Neil Osterweil

In patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a once-daily oral regimen of ibrutinib and venetoclax was associated with deep molecular remissions in both bone marrow and peripheral blood, including in patients with high-risk disease, according to investigators in the phase 2 CAPTIVATE MRD trial.

An intention-to-treat analysis of 164 patients with CLL/SLL treated with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a 75% rate of minimal residual disease (MRD) negativity in peripheral blood, and a 68% rate of MRD negativity in bone marrow among patients who received up to 12 cycles of the combination, reported Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif., and colleagues.

“This phase 2 study supports synergistic antitumor activity of the combination with notable deep responses across multiple compartments,” she said in an oral presentation during the virtual annual congress of the European Hematology Association.
 

Not ready to change practice

A hematologist/oncologist who was not involved in the study said that the data from CAPTIVATE MRD look good, but it’s still not known whether concurrent or sequential administration of the agents is optimal, and whether other regimens may be more effective in the first line.

“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab, and that’s actually the subject of the next large German cooperative group study, CLL17,” said Catherine C. Coombs, MD, assistant professor of medicine at the University of North Carolina, and the UNC Lineberger Cancer Center, Chapel Hill.

She noted that the combination of venetoclax and obinutuzumab (Gazyva) is also associated with high rates of MRD negativity in the first-line setting, and that use of this regimen allows clinicians to reserve ibrutinib or acalabrutinib (Calquence) for patients in the relapsed setting.
 

Prerandomization results

Dr. Siddiqi presented prerandomization results from the MRD cohort of the CAPTIVATE trial (NCT02910583), which is evaluating the combination of ibrutinib and venetoclax for depth of MRD response. Following 12 cycles of the combinations, patients in this cohort are then randomized based on confirmed MRD status, with patients who are MRD negative randomized to maintenance with either ibrutinib or placebo, and patients with residual disease (MRD positive) randomized to maintenance with either ibrutinib alone or with venetoclax.

A total of 164 patients with previously untreated CLL/SLL and active disease requiring treatment who were under age 70 and had good performance status were enrolled. Following an ibrutinib lead-in period with the drug given at 420 mg once daily for three cycles of 28 days, the patients were continued on ibrutinib, and were started on venetoclax with a ramp up to 400 mg once daily, for 12 additional cycles.

As planned, patients were assessed after 15 cycles for tumor lysis syndrome (TLS) risk assessment, MRD, and hematologic, clinical, imaging, and bone marrow exams for response.

The median patient age was 58, with poor-risk features such as deletion 17p seen in 16%, complex karyotype in 19%, and unmutated immunoglobulin heavy chain variable (IGHV) in 59%.

A total of 152 patients (90%) completed all 12 cycles of the combined agents, with a median treatment duration of 14.7 months on ibrutinib and 12 months on venetoclax. Eight patients had adverse events leading to discontinuation, but there were no treatment-related deaths.

A majority of patients had reductions in lymph node burden after the three-cycle ibrutinib lead in. TLS risk also decreased during the lead-in period, with 90% of patients who had a high baseline TLS risk shifting to medium or low-risk categories, and no patients moved into the high-risk category.

“Hospitalization because of this was no longer required in 66% of at-risk patients after three cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.

The best response of undetectable MRD was seen in peripheral blood of 75% of 163 evaluable patients, and in bone marrow of 72% of 155 patients. As noted before, the respective rates of MRD negativity in the intention-to-treat population were 75% and 68%. The proportion of patients with undetectable MRD in peripheral blood increased over time, from 57% after six cycles of the combination, she said.

The overall response rate was 97%, including 51% complete responses (CR) or CR with incomplete bone marrow recovery (CRi), and 46% partial (PR) or nodular PR (nPR). Among patients with CR/CRi, 85% had undetectable MRD in peripheral blood and 80% were MRD negative in bone marrow. In patients with PR/nPR, the respective rates were 69% and 59%. The high rates of undetectable MRD were seen irrespective of baseline disease characteristics, including bulky disease, cytogenetic risk category, del(17p) or TP53 mutation, and complex karyotype.

The most common adverse events with the combination were grade 1 or 2 diarrhea, arthralgia, fatigue, headache, and nausea. Grade 3 neutropenia was seen in 17% of patients, and grade 4 neutropenia was seen in 16%. Grade 3 febrile neutropenia and laboratory confirmed TLS occurred in 2 patients each (1%), and there were no grade 4 instances of either adverse event.

Postrandomization follow-up and analyses are currently being conducted, and results will be reported at a future meeting, real or virtual. An analysis of data on a separate cohort of 159 patients treated with the ibrutinib-venetoclax combination for a fixed duration is currently ongoing.

Dr. Siddiqi disclosed research funding and speakers bureau activity for Pharmacyclics, which sponsored the study, and others, as well as consulting/advising for several companies. Dr. Coombs disclosed consulting for AbbVie.

SOURCE: Siddiqi T et al. EHA25. Abstract S158.

In patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a once-daily oral regimen of ibrutinib and venetoclax was associated with deep molecular remissions in both bone marrow and peripheral blood, including in patients with high-risk disease, according to investigators in the phase 2 CAPTIVATE MRD trial.

An intention-to-treat analysis of 164 patients with CLL/SLL treated with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a 75% rate of minimal residual disease (MRD) negativity in peripheral blood, and a 68% rate of MRD negativity in bone marrow among patients who received up to 12 cycles of the combination, reported Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif., and colleagues.

“This phase 2 study supports synergistic antitumor activity of the combination with notable deep responses across multiple compartments,” she said in an oral presentation during the virtual annual congress of the European Hematology Association.
 

Not ready to change practice

A hematologist/oncologist who was not involved in the study said that the data from CAPTIVATE MRD look good, but it’s still not known whether concurrent or sequential administration of the agents is optimal, and whether other regimens may be more effective in the first line.

“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab, and that’s actually the subject of the next large German cooperative group study, CLL17,” said Catherine C. Coombs, MD, assistant professor of medicine at the University of North Carolina, and the UNC Lineberger Cancer Center, Chapel Hill.

She noted that the combination of venetoclax and obinutuzumab (Gazyva) is also associated with high rates of MRD negativity in the first-line setting, and that use of this regimen allows clinicians to reserve ibrutinib or acalabrutinib (Calquence) for patients in the relapsed setting.
 

Prerandomization results

Dr. Siddiqi presented prerandomization results from the MRD cohort of the CAPTIVATE trial (NCT02910583), which is evaluating the combination of ibrutinib and venetoclax for depth of MRD response. Following 12 cycles of the combinations, patients in this cohort are then randomized based on confirmed MRD status, with patients who are MRD negative randomized to maintenance with either ibrutinib or placebo, and patients with residual disease (MRD positive) randomized to maintenance with either ibrutinib alone or with venetoclax.

A total of 164 patients with previously untreated CLL/SLL and active disease requiring treatment who were under age 70 and had good performance status were enrolled. Following an ibrutinib lead-in period with the drug given at 420 mg once daily for three cycles of 28 days, the patients were continued on ibrutinib, and were started on venetoclax with a ramp up to 400 mg once daily, for 12 additional cycles.

As planned, patients were assessed after 15 cycles for tumor lysis syndrome (TLS) risk assessment, MRD, and hematologic, clinical, imaging, and bone marrow exams for response.

The median patient age was 58, with poor-risk features such as deletion 17p seen in 16%, complex karyotype in 19%, and unmutated immunoglobulin heavy chain variable (IGHV) in 59%.

A total of 152 patients (90%) completed all 12 cycles of the combined agents, with a median treatment duration of 14.7 months on ibrutinib and 12 months on venetoclax. Eight patients had adverse events leading to discontinuation, but there were no treatment-related deaths.

A majority of patients had reductions in lymph node burden after the three-cycle ibrutinib lead in. TLS risk also decreased during the lead-in period, with 90% of patients who had a high baseline TLS risk shifting to medium or low-risk categories, and no patients moved into the high-risk category.

“Hospitalization because of this was no longer required in 66% of at-risk patients after three cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.

The best response of undetectable MRD was seen in peripheral blood of 75% of 163 evaluable patients, and in bone marrow of 72% of 155 patients. As noted before, the respective rates of MRD negativity in the intention-to-treat population were 75% and 68%. The proportion of patients with undetectable MRD in peripheral blood increased over time, from 57% after six cycles of the combination, she said.

The overall response rate was 97%, including 51% complete responses (CR) or CR with incomplete bone marrow recovery (CRi), and 46% partial (PR) or nodular PR (nPR). Among patients with CR/CRi, 85% had undetectable MRD in peripheral blood and 80% were MRD negative in bone marrow. In patients with PR/nPR, the respective rates were 69% and 59%. The high rates of undetectable MRD were seen irrespective of baseline disease characteristics, including bulky disease, cytogenetic risk category, del(17p) or TP53 mutation, and complex karyotype.

The most common adverse events with the combination were grade 1 or 2 diarrhea, arthralgia, fatigue, headache, and nausea. Grade 3 neutropenia was seen in 17% of patients, and grade 4 neutropenia was seen in 16%. Grade 3 febrile neutropenia and laboratory confirmed TLS occurred in 2 patients each (1%), and there were no grade 4 instances of either adverse event.

Postrandomization follow-up and analyses are currently being conducted, and results will be reported at a future meeting, real or virtual. An analysis of data on a separate cohort of 159 patients treated with the ibrutinib-venetoclax combination for a fixed duration is currently ongoing.

Dr. Siddiqi disclosed research funding and speakers bureau activity for Pharmacyclics, which sponsored the study, and others, as well as consulting/advising for several companies. Dr. Coombs disclosed consulting for AbbVie.

SOURCE: Siddiqi T et al. EHA25. Abstract S158.

In patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a once-daily oral regimen of ibrutinib and venetoclax was associated with deep molecular remissions in both bone marrow and peripheral blood, including in patients with high-risk disease, according to investigators in the phase 2 CAPTIVATE MRD trial.

An intention-to-treat analysis of 164 patients with CLL/SLL treated with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a 75% rate of minimal residual disease (MRD) negativity in peripheral blood, and a 68% rate of MRD negativity in bone marrow among patients who received up to 12 cycles of the combination, reported Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif., and colleagues.

