “rigorously define which of these platforms deliver optimal results.”

Going forward, Dr. Mack and his colleagues will be working to increase the sensitivity of the Gaurdant360 assay to detect mutations at extremely low ctDNA level, as some tumors – glioblastomas, for example – diminish the ability to detect ctDNA. Improved sensitivity could also enable the use of the assay in earlier-stage cancers, he said.

This study was supported by funding from Guardant Health.

[email protected]

CHICAGO – Liquid biopsy, the testing of the blood for circulating tumor DNA (ctDNA), identified cancer mutations useful as biomarkers in 85% of all advanced cancer cases in the largest-ever genomic analysis performed using such technology.

In nearly half of those (49%), the biomarkers were associated with an approved targeted drug, Philip C. Mack, Ph.D., reported at the annual meeting of the American Society of Clinical Oncology.

The patterns of genetic changes detected in the 17,628 blood specimens analyzed for the study using a highly sensitive next-generation sequencing technique closely mirrored those identified using traditional tumor biopsies, suggesting that liquid biopsy provides a non-invasive alternative to tissue biopsy in certain cases, Dr. Mack, professor and director of molecular pharmacology at the University of California, Davis Comprehensive Cancer Center, said during a press briefing at the meeting.

Overall, taking into account FDA-approved drugs and eligibility for clinical trials, the ctDNA testing revealed a possible treatment option for 63.6% of the 15,191 patients who provided samples.

Further, the commercially available liquid biopsy assay used in the study (Guardant360) identified the presence of resistance alterations that could guide new therapy in patients with tumors that acquire resistance to an effective treatment, he said, noting that these resistance mutations are not typically present at the time of initial tissue-biopsy.

Of the patients included in the study, 37% had lung cancer, 14% had breast cancer, 10% had colorectal cancer, and 39% had other cancers. A comparison of genomic changes in ctDNA in 398 patients with available tumor tissue genetic test results showed that when ctDNA was positive for key abnormalities associated with tumor growth, the same mutations were reported in tissue 94% to 100% of the time.

©Zffoto/Thinkstock

Most of the ctDNA alterations were found at very low levels – with half occurring at a frequency below 0.4% of the total DNA in circulation; even at such low levels, the accuracy of the liquid biopsy assay remained high, Dr. Mack noted.

The ctDNA findings also compared well with those from publicly available population-scale sequencing projects, most notably the Cancer Genome Atlas, he said.

Alterations observed at ctDNA fractions as low as 0.06% responded to treatment, which highlights the importance of assay sensitivity.

Interest in comprehensive tumor genetic profiling to guide patients toward appropriate targeted therapies based on the molecular makeup of their tumors has been increasing, and the current findings underscore its potential value. Advantages of plasma testing include ease of use in any clinic setting, avoidance of biopsy-related complications, ability to monitor changes in disease over time, potential identification of mutations in metastatic lesions not observed in the original tumor biopsy (as genetic changes driving tumor growth often differ in different parts of the tumor), and the opportunity to identify treatment-induced resistance mechanisms, Dr. Mack said.

Additionally, liquid biopsy could be particularly helpful in cases involving tumors for which a traditional biopsy is difficult to obtain.

In fact, the clinical utility of liquid biopsy was evident among 362 lung cancer cases in the study. Tissue was insufficient for traditional biopsy in 63% of the cases, and ctDNA testing identified key genetic mutations at frequencies consistent with their prevalence in the published literature. Thus, ctDNA provided these patients with their only source of an actionable target, Dr. Mack noted.

As for whether liquid biopsy could or should replace tissue biopsy, he explained that it should be viewed more as an additional tool.

“I think there is always going to be a role for tissue-based biopsy,” he said, explaining that a tissue biopsy allows the pathologist to assess the morphological features of the cancer to diagnose it and determine what the tumor type is and where it originated. “That will always be required.”

Leftover tissue should be used for mutational testing, and this is the gold standard. It is in cases when the tissue is of insufficient quality or quantity to allow a broader array of testing that liquid biopsy can provide a complementary source of information, he said.

Further, while it would be ideal to have biopsies of any progressing lesion in a patient who initially had a great response to treatment, that is not feasible, he said.

“So probably, the biggest role for plasma analysis will be occurring down the road as patients are progressing on therapies, as their tumors are evolving, as a way to monitor progression of those cancers,” he said.

Dr. Sumanta Kumar Pal, an ASCO spokesperson and a panel member at the press briefing, noted that “the data that Dr. Mack reported provides key insights into the feasibility of the so-called liquid biopsy.”

“We’re increasingly using genomic data from day-to-day in our clinics to guide therapies,” he said, reiterating that tests such as this provide a useful alternative to tissue-based testing, particularly for the many patients in clinics who have tumors that are challenging to access, such as tumors on bone or near the brain.

“The authors have demonstrated not only the feasibility of the test in detecting alterations, but that the results are often potentially actionable as well ... As oncologists obtain this assay, it’s important to keep in mind trials such as the ASCO-led TAPUR study. TAPUR can potentially link patients with selected genomic alterations to relevant therapies that would otherwise be challenging to access,” he said.

Dr. Pal also noted that there are several other blood-based genomic tests emerging, and it will be important to “rigorously define which of these platforms deliver optimal results.”