“This phase 2 study supports synergistic antitumor activity of the combination with notable deep responses across multiple compartments,” she said in an oral presentation during the virtual annual congress of the European Hematology Association.
 

Not ready to change practice

A hematologist/oncologist who was not involved in the study said that the data from CAPTIVATE MRD look good, but it’s still not known whether concurrent or sequential administration of the agents is optimal, and whether other regimens may be more effective in the first line.

“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab, and that’s actually the subject of the next large German cooperative group study, CLL17,” said Catherine C. Coombs, MD, assistant professor of medicine at the University of North Carolina, and the UNC Lineberger Cancer Center, Chapel Hill.

She noted that the combination of venetoclax and obinutuzumab (Gazyva) is also associated with high rates of MRD negativity in the first-line setting, and that use of this regimen allows clinicians to reserve ibrutinib or acalabrutinib (Calquence) for patients in the relapsed setting.
 

Prerandomization results

Dr. Siddiqi presented prerandomization results from the MRD cohort of the CAPTIVATE trial (NCT02910583), which is evaluating the combination of ibrutinib and venetoclax for depth of MRD response. Following 12 cycles of the combinations, patients in this cohort are then randomized based on confirmed MRD status, with patients who are MRD negative randomized to maintenance with either ibrutinib or placebo, and patients with residual disease (MRD positive) randomized to maintenance with either ibrutinib alone or with venetoclax.

A total of 164 patients with previously untreated CLL/SLL and active disease requiring treatment who were under age 70 and had good performance status were enrolled. Following an ibrutinib lead-in period with the drug given at 420 mg once daily for three cycles of 28 days, the patients were continued on ibrutinib, and were started on venetoclax with a ramp up to 400 mg once daily, for 12 additional cycles.

As planned, patients were assessed after 15 cycles for tumor lysis syndrome (TLS) risk assessment, MRD, and hematologic, clinical, imaging, and bone marrow exams for response.

The median patient age was 58, with poor-risk features such as deletion 17p seen in 16%, complex karyotype in 19%, and unmutated immunoglobulin heavy chain variable (IGHV) in 59%.

A total of 152 patients (90%) completed all 12 cycles of the combined agents, with a median treatment duration of 14.7 months on ibrutinib and 12 months on venetoclax. Eight patients had adverse events leading to discontinuation, but there were no treatment-related deaths.

A majority of patients had reductions in lymph node burden after the three-cycle ibrutinib lead in. TLS risk also decreased during the lead-in period, with 90% of patients who had a high baseline TLS risk shifting to medium or low-risk categories, and no patients moved into the high-risk category.

“Hospitalization because of this was no longer required in 66% of at-risk patients after three cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.

The best response of undetectable MRD was seen in peripheral blood of 75% of 163 evaluable patients, and in bone marrow of 72% of 155 patients. As noted before, the respective rates of MRD negativity in the intention-to-treat population were 75% and 68%. The proportion of patients with undetectable MRD in peripheral blood increased over time, from 57% after six cycles of the combination, she said.

The overall response rate was 97%, including 51% complete responses (CR) or CR with incomplete bone marrow recovery (CRi), and 46% partial (PR) or nodular PR (nPR). Among patients with CR/CRi, 85% had undetectable MRD in peripheral blood and 80% were MRD negative in bone marrow. In patients with PR/nPR, the respective rates were 69% and 59%. The high rates of undetectable MRD were seen irrespective of baseline disease characteristics, including bulky disease, cytogenetic risk category, del(17p) or TP53 mutation, and complex karyotype.

The most common adverse events with the combination were grade 1 or 2 diarrhea, arthralgia, fatigue, headache, and nausea. Grade 3 neutropenia was seen in 17% of patients, and grade 4 neutropenia was seen in 16%. Grade 3 febrile neutropenia and laboratory confirmed TLS occurred in 2 patients each (1%), and there were no grade 4 instances of either adverse event.

Postrandomization follow-up and analyses are currently being conducted, and results will be reported at a future meeting, real or virtual. An analysis of data on a separate cohort of 159 patients treated with the ibrutinib-venetoclax combination for a fixed duration is currently ongoing.

Dr. Siddiqi disclosed research funding and speakers bureau activity for Pharmacyclics, which sponsored the study, and others, as well as consulting/advising for several companies. Dr. Coombs disclosed consulting for AbbVie.

SOURCE: Siddiqi T et al. EHA25. Abstract S158.

Adding venetoclax to azacitidine significantly extended survival of patients with previously untreated acute myeloid leukemia (AML) who were ineligible for standard induction therapy, results of the phase 3 VIALE-A trial showed.

Median overall survival for patients treated with venetoclax (Venclexta) and azacitidine was 14.7 months, compared with 9.6 months for patients who received azacitidine with a placebo, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Cancer Center, Houston.

“The combination of [azacitidine] and [venetoclax] was associated with statistically significant and clinically meaningful improvements in overall survival, response rates, duration of remission, and transfusion independence, representing a true paradigm shift in the treatment of our older patients with AML,” she said in a late-breaking abstract presentation at the virtual annual congress of the European Hematology Association.

Patients with newly diagnosed AML who are aged 75 years and older or have significant comorbidities are often not able to withstand the rigors of standard induction therapy for AML and have instead been treated with low-dose hypomethylating agents or cytarabine, but these therapies typically are associated with inferior outcomes, Dr. DiNardo said.

Venetoclax has shown good single-agent activity against relapsed/refractory AML. Early efficacy results of a phase 1b study, reported at the 2017 EHA Congress, showed that, among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall response rate, and that older patients were able to tolerate the regimen.
 

No surprise

The results of the VIALE-A study merely confirm what hematologists/oncologists have known for several years, said Joshua F. Zeidner, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“Most leukemia clinicians have been using this regimen as a standard of care prior to these results,” he said in an interview. Dr. Zeidner was not involved in the study.

In November 2018, the Food and Drug Administration granted accelerated approval to venetoclax in combination with either azacitidine or decitabine or low-dose cytarabine in adults with newly diagnosed AML who because of age or comorbidities were ineligible for standard intensive induction regimens. Dr. Zeidner noted, however, that there are still questions about the combination in this population that need further exploration.

Despite being labeled as a “low-intensity” therapy, “I think low intensity is sort of a misnomer here,” he said. “It’s very challenging to give this regimen in the community because of all of the cytopenias, a high degree of transfusion dependence that these patients have, at least in the first few cycles, and all the rigorous laboratory monitoring and drug interactions that are common with venetoclax really lead to a lot of challenges in the community.”

Also still unanswered are questions about how to dose patients with early responses who have potential dose-limiting toxicities such as neutropenia and thrombocytopenia, he said.

It’s also unclear whether patients will require hospitalization during the ramp-up phase of venetoclax, as was done in some clinical trials, because of risk of tumor lysis syndrome. In the VIALE-A study, however, there were only three minor biochemical cases of tumor lysis syndrome in the experimental arm, and none of these cases required dose modification or treatment discontinuation.

“This begets the question whether patients need to be hospitalized at for the initiation of this treatment,” Dr. Zeidner said. Additional studies will also be needed to see whether certain subgroups of patients would be likely to derive particular benefit from venetoclax plus azacitidine, such as patients with IDH1 or IDH2 somatic mutations.
 

Randomized confirmatory trial

The VIALE-A study was a randomized, placebo-controlled trial designed to put the early promise of the combination to the test.

Investigators enrolled 433 adults with newly diagnosed AML who were ineligible for induction therapy either because they were 75 or older or were younger than 75 but had one or more of the following comorbidities: heart failure requiring treatment or a left ventricular ejection fraction of 50% or less, chronic stable angina, diffusion lung capacity for carbon monoxide of 65% or less or forced expiratory volume in 1 second of 65% or less, or Eastern Cooperative Oncology Group performance status score of 2-3.

After stratification by age, cytogenetic risk, and geographic region, the patients were randomized in a 2:1 fashion to receive azacitidine 75 mg/m² either subcutaneously or intravenously on days 1-7 of each 28-day cycle, plus either oral venetoclax 400 mg daily following a 3-day ramp up in the first cycle (286 patients) or placebo (145 patients).

The median age in each arm was 76 years. Approximately 75% of patients in each arm had de novo AML.

Approximately half of all patients in each arm has bone marrow blast counts of 50% or greater. Two-thirds of patients had intermediate cytogenetic risk and one-third had poor risk disease. Somatic mutation rates, including mutations in IDH1/2, FLT3, NPM1 and TP53, were roughly comparable between the arms.

As noted before, median overall survival, the primary endpoint, was significantly longer with venetoclax, at 14.7 versus 9.6 months, translating into a hazard ratio for death with venetoclax of 0.66 (P < .001).

Although the numbers were relatively small, an analysis of overall survival by subgroups showed either a significant advantage or trend favoring venetoclax in all subgroups, notably among patients with difficult-to-treat disease, including patients 75 years and older and those with secondary AML, Dr. DiNardo said.

The combined complete response and CR with incomplete recovery (CRi) response rate was 66.4% with venetoclax, compared with 28.3% with azacitidine alone. The median time to a CR/CRi was shorter with the combination at 1.3 versus 2.8 months for azacitidine plus placebo, and the median duration of a CR/CRi response was longer, at 17.5 versus 13.4 months, respectively.

Response rates were also notably higher with venetoclax in all cytogenetic risk, AML subtype, molecular mutation, age, ECOG score, and bone marrow blast subgroups.

Additionally, significantly more patients treated with venetoclax/azacitidine were transfusion independent for a minimum of 8 weeks for platelets or combined red cells and platelets, Dr. DiNardo noted.

Median event-free survival – time from randomization to relapse, death, or treatment failure – was 9.8 months in the venetoclax arm versus 7 months in the placebo arm (HR, 0.63; P < .001).

All patients experienced at least one treatment-emergent adverse event. Grade 3 or greater hematologic adverse events were seen 82% of patients in the venetoclax arm and 68% in the placebo arm. The respective rates of grade 3 or greater neutropenia were 42% versus 29%, and febrile neutropenia were 42% versus 19%. Thrombocytopenia, anemia, and leukopenia rates were also higher among patients who received venetoclax.

Grade 1-2 gastrointestinal events were the most frequent nonhematologic adverse events. There was no increase in early deaths seen with the study combination.

The study was supported by AbbVie and Genentech. Dr. DiNardo disclosed research funding from and advisory board activities for those companies and from others. Dr. Zeidner disclosed serving on an independent review committee for AbbVie and advisory board activity for Genentech and others.

SOURCE: DiNardo C et al. EHA25, Abstract LB2601.

Adding venetoclax to azacitidine significantly extended survival of patients with previously untreated acute myeloid leukemia (AML) who were ineligible for standard induction therapy, results of the phase 3 VIALE-A trial showed.

Median overall survival for patients treated with venetoclax (Venclexta) and azacitidine was 14.7 months, compared with 9.6 months for patients who received azacitidine with a placebo, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Cancer Center, Houston.

“The combination of [azacitidine] and [venetoclax] was associated with statistically significant and clinically meaningful improvements in overall survival, response rates, duration of remission, and transfusion independence, representing a true paradigm shift in the treatment of our older patients with AML,” she said in a late-breaking abstract presentation at the virtual annual congress of the European Hematology Association.

Patients with newly diagnosed AML who are aged 75 years and older or have significant comorbidities are often not able to withstand the rigors of standard induction therapy for AML and have instead been treated with low-dose hypomethylating agents or cytarabine, but these therapies typically are associated with inferior outcomes, Dr. DiNardo said.

Venetoclax has shown good single-agent activity against relapsed/refractory AML. Early efficacy results of a phase 1b study, reported at the 2017 EHA Congress, showed that, among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall response rate, and that older patients were able to tolerate the regimen.
 

No surprise

The results of the VIALE-A study merely confirm what hematologists/oncologists have known for several years, said Joshua F. Zeidner, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“Most leukemia clinicians have been using this regimen as a standard of care prior to these results,” he said in an interview. Dr. Zeidner was not involved in the study.

In November 2018, the Food and Drug Administration granted accelerated approval to venetoclax in combination with either azacitidine or decitabine or low-dose cytarabine in adults with newly diagnosed AML who because of age or comorbidities were ineligible for standard intensive induction regimens. Dr. Zeidner noted, however, that there are still questions about the combination in this population that need further exploration.

Despite being labeled as a “low-intensity” therapy, “I think low intensity is sort of a misnomer here,” he said. “It’s very challenging to give this regimen in the community because of all of the cytopenias, a high degree of transfusion dependence that these patients have, at least in the first few cycles, and all the rigorous laboratory monitoring and drug interactions that are common with venetoclax really lead to a lot of challenges in the community.”

Also still unanswered are questions about how to dose patients with early responses who have potential dose-limiting toxicities such as neutropenia and thrombocytopenia, he said.

It’s also unclear whether patients will require hospitalization during the ramp-up phase of venetoclax, as was done in some clinical trials, because of risk of tumor lysis syndrome. In the VIALE-A study, however, there were only three minor biochemical cases of tumor lysis syndrome in the experimental arm, and none of these cases required dose modification or treatment discontinuation.

“This begets the question whether patients need to be hospitalized at for the initiation of this treatment,” Dr. Zeidner said. Additional studies will also be needed to see whether certain subgroups of patients would be likely to derive particular benefit from venetoclax plus azacitidine, such as patients with IDH1 or IDH2 somatic mutations.
 

Randomized confirmatory trial

The VIALE-A study was a randomized, placebo-controlled trial designed to put the early promise of the combination to the test.

Investigators enrolled 433 adults with newly diagnosed AML who were ineligible for induction therapy either because they were 75 or older or were younger than 75 but had one or more of the following comorbidities: heart failure requiring treatment or a left ventricular ejection fraction of 50% or less, chronic stable angina, diffusion lung capacity for carbon monoxide of 65% or less or forced expiratory volume in 1 second of 65% or less, or Eastern Cooperative Oncology Group performance status score of 2-3.

After stratification by age, cytogenetic risk, and geographic region, the patients were randomized in a 2:1 fashion to receive azacitidine 75 mg/m² either subcutaneously or intravenously on days 1-7 of each 28-day cycle, plus either oral venetoclax 400 mg daily following a 3-day ramp up in the first cycle (286 patients) or placebo (145 patients).

The median age in each arm was 76 years. Approximately 75% of patients in each arm had de novo AML.

Approximately half of all patients in each arm has bone marrow blast counts of 50% or greater. Two-thirds of patients had intermediate cytogenetic risk and one-third had poor risk disease. Somatic mutation rates, including mutations in IDH1/2, FLT3, NPM1 and TP53, were roughly comparable between the arms.

As noted before, median overall survival, the primary endpoint, was significantly longer with venetoclax, at 14.7 versus 9.6 months, translating into a hazard ratio for death with venetoclax of 0.66 (P < .001).

Although the numbers were relatively small, an analysis of overall survival by subgroups showed either a significant advantage or trend favoring venetoclax in all subgroups, notably among patients with difficult-to-treat disease, including patients 75 years and older and those with secondary AML, Dr. DiNardo said.

The combined complete response and CR with incomplete recovery (CRi) response rate was 66.4% with venetoclax, compared with 28.3% with azacitidine alone. The median time to a CR/CRi was shorter with the combination at 1.3 versus 2.8 months for azacitidine plus placebo, and the median duration of a CR/CRi response was longer, at 17.5 versus 13.4 months, respectively.

Response rates were also notably higher with venetoclax in all cytogenetic risk, AML subtype, molecular mutation, age, ECOG score, and bone marrow blast subgroups.

Additionally, significantly more patients treated with venetoclax/azacitidine were transfusion independent for a minimum of 8 weeks for platelets or combined red cells and platelets, Dr. DiNardo noted.

Median event-free survival – time from randomization to relapse, death, or treatment failure – was 9.8 months in the venetoclax arm versus 7 months in the placebo arm (HR, 0.63; P < .001).

All patients experienced at least one treatment-emergent adverse event. Grade 3 or greater hematologic adverse events were seen 82% of patients in the venetoclax arm and 68% in the placebo arm. The respective rates of grade 3 or greater neutropenia were 42% versus 29%, and febrile neutropenia were 42% versus 19%. Thrombocytopenia, anemia, and leukopenia rates were also higher among patients who received venetoclax.

Grade 1-2 gastrointestinal events were the most frequent nonhematologic adverse events. There was no increase in early deaths seen with the study combination.

The study was supported by AbbVie and Genentech. Dr. DiNardo disclosed research funding from and advisory board activities for those companies and from others. Dr. Zeidner disclosed serving on an independent review committee for AbbVie and advisory board activity for Genentech and others.

SOURCE: DiNardo C et al. EHA25, Abstract LB2601.

Adding venetoclax to azacitidine significantly extended survival of patients with previously untreated acute myeloid leukemia (AML) who were ineligible for standard induction therapy, results of the phase 3 VIALE-A trial showed.

Median overall survival for patients treated with venetoclax (Venclexta) and azacitidine was 14.7 months, compared with 9.6 months for patients who received azacitidine with a placebo, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Cancer Center, Houston.

“The combination of [azacitidine] and [venetoclax] was associated with statistically significant and clinically meaningful improvements in overall survival, response rates, duration of remission, and transfusion independence, representing a true paradigm shift in the treatment of our older patients with AML,” she said in a late-breaking abstract presentation at the virtual annual congress of the European Hematology Association.

Patients with newly diagnosed AML who are aged 75 years and older or have significant comorbidities are often not able to withstand the rigors of standard induction therapy for AML and have instead been treated with low-dose hypomethylating agents or cytarabine, but these therapies typically are associated with inferior outcomes, Dr. DiNardo said.

Venetoclax has shown good single-agent activity against relapsed/refractory AML. Early efficacy results of a phase 1b study, reported at the 2017 EHA Congress, showed that, among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall response rate, and that older patients were able to tolerate the regimen.
 

No surprise

The results of the VIALE-A study merely confirm what hematologists/oncologists have known for several years, said Joshua F. Zeidner, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“Most leukemia clinicians have been using this regimen as a standard of care prior to these results,” he said in an interview. Dr. Zeidner was not involved in the study.

In November 2018, the Food and Drug Administration granted accelerated approval to venetoclax in combination with either azacitidine or decitabine or low-dose cytarabine in adults with newly diagnosed AML who because of age or comorbidities were ineligible for standard intensive induction regimens. Dr. Zeidner noted, however, that there are still questions about the combination in this population that need further exploration.

Despite being labeled as a “low-intensity” therapy, “I think low intensity is sort of a misnomer here,” he said. “It’s very challenging to give this regimen in the community because of all of the cytopenias, a high degree of transfusion dependence that these patients have, at least in the first few cycles, and all the rigorous laboratory monitoring and drug interactions that are common with venetoclax really lead to a lot of challenges in the community.”

Also still unanswered are questions about how to dose patients with early responses who have potential dose-limiting toxicities such as neutropenia and thrombocytopenia, he said.

It’s also unclear whether patients will require hospitalization during the ramp-up phase of venetoclax, as was done in some clinical trials, because of risk of tumor lysis syndrome. In the VIALE-A study, however, there were only three minor biochemical cases of tumor lysis syndrome in the experimental arm, and none of these cases required dose modification or treatment discontinuation.

“This begets the question whether patients need to be hospitalized at for the initiation of this treatment,” Dr. Zeidner said. Additional studies will also be needed to see whether certain subgroups of patients would be likely to derive particular benefit from venetoclax plus azacitidine, such as patients with IDH1 or IDH2 somatic mutations.
 

Randomized confirmatory trial

The VIALE-A study was a randomized, placebo-controlled trial designed to put the early promise of the combination to the test.

Investigators enrolled 433 adults with newly diagnosed AML who were ineligible for induction therapy either because they were 75 or older or were younger than 75 but had one or more of the following comorbidities: heart failure requiring treatment or a left ventricular ejection fraction of 50% or less, chronic stable angina, diffusion lung capacity for carbon monoxide of 65% or less or forced expiratory volume in 1 second of 65% or less, or Eastern Cooperative Oncology Group performance status score of 2-3.