Going forward, Dr. Mack and his colleagues will be working to increase the sensitivity of the Gaurdant360 assay to detect mutations at extremely low ctDNA level, as some tumors – glioblastomas, for example – diminish the ability to detect ctDNA. Improved sensitivity could also enable the use of the assay in earlier-stage cancers, he said.

This study was supported by funding from Guardant Health.

[email protected]

CHICAGO – Liquid biopsy, the testing of the blood for circulating tumor DNA (ctDNA), identified cancer mutations useful as biomarkers in 85% of all advanced cancer cases in the largest-ever genomic analysis performed using such technology.

In nearly half of those (49%), the biomarkers were associated with an approved targeted drug, Philip C. Mack, Ph.D., reported at the annual meeting of the American Society of Clinical Oncology.

The patterns of genetic changes detected in the 17,628 blood specimens analyzed for the study using a highly sensitive next-generation sequencing technique closely mirrored those identified using traditional tumor biopsies, suggesting that liquid biopsy provides a non-invasive alternative to tissue biopsy in certain cases, Dr. Mack, professor and director of molecular pharmacology at the University of California, Davis Comprehensive Cancer Center, said during a press briefing at the meeting.

Overall, taking into account FDA-approved drugs and eligibility for clinical trials, the ctDNA testing revealed a possible treatment option for 63.6% of the 15,191 patients who provided samples.

Further, the commercially available liquid biopsy assay used in the study (Guardant360) identified the presence of resistance alterations that could guide new therapy in patients with tumors that acquire resistance to an effective treatment, he said, noting that these resistance mutations are not typically present at the time of initial tissue-biopsy.

Of the patients included in the study, 37% had lung cancer, 14% had breast cancer, 10% had colorectal cancer, and 39% had other cancers. A comparison of genomic changes in ctDNA in 398 patients with available tumor tissue genetic test results showed that when ctDNA was positive for key abnormalities associated with tumor growth, the same mutations were reported in tissue 94% to 100% of the time.

©Zffoto/Thinkstock

Most of the ctDNA alterations were found at very low levels – with half occurring at a frequency below 0.4% of the total DNA in circulation; even at such low levels, the accuracy of the liquid biopsy assay remained high, Dr. Mack noted.

The ctDNA findings also compared well with those from publicly available population-scale sequencing projects, most notably the Cancer Genome Atlas, he said.

Alterations observed at ctDNA fractions as low as 0.06% responded to treatment, which highlights the importance of assay sensitivity.

Interest in comprehensive tumor genetic profiling to guide patients toward appropriate targeted therapies based on the molecular makeup of their tumors has been increasing, and the current findings underscore its potential value. Advantages of plasma testing include ease of use in any clinic setting, avoidance of biopsy-related complications, ability to monitor changes in disease over time, potential identification of mutations in metastatic lesions not observed in the original tumor biopsy (as genetic changes driving tumor growth often differ in different parts of the tumor), and the opportunity to identify treatment-induced resistance mechanisms, Dr. Mack said.

Additionally, liquid biopsy could be particularly helpful in cases involving tumors for which a traditional biopsy is difficult to obtain.

In fact, the clinical utility of liquid biopsy was evident among 362 lung cancer cases in the study. Tissue was insufficient for traditional biopsy in 63% of the cases, and ctDNA testing identified key genetic mutations at frequencies consistent with their prevalence in the published literature. Thus, ctDNA provided these patients with their only source of an actionable target, Dr. Mack noted.

As for whether liquid biopsy could or should replace tissue biopsy, he explained that it should be viewed more as an additional tool.

“I think there is always going to be a role for tissue-based biopsy,” he said, explaining that a tissue biopsy allows the pathologist to assess the morphological features of the cancer to diagnose it and determine what the tumor type is and where it originated. “That will always be required.”

Leftover tissue should be used for mutational testing, and this is the gold standard. It is in cases when the tissue is of insufficient quality or quantity to allow a broader array of testing that liquid biopsy can provide a complementary source of information, he said.

Further, while it would be ideal to have biopsies of any progressing lesion in a patient who initially had a great response to treatment, that is not feasible, he said.

“So probably, the biggest role for plasma analysis will be occurring down the road as patients are progressing on therapies, as their tumors are evolving, as a way to monitor progression of those cancers,” he said.

Dr. Sumanta Kumar Pal, an ASCO spokesperson and a panel member at the press briefing, noted that “the data that Dr. Mack reported provides key insights into the feasibility of the so-called liquid biopsy.”

“We’re increasingly using genomic data from day-to-day in our clinics to guide therapies,” he said, reiterating that tests such as this provide a useful alternative to tissue-based testing, particularly for the many patients in clinics who have tumors that are challenging to access, such as tumors on bone or near the brain.

“The authors have demonstrated not only the feasibility of the test in detecting alterations, but that the results are often potentially actionable as well ... As oncologists obtain this assay, it’s important to keep in mind trials such as the ASCO-led TAPUR study. TAPUR can potentially link patients with selected genomic alterations to relevant therapies that would otherwise be challenging to access,” he said.

Dr. Pal also noted that there are several other blood-based genomic tests emerging, and it will be important to “rigorously define which of these platforms deliver optimal results.”

Going forward, Dr. Mack and his colleagues will be working to increase the sensitivity of the Gaurdant360 assay to detect mutations at extremely low ctDNA level, as some tumors – glioblastomas, for example – diminish the ability to detect ctDNA. Improved sensitivity could also enable the use of the assay in earlier-stage cancers, he said.

This study was supported by funding from Guardant Health.

[email protected]