After stratification by age, cytogenetic risk, and geographic region, the patients were randomized in a 2:1 fashion to receive azacitidine 75 mg/m² either subcutaneously or intravenously on days 1-7 of each 28-day cycle, plus either oral venetoclax 400 mg daily following a 3-day ramp up in the first cycle (286 patients) or placebo (145 patients).

The median age in each arm was 76 years. Approximately 75% of patients in each arm had de novo AML.

Approximately half of all patients in each arm has bone marrow blast counts of 50% or greater. Two-thirds of patients had intermediate cytogenetic risk and one-third had poor risk disease. Somatic mutation rates, including mutations in IDH1/2, FLT3, NPM1 and TP53, were roughly comparable between the arms.

As noted before, median overall survival, the primary endpoint, was significantly longer with venetoclax, at 14.7 versus 9.6 months, translating into a hazard ratio for death with venetoclax of 0.66 (P < .001).

Although the numbers were relatively small, an analysis of overall survival by subgroups showed either a significant advantage or trend favoring venetoclax in all subgroups, notably among patients with difficult-to-treat disease, including patients 75 years and older and those with secondary AML, Dr. DiNardo said.

The combined complete response and CR with incomplete recovery (CRi) response rate was 66.4% with venetoclax, compared with 28.3% with azacitidine alone. The median time to a CR/CRi was shorter with the combination at 1.3 versus 2.8 months for azacitidine plus placebo, and the median duration of a CR/CRi response was longer, at 17.5 versus 13.4 months, respectively.

Response rates were also notably higher with venetoclax in all cytogenetic risk, AML subtype, molecular mutation, age, ECOG score, and bone marrow blast subgroups.

Additionally, significantly more patients treated with venetoclax/azacitidine were transfusion independent for a minimum of 8 weeks for platelets or combined red cells and platelets, Dr. DiNardo noted.

Median event-free survival – time from randomization to relapse, death, or treatment failure – was 9.8 months in the venetoclax arm versus 7 months in the placebo arm (HR, 0.63; P < .001).

All patients experienced at least one treatment-emergent adverse event. Grade 3 or greater hematologic adverse events were seen 82% of patients in the venetoclax arm and 68% in the placebo arm. The respective rates of grade 3 or greater neutropenia were 42% versus 29%, and febrile neutropenia were 42% versus 19%. Thrombocytopenia, anemia, and leukopenia rates were also higher among patients who received venetoclax.

Grade 1-2 gastrointestinal events were the most frequent nonhematologic adverse events. There was no increase in early deaths seen with the study combination.

The study was supported by AbbVie and Genentech. Dr. DiNardo disclosed research funding from and advisory board activities for those companies and from others. Dr. Zeidner disclosed serving on an independent review committee for AbbVie and advisory board activity for Genentech and others.

SOURCE: DiNardo C et al. EHA25, Abstract LB2601.

For patients with high-risk chronic lymphocytic leukemia (CLL), first-line therapy with a triple combination of targeted agents showed encouraging response rates in the phase 2 CLL2-GIVe trial.

Among 41 patients with untreated CLL bearing deleterious TP53 mutations and/or the 17p chromosomal deletion who received the GIVe regimen consisting of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta), the complete response rate at final restaging was 58.5%, and 33 patients with a confirmed response were negative for minimal residual disease after a median follow-up of 18.6 months, reported Henriette Huber, MD, of University Hospital Ulm, Germany.

“The GIVe regimen is promising first-line therapy for patients with high-risk CLL,” she said in a presentation during the virtual annual congress of the European Hematology Association.

The overall safety profile of the combination was acceptable, she said, but added that “some higher-grade infections are of concern.” The rate of grade 3 or greater infections/infestations in the study was 19.5%.

Sound rationale (with caveat)

Another adverse event of concern is the rate of atrial fibrillation in the comparatively young patient population (median age 62), noted Alexey Danilov, MD, PhD, of City of Hope in Duarte Calif., who commented on the study for MDedge.

He pointed out that second-generation Bruton’s tyrosine kinase (BTK) inhibitors such as acalabrutinib (Calquence) may pose a lower risk of atrial fibrillation than the BTK inhibitor ibrutinib used in the CLL2-GIVe study.

In general, however, the rationale for the combination is sound, Dr. Danilov said.

“Of all the patient populations that we deal with within CLL, this probably would be most appropriate for this type of therapy. Patients with deletion 17p or TP53 mutations still represent an unmet medical need compared to other patients who don’t have those mutations,” he said.

Patients with CLL bearing the mutations have lower clinical response rates to novel therapies and generally do not respond well to chemoimmunotherapy, he said.

“The question becomes whether using these all at the same time, versus sequential strategies – using one drug and then after that, at relapse, another – is better, and obviously this trial doesn’t address that,” he said.
 

Three targets

The investigators enrolled 24 men and 17 women with untreated CLL with del(17p) and/or TP53 mutations and adequate organ function (creatinine clearance rate of more than 50 mL/min). The median age was 62 (range 35-85 years); 78% of patients had Binet stage B or C disease. The median Cumulative Illness Rating Scale (CIRS) score was 3 (range 0 to 8).

All patients received treatment with the combination for 6 months. The CD20 inhibitor obinutuzumab was given in a dose of 1,000 mg on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6. The BTK inhibitor ibrutinib was given continuously at a dose of 420 mg per day beginning on the first day of the first cycle. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, was started on day 22 of cycle 1, and was increased to 400 mg per day over 5 weeks until the end of cycle 12.

If patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) according to International Workshop on CLL criteria at final restaging (performed with imaging at the end of cycle 12 followed by bone marrow biopsy 2 months later), ibrutinib would be stopped beginning at cycle 15. Patients who did not have a CR or CRi would continue on ibrutinib until cycle 36.

Encouraging results

All but 3 of the 41 patients reached final restaging. Analyses of efficacy and safety included all 41 patients.

The CR/CRi rate at final restaging, the primary endpoint, was accomplished in 24 patients (58.8%), and 14 patients (34.1%) had a partial response.

Of the three patients for whom responses could not be assessed, two died (one from ovarian cancer which was retrospectively determined to have been present at enrollment, and one at cycle 9 from cardiac failure), and the third patient withdrew consent at cycle 10.

In all, 33 patients (80.5%) were MRD-negative in peripheral blood, 4 remained MRD positive, and 4 were not assessed. Per protocol, 22 patients with undetectable MRD and a CR or CRi discontinued therapy at week 15. An additional 13 patients also discontinued therapy because of adverse events or other reasons, and 6 remained on therapy beyond cycle 15.

The most frequent adverse events of any grade through the end of cycle 14 were gastrointestinal disorders in 83%, none higher than grade 2; infections and infestations in 70.7%, of which 19.5% were grade 3 or greater in severity; and blood and lymphatic system disorders in 58.5%, most of which (53.7%) were grade 3 or greater.

Cardiac disorders were reported in 19.5% of all patients, including 12.2% with atrial fibrillation; grade 3 or greater atrial fibrillation occurred in 2.4% of patients.

There was one case each of cerebral aspergillosis, progressive multifocal leukoencephalopathy (without PCR testing), urosepsis, staphylococcal sepsis and febrile infection.

Laboratory confirmed tumor lysis syndrome, all grade 3 or greater, was reported in 9.8% of patients. Infusion-related reactions were reported in 29.3% of patients, with a total of 7.3% being grade 3 or greater.

The trial was supported by Janssen-Cilag and Roche. Dr. Huber disclosed travel reimbursement from Novartis. Dr. Danilov disclosed consulting for AbbVie, Janssen, and Genentech.

SOURCE: Huber H et al. EHA Congress. Abstract S157.

For patients with high-risk chronic lymphocytic leukemia (CLL), first-line therapy with a triple combination of targeted agents showed encouraging response rates in the phase 2 CLL2-GIVe trial.

Among 41 patients with untreated CLL bearing deleterious TP53 mutations and/or the 17p chromosomal deletion who received the GIVe regimen consisting of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta), the complete response rate at final restaging was 58.5%, and 33 patients with a confirmed response were negative for minimal residual disease after a median follow-up of 18.6 months, reported Henriette Huber, MD, of University Hospital Ulm, Germany.

“The GIVe regimen is promising first-line therapy for patients with high-risk CLL,” she said in a presentation during the virtual annual congress of the European Hematology Association.

The overall safety profile of the combination was acceptable, she said, but added that “some higher-grade infections are of concern.” The rate of grade 3 or greater infections/infestations in the study was 19.5%.

Sound rationale (with caveat)

Another adverse event of concern is the rate of atrial fibrillation in the comparatively young patient population (median age 62), noted Alexey Danilov, MD, PhD, of City of Hope in Duarte Calif., who commented on the study for MDedge.

He pointed out that second-generation Bruton’s tyrosine kinase (BTK) inhibitors such as acalabrutinib (Calquence) may pose a lower risk of atrial fibrillation than the BTK inhibitor ibrutinib used in the CLL2-GIVe study.

In general, however, the rationale for the combination is sound, Dr. Danilov said.

“Of all the patient populations that we deal with within CLL, this probably would be most appropriate for this type of therapy. Patients with deletion 17p or TP53 mutations still represent an unmet medical need compared to other patients who don’t have those mutations,” he said.

Patients with CLL bearing the mutations have lower clinical response rates to novel therapies and generally do not respond well to chemoimmunotherapy, he said.

“The question becomes whether using these all at the same time, versus sequential strategies – using one drug and then after that, at relapse, another – is better, and obviously this trial doesn’t address that,” he said.
 

Three targets

The investigators enrolled 24 men and 17 women with untreated CLL with del(17p) and/or TP53 mutations and adequate organ function (creatinine clearance rate of more than 50 mL/min). The median age was 62 (range 35-85 years); 78% of patients had Binet stage B or C disease. The median Cumulative Illness Rating Scale (CIRS) score was 3 (range 0 to 8).

All patients received treatment with the combination for 6 months. The CD20 inhibitor obinutuzumab was given in a dose of 1,000 mg on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6. The BTK inhibitor ibrutinib was given continuously at a dose of 420 mg per day beginning on the first day of the first cycle. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, was started on day 22 of cycle 1, and was increased to 400 mg per day over 5 weeks until the end of cycle 12.

If patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) according to International Workshop on CLL criteria at final restaging (performed with imaging at the end of cycle 12 followed by bone marrow biopsy 2 months later), ibrutinib would be stopped beginning at cycle 15. Patients who did not have a CR or CRi would continue on ibrutinib until cycle 36.

Encouraging results

All but 3 of the 41 patients reached final restaging. Analyses of efficacy and safety included all 41 patients.

The CR/CRi rate at final restaging, the primary endpoint, was accomplished in 24 patients (58.8%), and 14 patients (34.1%) had a partial response.

Of the three patients for whom responses could not be assessed, two died (one from ovarian cancer which was retrospectively determined to have been present at enrollment, and one at cycle 9 from cardiac failure), and the third patient withdrew consent at cycle 10.

In all, 33 patients (80.5%) were MRD-negative in peripheral blood, 4 remained MRD positive, and 4 were not assessed. Per protocol, 22 patients with undetectable MRD and a CR or CRi discontinued therapy at week 15. An additional 13 patients also discontinued therapy because of adverse events or other reasons, and 6 remained on therapy beyond cycle 15.

The most frequent adverse events of any grade through the end of cycle 14 were gastrointestinal disorders in 83%, none higher than grade 2; infections and infestations in 70.7%, of which 19.5% were grade 3 or greater in severity; and blood and lymphatic system disorders in 58.5%, most of which (53.7%) were grade 3 or greater.

Cardiac disorders were reported in 19.5% of all patients, including 12.2% with atrial fibrillation; grade 3 or greater atrial fibrillation occurred in 2.4% of patients.

There was one case each of cerebral aspergillosis, progressive multifocal leukoencephalopathy (without PCR testing), urosepsis, staphylococcal sepsis and febrile infection.

Laboratory confirmed tumor lysis syndrome, all grade 3 or greater, was reported in 9.8% of patients. Infusion-related reactions were reported in 29.3% of patients, with a total of 7.3% being grade 3 or greater.

The trial was supported by Janssen-Cilag and Roche. Dr. Huber disclosed travel reimbursement from Novartis. Dr. Danilov disclosed consulting for AbbVie, Janssen, and Genentech.

SOURCE: Huber H et al. EHA Congress. Abstract S157.

For patients with high-risk chronic lymphocytic leukemia (CLL), first-line therapy with a triple combination of targeted agents showed encouraging response rates in the phase 2 CLL2-GIVe trial.

Among 41 patients with untreated CLL bearing deleterious TP53 mutations and/or the 17p chromosomal deletion who received the GIVe regimen consisting of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta), the complete response rate at final restaging was 58.5%, and 33 patients with a confirmed response were negative for minimal residual disease after a median follow-up of 18.6 months, reported Henriette Huber, MD, of University Hospital Ulm, Germany.

“The GIVe regimen is promising first-line therapy for patients with high-risk CLL,” she said in a presentation during the virtual annual congress of the European Hematology Association.

The overall safety profile of the combination was acceptable, she said, but added that “some higher-grade infections are of concern.” The rate of grade 3 or greater infections/infestations in the study was 19.5%.

Sound rationale (with caveat)

Another adverse event of concern is the rate of atrial fibrillation in the comparatively young patient population (median age 62), noted Alexey Danilov, MD, PhD, of City of Hope in Duarte Calif., who commented on the study for MDedge.

He pointed out that second-generation Bruton’s tyrosine kinase (BTK) inhibitors such as acalabrutinib (Calquence) may pose a lower risk of atrial fibrillation than the BTK inhibitor ibrutinib used in the CLL2-GIVe study.

In general, however, the rationale for the combination is sound, Dr. Danilov said.

“Of all the patient populations that we deal with within CLL, this probably would be most appropriate for this type of therapy. Patients with deletion 17p or TP53 mutations still represent an unmet medical need compared to other patients who don’t have those mutations,” he said.

Patients with CLL bearing the mutations have lower clinical response rates to novel therapies and generally do not respond well to chemoimmunotherapy, he said.

“The question becomes whether using these all at the same time, versus sequential strategies – using one drug and then after that, at relapse, another – is better, and obviously this trial doesn’t address that,” he said.
 

Three targets

The investigators enrolled 24 men and 17 women with untreated CLL with del(17p) and/or TP53 mutations and adequate organ function (creatinine clearance rate of more than 50 mL/min). The median age was 62 (range 35-85 years); 78% of patients had Binet stage B or C disease. The median Cumulative Illness Rating Scale (CIRS) score was 3 (range 0 to 8).

All patients received treatment with the combination for 6 months. The CD20 inhibitor obinutuzumab was given in a dose of 1,000 mg on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6. The BTK inhibitor ibrutinib was given continuously at a dose of 420 mg per day beginning on the first day of the first cycle. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, was started on day 22 of cycle 1, and was increased to 400 mg per day over 5 weeks until the end of cycle 12.

If patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) according to International Workshop on CLL criteria at final restaging (performed with imaging at the end of cycle 12 followed by bone marrow biopsy 2 months later), ibrutinib would be stopped beginning at cycle 15. Patients who did not have a CR or CRi would continue on ibrutinib until cycle 36.

Encouraging results

All but 3 of the 41 patients reached final restaging. Analyses of efficacy and safety included all 41 patients.

The CR/CRi rate at final restaging, the primary endpoint, was accomplished in 24 patients (58.8%), and 14 patients (34.1%) had a partial response.

Of the three patients for whom responses could not be assessed, two died (one from ovarian cancer which was retrospectively determined to have been present at enrollment, and one at cycle 9 from cardiac failure), and the third patient withdrew consent at cycle 10.

In all, 33 patients (80.5%) were MRD-negative in peripheral blood, 4 remained MRD positive, and 4 were not assessed. Per protocol, 22 patients with undetectable MRD and a CR or CRi discontinued therapy at week 15. An additional 13 patients also discontinued therapy because of adverse events or other reasons, and 6 remained on therapy beyond cycle 15.

The most frequent adverse events of any grade through the end of cycle 14 were gastrointestinal disorders in 83%, none higher than grade 2; infections and infestations in 70.7%, of which 19.5% were grade 3 or greater in severity; and blood and lymphatic system disorders in 58.5%, most of which (53.7%) were grade 3 or greater.

Cardiac disorders were reported in 19.5% of all patients, including 12.2% with atrial fibrillation; grade 3 or greater atrial fibrillation occurred in 2.4% of patients.

There was one case each of cerebral aspergillosis, progressive multifocal leukoencephalopathy (without PCR testing), urosepsis, staphylococcal sepsis and febrile infection.

Laboratory confirmed tumor lysis syndrome, all grade 3 or greater, was reported in 9.8% of patients. Infusion-related reactions were reported in 29.3% of patients, with a total of 7.3% being grade 3 or greater.

The trial was supported by Janssen-Cilag and Roche. Dr. Huber disclosed travel reimbursement from Novartis. Dr. Danilov disclosed consulting for AbbVie, Janssen, and Genentech.

SOURCE: Huber H et al. EHA Congress. Abstract S157.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding celecoxib to standard adjuvant chemotherapy with the FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) regimen did not improve survival for patients with stage III colon cancer, results of the phase 3 CALGB/SWOG 80702 trial showed.

The trial included 2,526 patients randomized to either 6 or 12 cycles of adjuvant FOLFOX with either celecoxib or placebo. The 3-year disease-free survival (DFS) rate was 76.3% for patients on celecoxib and 73.4% for those on placebo. The 5-year overall survival (OS) was 84% and 81.8%, respectively.

“The addition of celecoxib to FOLFOX adjuvant therapy in stage III colon cancer did not significantly improve disease-free or overall survival,” Jeffrey A. Meyerhardt, MD, of the Dana-Farber Cancer Institute in Boston, said while presenting the results as part of the American Society of Clinical Oncology virtual scientific program.

“We did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for disease-free survival. Similarly, we did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for overall survival,” Dr. Meyerhardt said.

“Simply put, celecoxib should not be used for the secondary prevention of colon cancer,” said invited discussant Christopher Lieu, MD, of the University of Colorado Cancer Center, Aurora.
 

Trial details

The 80702 trial was designed to test whether the COX-2 inhibitor celecoxib could help further reduce the risk of recurrence when added to adjuvant chemotherapy with 3 or 6 months of FOLFOX. Data on the FOLFOX portion of the trial were previously reported as part of the International Duration Evaluation of Adjuvant Therapy collaboration (N Engl J Med. 2018;378:1177-88).

The trial enrolled 2,526 patients with resected stage III colon cancer. They were randomized to receive 3 or 6 months (6 or 12 cycles) of FOLFOX with either concurrent celecoxib at 400 mg daily (n = 1,265) or placebo (n = 1,261) for 3 years from the start of the trial.

The primary endpoint of 3-year DFS did not differ between the groups (hazard ratio, 0.90; P = .16). Likewise, 5-year OS rates did not differ significantly (HR, 0.89; P = .22).

As Dr. Meyerhardt said, there were no significant interactions detected among any subgroups for DFS or OS, including by age, N or T stage, risk group, concurrent low-dose aspirin use, sex, race/ethnicity, baseline performance status, FOLFOX duration, body mass index, or tumor location.

Rates of toxicities were similar between the groups, except for a higher incidence of hypertension of any grade with celecoxib during FOLFOX therapy (14.6% vs. 10.9%, P = .01) and a grade 2 or greater creatinine increase with celecoxib after FOLFOX (1.7% vs. 0.5%, P = .01).

About 40% of patients completed all 3 years of celecoxib or placebo. Reasons for discontinuation included recurrent disease, adverse events, patient withdrawal from the study, physician decision, or other complicating disease.
 

Why didn’t it work?

Previous studies have indicated that aspirin and cyclooxygenase (COX)-2 inhibitors are associated with a reduced risk of colorectal polyps and cancer, Dr. Lieu said. So why didn’t celecoxib improve survival in the current trial?

“There are obviously COX-1 and COX-independent targets that aspirin hit that celecoxib does not, and its survival impact of affecting these targets is still largely unclear,” Dr. Lieu said.

He added that ongoing trials – including the Add-Aspirin and ASCOLT studies – should provide more insight.

The current trial was sponsored by the Alliance for Clinical Trials in Oncology in collaboration with the National Cancer Institute. Pfizer provided the celecoxib and placebo. Dr. Meyerhardt disclosed relationships with Cota Healthcare, Taiho Pharmaceutical, and Array BioPharma. Dr. Lieu disclosed relationships with Foundation Medicine, Ipsen, Merck, and Immune Design.

SOURCE: Meyerhardt JA et al. ASCO 2020, Abstract 4003.

Adding celecoxib to standard adjuvant chemotherapy with the FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) regimen did not improve survival for patients with stage III colon cancer, results of the phase 3 CALGB/SWOG 80702 trial showed.

The trial included 2,526 patients randomized to either 6 or 12 cycles of adjuvant FOLFOX with either celecoxib or placebo. The 3-year disease-free survival (DFS) rate was 76.3% for patients on celecoxib and 73.4% for those on placebo. The 5-year overall survival (OS) was 84% and 81.8%, respectively.

“The addition of celecoxib to FOLFOX adjuvant therapy in stage III colon cancer did not significantly improve disease-free or overall survival,” Jeffrey A. Meyerhardt, MD, of the Dana-Farber Cancer Institute in Boston, said while presenting the results as part of the American Society of Clinical Oncology virtual scientific program.

“We did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for disease-free survival. Similarly, we did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for overall survival,” Dr. Meyerhardt said.

“Simply put, celecoxib should not be used for the secondary prevention of colon cancer,” said invited discussant Christopher Lieu, MD, of the University of Colorado Cancer Center, Aurora.
 

Trial details

The 80702 trial was designed to test whether the COX-2 inhibitor celecoxib could help further reduce the risk of recurrence when added to adjuvant chemotherapy with 3 or 6 months of FOLFOX. Data on the FOLFOX portion of the trial were previously reported as part of the International Duration Evaluation of Adjuvant Therapy collaboration (N Engl J Med. 2018;378:1177-88).

The trial enrolled 2,526 patients with resected stage III colon cancer. They were randomized to receive 3 or 6 months (6 or 12 cycles) of FOLFOX with either concurrent celecoxib at 400 mg daily (n = 1,265) or placebo (n = 1,261) for 3 years from the start of the trial.

The primary endpoint of 3-year DFS did not differ between the groups (hazard ratio, 0.90; P = .16). Likewise, 5-year OS rates did not differ significantly (HR, 0.89; P = .22).

As Dr. Meyerhardt said, there were no significant interactions detected among any subgroups for DFS or OS, including by age, N or T stage, risk group, concurrent low-dose aspirin use, sex, race/ethnicity, baseline performance status, FOLFOX duration, body mass index, or tumor location.

Rates of toxicities were similar between the groups, except for a higher incidence of hypertension of any grade with celecoxib during FOLFOX therapy (14.6% vs. 10.9%, P = .01) and a grade 2 or greater creatinine increase with celecoxib after FOLFOX (1.7% vs. 0.5%, P = .01).

About 40% of patients completed all 3 years of celecoxib or placebo. Reasons for discontinuation included recurrent disease, adverse events, patient withdrawal from the study, physician decision, or other complicating disease.
 

Why didn’t it work?

Previous studies have indicated that aspirin and cyclooxygenase (COX)-2 inhibitors are associated with a reduced risk of colorectal polyps and cancer, Dr. Lieu said. So why didn’t celecoxib improve survival in the current trial?

“There are obviously COX-1 and COX-independent targets that aspirin hit that celecoxib does not, and its survival impact of affecting these targets is still largely unclear,” Dr. Lieu said.

He added that ongoing trials – including the Add-Aspirin and ASCOLT studies – should provide more insight.

The current trial was sponsored by the Alliance for Clinical Trials in Oncology in collaboration with the National Cancer Institute. Pfizer provided the celecoxib and placebo. Dr. Meyerhardt disclosed relationships with Cota Healthcare, Taiho Pharmaceutical, and Array BioPharma. Dr. Lieu disclosed relationships with Foundation Medicine, Ipsen, Merck, and Immune Design.

SOURCE: Meyerhardt JA et al. ASCO 2020, Abstract 4003.

Adding celecoxib to standard adjuvant chemotherapy with the FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) regimen did not improve survival for patients with stage III colon cancer, results of the phase 3 CALGB/SWOG 80702 trial showed.

The trial included 2,526 patients randomized to either 6 or 12 cycles of adjuvant FOLFOX with either celecoxib or placebo. The 3-year disease-free survival (DFS) rate was 76.3% for patients on celecoxib and 73.4% for those on placebo. The 5-year overall survival (OS) was 84% and 81.8%, respectively.

“The addition of celecoxib to FOLFOX adjuvant therapy in stage III colon cancer did not significantly improve disease-free or overall survival,” Jeffrey A. Meyerhardt, MD, of the Dana-Farber Cancer Institute in Boston, said while presenting the results as part of the American Society of Clinical Oncology virtual scientific program.

“We did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for disease-free survival. Similarly, we did not detect a significant interaction between celecoxib and duration of FOLFOX therapy for overall survival,” Dr. Meyerhardt said.

“Simply put, celecoxib should not be used for the secondary prevention of colon cancer,” said invited discussant Christopher Lieu, MD, of the University of Colorado Cancer Center, Aurora.
 

Trial details

The 80702 trial was designed to test whether the COX-2 inhibitor celecoxib could help further reduce the risk of recurrence when added to adjuvant chemotherapy with 3 or 6 months of FOLFOX. Data on the FOLFOX portion of the trial were previously reported as part of the International Duration Evaluation of Adjuvant Therapy collaboration (N Engl J Med. 2018;378:1177-88).

The trial enrolled 2,526 patients with resected stage III colon cancer. They were randomized to receive 3 or 6 months (6 or 12 cycles) of FOLFOX with either concurrent celecoxib at 400 mg daily (n = 1,265) or placebo (n = 1,261) for 3 years from the start of the trial.

The primary endpoint of 3-year DFS did not differ between the groups (hazard ratio, 0.90; P = .16). Likewise, 5-year OS rates did not differ significantly (HR, 0.89; P = .22).

As Dr. Meyerhardt said, there were no significant interactions detected among any subgroups for DFS or OS, including by age, N or T stage, risk group, concurrent low-dose aspirin use, sex, race/ethnicity, baseline performance status, FOLFOX duration, body mass index, or tumor location.

Rates of toxicities were similar between the groups, except for a higher incidence of hypertension of any grade with celecoxib during FOLFOX therapy (14.6% vs. 10.9%, P = .01) and a grade 2 or greater creatinine increase with celecoxib after FOLFOX (1.7% vs. 0.5%, P = .01).

About 40% of patients completed all 3 years of celecoxib or placebo. Reasons for discontinuation included recurrent disease, adverse events, patient withdrawal from the study, physician decision, or other complicating disease.
 

Why didn’t it work?

Previous studies have indicated that aspirin and cyclooxygenase (COX)-2 inhibitors are associated with a reduced risk of colorectal polyps and cancer, Dr. Lieu said. So why didn’t celecoxib improve survival in the current trial?

“There are obviously COX-1 and COX-independent targets that aspirin hit that celecoxib does not, and its survival impact of affecting these targets is still largely unclear,” Dr. Lieu said.

He added that ongoing trials – including the Add-Aspirin and ASCOLT studies – should provide more insight.

The current trial was sponsored by the Alliance for Clinical Trials in Oncology in collaboration with the National Cancer Institute. Pfizer provided the celecoxib and placebo. Dr. Meyerhardt disclosed relationships with Cota Healthcare, Taiho Pharmaceutical, and Array BioPharma. Dr. Lieu disclosed relationships with Foundation Medicine, Ipsen, Merck, and Immune Design.

SOURCE: Meyerhardt JA et al. ASCO 2020, Abstract 4003.

In a phase 3 trial, combining cytoreductive surgery with chemotherapy significantly prolonged progression-free and overall survival among select patients with recurrent ovarian cancer who had a platinum-free interval of more than 6 months.

The trial, AGO DESKTOP III/ENGOT ov20, is the first prospective, randomized study showing an overall survival benefit for debulking surgery in patients with recurrent ovarian cancer.

Among 406 patients in first relapse, the median overall survival was 53.7 months for those randomized to cytoreductive surgery plus chemotherapy and 46 months for patients randomized to chemotherapy alone (P = .02).

“The overall survival benefit was highest and exclusively seen in the cohort with complete resection, indicating the importance of a thorough selection process of both the right patient and the right center,” said investigator Andreas du Bois, MD, of the Kliniken Essen-Mitte (Germany).

The median survival gain for patients with platinum-free intervals of more than 6 months who undergo complete resection is nearly 16 months “and is worth going for,” he added.

Dr. du Bois presented these results as part of the American Society of Clinical Oncology virtual scientific program (Abstract 6000).

In another trial, SOC-1, that was also presented in the virtual program, investigators reported a progression-free survival advantage of 5.5 months for patients with recurrent ovarian cancer who underwent debulking surgery, compared with those who did not (Abstract 6001).

 

Different trials, different results

The invited discussant for Dr. du Bois’s presentation was Robert L. Coleman, MD, chief scientific officer of the U.S. Oncology Network in The Woodlands, Tex., who was the principal investigator of the GOG-0213 trial (N Engl J Med. 2019;381:1929-39).

That trial did not show an overall survival advantage to secondary surgical cytoreduction followed by chemotherapy, compared with chemotherapy alone, among 485 women with platinum-sensitive recurrent ovarian cancer.

Referring to both AGO DESKTOP III and SOC-1, Dr. Coleman noted that, “while only DESKTOP III met its primary endpoint of improving overall survival, both demonstrated a benefit on PFS [progression-free survival].” Both trials also support a triage algorithm for selecting the approximately 75% of patients who are likely to benefit from secondary cytoreductive surgery.

“However, the price paid for being wrong is substantial, with no benefit seen in progression-free survival and possibly a detriment in overall survival. Because of these observations, both [presenters of SOC-1 and AGO DESKTOP III data] recommended that procedures be limited to select women having surgery performed at sites of excellence,” Dr. Coleman said.

Potential explanations for the differential findings of a secondary surgery benefit in DESKTOP III and SOC-1 versus GOG-0213 include the use of a selection algorithm in the former versus investigator selection based on clinical parameters and imaging in the latter.

In addition, “while platinum-based therapy was the rule in all trials, the use of concomitant and maintenance bevacizumab, a regimen found to improve overall survival in GOG-0213, was used in substantially higher numbers of patients in that trial relative to the two current trials,” Dr. Coleman said.

The GOG-0213 trial also demonstrated an advantage for adjuvant therapy with platinum-based chemotherapy and bevacizumab, which was given to 84% of patients in GOG-0213. That trial had a median overall survival for patients who did not undergo surgery of 65.7 months, compared with 46 months in AGO DESKTOP III and 53.9 months in SOC-1, Dr. Coleman said.
 

Third time’s a charm

As its name implies, the AGO DESKTOP III trial is the third in a series. AGO DESKTOP I developed the hypothesis that a positive AGO score – consisting of an Eastern Cooperative Oncology Group performance status score of 0, complete resection during first-line therapy, and ascites less than 500 mL – could be predictive of favorable outcomes with debulking surgery (Ann Surg Oncol. 2006 Dec;13[12]:1702-10).

AGO DESKTOP II was a prospective, multicenter trial testing the score in patients with platinum-free intervals of more than 6 months (Int J Gynecol Cancer. 2011 Feb;21[2]:289-95). In this trial, 51% of patients had a positive AGO score, and the score was shown to predict, with 95% probability, complete resectability in two-thirds of these patients, Dr. Du Bois said.

In AGO DESKTOP III, 407 patients were prospectively randomized to second-line chemotherapy alone (n = 201) or to cytoreductive surgery (n = 206) followed by the same chemotherapy, with platinum-containing regimens highly recommended.

Patient characteristics were well balanced between the arms. Nearly all patients (99%) in each arm had prior platinum exposure, and 75% had a platinum-free interval of more than 12 months (a median of 21.1 months in the surgery arm versus 18.7 months in the no-surgery arm).
 

Complete resections extend OS

There were 8 patients (4%) in the chemotherapy-only arm and 14 (6.8%) in the surgery arm who were noncompliant with randomization. The complete resection rate was 74.2%.

Following randomization, 88.8% of patients in the surgery arm and 90% in the no-surgery arm received platinum-containing chemotherapy; 22.8% and 23.4%, respectively, received bevacizumab; and 3.9% and 6.0% received a poly (ADP-ribose) polymerase inhibitor.

The median overall survival in the intention-to-treat population was 53.7 months in the surgery arm and 46 months in the no-surgery arm, an absolute difference of 7.7 months (hazard ratio, 0.75; P = .02).

The median progression-free survival, assessed in the intention-to-treat population after database closure in January 2020, was 18.4 months with surgery and 14 months without (HR, 0.66; P < .001).

A post hoc analysis showed the importance of complete versus partial resection. The median overall survival was 61.9 months in patients with complete resections and 28.8 months for patients with residual tumor after cytoreductive surgery, an absolute difference of nearly 3 years (HR, 0.40; P < .001).

Comparing only those patients with complete resections with patients who did not undergo surgery, the respective median overall survival was 61.9 months and 46 months (HR, 0.57; P < .001).

AGO DESKTOP III was sponsored by the AGO study group in collaboration with other oncology groups, Medac, and GlaxoSmithKline. Dr. du Bois and Dr. Coleman disclosed relationships with many companies.

SOURCE: du Bois A et al. ASCO 2020, Abstract 6000.

In a phase 3 trial, combining cytoreductive surgery with chemotherapy significantly prolonged progression-free and overall survival among select patients with recurrent ovarian cancer who had a platinum-free interval of more than 6 months.

The trial, AGO DESKTOP III/ENGOT ov20, is the first prospective, randomized study showing an overall survival benefit for debulking surgery in patients with recurrent ovarian cancer.

Among 406 patients in first relapse, the median overall survival was 53.7 months for those randomized to cytoreductive surgery plus chemotherapy and 46 months for patients randomized to chemotherapy alone (P = .02).

“The overall survival benefit was highest and exclusively seen in the cohort with complete resection, indicating the importance of a thorough selection process of both the right patient and the right center,” said investigator Andreas du Bois, MD, of the Kliniken Essen-Mitte (Germany).

The median survival gain for patients with platinum-free intervals of more than 6 months who undergo complete resection is nearly 16 months “and is worth going for,” he added.

Dr. du Bois presented these results as part of the American Society of Clinical Oncology virtual scientific program (Abstract 6000).

In another trial, SOC-1, that was also presented in the virtual program, investigators reported a progression-free survival advantage of 5.5 months for patients with recurrent ovarian cancer who underwent debulking surgery, compared with those who did not (Abstract 6001).

 

Different trials, different results

The invited discussant for Dr. du Bois’s presentation was Robert L. Coleman, MD, chief scientific officer of the U.S. Oncology Network in The Woodlands, Tex., who was the principal investigator of the GOG-0213 trial (N Engl J Med. 2019;381:1929-39).

That trial did not show an overall survival advantage to secondary surgical cytoreduction followed by chemotherapy, compared with chemotherapy alone, among 485 women with platinum-sensitive recurrent ovarian cancer.

Referring to both AGO DESKTOP III and SOC-1, Dr. Coleman noted that, “while only DESKTOP III met its primary endpoint of improving overall survival, both demonstrated a benefit on PFS [progression-free survival].” Both trials also support a triage algorithm for selecting the approximately 75% of patients who are likely to benefit from secondary cytoreductive surgery.

“However, the price paid for being wrong is substantial, with no benefit seen in progression-free survival and possibly a detriment in overall survival. Because of these observations, both [presenters of SOC-1 and AGO DESKTOP III data] recommended that procedures be limited to select women having surgery performed at sites of excellence,” Dr. Coleman said.

Potential explanations for the differential findings of a secondary surgery benefit in DESKTOP III and SOC-1 versus GOG-0213 include the use of a selection algorithm in the former versus investigator selection based on clinical parameters and imaging in the latter.

In addition, “while platinum-based therapy was the rule in all trials, the use of concomitant and maintenance bevacizumab, a regimen found to improve overall survival in GOG-0213, was used in substantially higher numbers of patients in that trial relative to the two current trials,” Dr. Coleman said.

The GOG-0213 trial also demonstrated an advantage for adjuvant therapy with platinum-based chemotherapy and bevacizumab, which was given to 84% of patients in GOG-0213. That trial had a median overall survival for patients who did not undergo surgery of 65.7 months, compared with 46 months in AGO DESKTOP III and 53.9 months in SOC-1, Dr. Coleman said.
 

Third time’s a charm

As its name implies, the AGO DESKTOP III trial is the third in a series. AGO DESKTOP I developed the hypothesis that a positive AGO score – consisting of an Eastern Cooperative Oncology Group performance status score of 0, complete resection during first-line therapy, and ascites less than 500 mL – could be predictive of favorable outcomes with debulking surgery (Ann Surg Oncol. 2006 Dec;13[12]:1702-10).

AGO DESKTOP II was a prospective, multicenter trial testing the score in patients with platinum-free intervals of more than 6 months (Int J Gynecol Cancer. 2011 Feb;21[2]:289-95). In this trial, 51% of patients had a positive AGO score, and the score was shown to predict, with 95% probability, complete resectability in two-thirds of these patients, Dr. Du Bois said.

In AGO DESKTOP III, 407 patients were prospectively randomized to second-line chemotherapy alone (n = 201) or to cytoreductive surgery (n = 206) followed by the same chemotherapy, with platinum-containing regimens highly recommended.

Patient characteristics were well balanced between the arms. Nearly all patients (99%) in each arm had prior platinum exposure, and 75% had a platinum-free interval of more than 12 months (a median of 21.1 months in the surgery arm versus 18.7 months in the no-surgery arm).
 

Complete resections extend OS

There were 8 patients (4%) in the chemotherapy-only arm and 14 (6.8%) in the surgery arm who were noncompliant with randomization. The complete resection rate was 74.2%.

Following randomization, 88.8% of patients in the surgery arm and 90% in the no-surgery arm received platinum-containing chemotherapy; 22.8% and 23.4%, respectively, received bevacizumab; and 3.9% and 6.0% received a poly (ADP-ribose) polymerase inhibitor.

The median overall survival in the intention-to-treat population was 53.7 months in the surgery arm and 46 months in the no-surgery arm, an absolute difference of 7.7 months (hazard ratio, 0.75; P = .02).

The median progression-free survival, assessed in the intention-to-treat population after database closure in January 2020, was 18.4 months with surgery and 14 months without (HR, 0.66; P < .001).

A post hoc analysis showed the importance of complete versus partial resection. The median overall survival was 61.9 months in patients with complete resections and 28.8 months for patients with residual tumor after cytoreductive surgery, an absolute difference of nearly 3 years (HR, 0.40; P < .001).

Comparing only those patients with complete resections with patients who did not undergo surgery, the respective median overall survival was 61.9 months and 46 months (HR, 0.57; P < .001).

AGO DESKTOP III was sponsored by the AGO study group in collaboration with other oncology groups, Medac, and GlaxoSmithKline. Dr. du Bois and Dr. Coleman disclosed relationships with many companies.

SOURCE: du Bois A et al. ASCO 2020, Abstract 6000.

In a phase 3 trial, combining cytoreductive surgery with chemotherapy significantly prolonged progression-free and overall survival among select patients with recurrent ovarian cancer who had a platinum-free interval of more than 6 months.

The trial, AGO DESKTOP III/ENGOT ov20, is the first prospective, randomized study showing an overall survival benefit for debulking surgery in patients with recurrent ovarian cancer.

Among 406 patients in first relapse, the median overall survival was 53.7 months for those randomized to cytoreductive surgery plus chemotherapy and 46 months for patients randomized to chemotherapy alone (P = .02).

“The overall survival benefit was highest and exclusively seen in the cohort with complete resection, indicating the importance of a thorough selection process of both the right patient and the right center,” said investigator Andreas du Bois, MD, of the Kliniken Essen-Mitte (Germany).

The median survival gain for patients with platinum-free intervals of more than 6 months who undergo complete resection is nearly 16 months “and is worth going for,” he added.

Dr. du Bois presented these results as part of the American Society of Clinical Oncology virtual scientific program (Abstract 6000).

In another trial, SOC-1, that was also presented in the virtual program, investigators reported a progression-free survival advantage of 5.5 months for patients with recurrent ovarian cancer who underwent debulking surgery, compared with those who did not (Abstract 6001).

 

Different trials, different results

The invited discussant for Dr. du Bois’s presentation was Robert L. Coleman, MD, chief scientific officer of the U.S. Oncology Network in The Woodlands, Tex., who was the principal investigator of the GOG-0213 trial (N Engl J Med. 2019;381:1929-39).

That trial did not show an overall survival advantage to secondary surgical cytoreduction followed by chemotherapy, compared with chemotherapy alone, among 485 women with platinum-sensitive recurrent ovarian cancer.

Referring to both AGO DESKTOP III and SOC-1, Dr. Coleman noted that, “while only DESKTOP III met its primary endpoint of improving overall survival, both demonstrated a benefit on PFS [progression-free survival].” Both trials also support a triage algorithm for selecting the approximately 75% of patients who are likely to benefit from secondary cytoreductive surgery.

“However, the price paid for being wrong is substantial, with no benefit seen in progression-free survival and possibly a detriment in overall survival. Because of these observations, both [presenters of SOC-1 and AGO DESKTOP III data] recommended that procedures be limited to select women having surgery performed at sites of excellence,” Dr. Coleman said.

Potential explanations for the differential findings of a secondary surgery benefit in DESKTOP III and SOC-1 versus GOG-0213 include the use of a selection algorithm in the former versus investigator selection based on clinical parameters and imaging in the latter.

In addition, “while platinum-based therapy was the rule in all trials, the use of concomitant and maintenance bevacizumab, a regimen found to improve overall survival in GOG-0213, was used in substantially higher numbers of patients in that trial relative to the two current trials,” Dr. Coleman said.

The GOG-0213 trial also demonstrated an advantage for adjuvant therapy with platinum-based chemotherapy and bevacizumab, which was given to 84% of patients in GOG-0213. That trial had a median overall survival for patients who did not undergo surgery of 65.7 months, compared with 46 months in AGO DESKTOP III and 53.9 months in SOC-1, Dr. Coleman said.
 

Third time’s a charm

As its name implies, the AGO DESKTOP III trial is the third in a series. AGO DESKTOP I developed the hypothesis that a positive AGO score – consisting of an Eastern Cooperative Oncology Group performance status score of 0, complete resection during first-line therapy, and ascites less than 500 mL – could be predictive of favorable outcomes with debulking surgery (Ann Surg Oncol. 2006 Dec;13[12]:1702-10).

AGO DESKTOP II was a prospective, multicenter trial testing the score in patients with platinum-free intervals of more than 6 months (Int J Gynecol Cancer. 2011 Feb;21[2]:289-95). In this trial, 51% of patients had a positive AGO score, and the score was shown to predict, with 95% probability, complete resectability in two-thirds of these patients, Dr. Du Bois said.

In AGO DESKTOP III, 407 patients were prospectively randomized to second-line chemotherapy alone (n = 201) or to cytoreductive surgery (n = 206) followed by the same chemotherapy, with platinum-containing regimens highly recommended.

Patient characteristics were well balanced between the arms. Nearly all patients (99%) in each arm had prior platinum exposure, and 75% had a platinum-free interval of more than 12 months (a median of 21.1 months in the surgery arm versus 18.7 months in the no-surgery arm).
 

Complete resections extend OS

There were 8 patients (4%) in the chemotherapy-only arm and 14 (6.8%) in the surgery arm who were noncompliant with randomization. The complete resection rate was 74.2%.

Following randomization, 88.8% of patients in the surgery arm and 90% in the no-surgery arm received platinum-containing chemotherapy; 22.8% and 23.4%, respectively, received bevacizumab; and 3.9% and 6.0% received a poly (ADP-ribose) polymerase inhibitor.

The median overall survival in the intention-to-treat population was 53.7 months in the surgery arm and 46 months in the no-surgery arm, an absolute difference of 7.7 months (hazard ratio, 0.75; P = .02).

The median progression-free survival, assessed in the intention-to-treat population after database closure in January 2020, was 18.4 months with surgery and 14 months without (HR, 0.66; P < .001).

A post hoc analysis showed the importance of complete versus partial resection. The median overall survival was 61.9 months in patients with complete resections and 28.8 months for patients with residual tumor after cytoreductive surgery, an absolute difference of nearly 3 years (HR, 0.40; P < .001).

Comparing only those patients with complete resections with patients who did not undergo surgery, the respective median overall survival was 61.9 months and 46 months (HR, 0.57; P < .001).

AGO DESKTOP III was sponsored by the AGO study group in collaboration with other oncology groups, Medac, and GlaxoSmithKline. Dr. du Bois and Dr. Coleman disclosed relationships with many companies.

SOURCE: du Bois A et al. ASCO 2020, Abstract 6000.

In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.

Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.

Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.

Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.

“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.

Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.

“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
 

Past data

An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.

The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.

She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
 

E2108 details

In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.

In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.

A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.

In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.

Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
 

Survival, progression, and HRQOL

At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).

An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.

Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).

At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).

“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.

She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.

The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.

SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.

In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.

Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.

Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.

Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.

“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.

Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.

“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
 

Past data

An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.

The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.

She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
 

E2108 details

In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.

In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.

A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.

In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.

Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
 

Survival, progression, and HRQOL

At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).

An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.

Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).

At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).

“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.

She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.

The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.

SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.

In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.

Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.

Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.

Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.

“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.

Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.

“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
 

Past data

An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.

The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.

She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
 

E2108 details

In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.

In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.

A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.

In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.

Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
 

Survival, progression, and HRQOL

At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).

An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.

Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).

At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).

“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.

She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.

The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.

SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.

Relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, was more effective than injectable leuprolide at maintaining castration levels of testosterone in men with advanced prostate cancer, according to investigators from the phase 3 HERO trial.

Relugolix was also associated with a significantly lower incidence of major adverse cardiovascular events (MACE), reported Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, S.C., in a presentation made as a part of the American Society of Clinical Oncology virtual scientific program. The study was published simultaneously in The New England Journal of Medicine.

“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT [androgen-deprivation therapy] in advanced prostate cancer,” Dr. Shore said. He added that a potential advantage of relugolix compared with the leutenizing hormone-releasing hormone (LHRH) agonist leuprolide is the oral agent’s adverse event profile.

“Of note, and importantly, cardiovascular mortality is the leading cause of death for patients with prostate cancer. The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors, including obesity, diabetes, hypertension, and hyperlipidemia,” Dr. Shore said.

LHRH agonists also cause an initial testosterone surge that may cause an early but transient symptom flare. In contrast, relugolix has a direct inhibitory effect on pituitary GnRH receptors, leading to suppression of both leutenizing hormone and follicle-stimulating hormone, with no testosterone flare.
 

Study details

In the HERO trial, men with advanced prostate cancer were randomized in a 2:1 ratio to receive either relugolix at a 360-mg loading dose on day 1 followed by a 120-mg oral dose once daily (n = 622) or leuprolide delivered via depot injection every 3 months (n = 308) for a total of 48 weeks.

About half of all patients in each arm had biochemical (prostate-specific antigen, or “PSA”) relapse, 23% had newly diagnosed androgen-sensitive metastatic disease, and the remaining men (26%-28%) had advanced localized disease.

Patients with a history of a MACE event – a composite of nonfatal myocardial infarction, nonfatal stroke, and death from any cause – within 6 months were excluded.

The median PSA level at baseline was 11.7 mg/mL in the relugolix arm and 9.4 ng/mL in the leuprolide arm. Respective median testosterone levels were 415.8 ng/dL and 395.9 ng/dL.

“Of note, more than 90% of men enrolled in this study had at least one cardiovascular risk factor,” Dr. Shore said. “Tobacco use and obesity were common, as were diabetes and hypertension. Fourteen percent of men reported a prior history of major adverse cardiovascular event, such as a heart attack or stroke; this is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study’s cardiovascular exclusion criteria.”
 

Efficacy

Sustained testosterone suppression to castration levels (less than 50 ng/dL) was achieved through 48 weeks in 96.7% of patients on relugolix, compared with 88.8% of men on leuprolide.

The absolute difference of 7.9% reached the statistical definitions for both noninferiority and superiority of relugolix over leuprolide (P for superiority < .001).

Mean testosterone levels on day 4 had decreased to below 50 ng/dL for relugolix and were maintained at castration levels until the end of treatment. In the leuprolide group, the mean testosterone level on day 4 was 625 ng/dL, which declined to castration levels by day 29 and remained below 50 ng/dL after the end of treatment at week 53. In contrast, testosterone levels in the relugolix arm began to recover immediately after the cessation of therapy.

Results with relugolix were significantly better than with leuprolide for the following endpoints (P < .0001 for all comparisons):

• Proportion of patients with PSA response at day 15 and confirmed at day 29 (79.4% vs. 19.8%)
• Cumulative probability of testosterone suppression to less than 50 ng/dL on day 15 (98.7% vs. 12.05%)
• Cumulative probability of profound testosterone suppression to less than 20 ng/dL on day 15 (78.38% vs. 0.98%)
• Mean follicle-stimulating hormone level at the end of week 24 (1.72 vs. 5.95 IU/L).

Safety

Treatment-related adverse events occurred in 73.6% of patients treated with relugolix and 68.8% of those who received leuprolide. Grade 3 or greater adverse events occurred in 3.4% and 2.6%, respectively. The respective incidences of fatal adverse events were 1.1% and 2.9%.

At 48 weeks, MACE had occurred in 2.9% of patients on relugolix and 6.2% on leuprolide. Among men with a history of a MACE event more than 6 months before study entry, leuprolide was associated with a nearly sixfold increased risk for a new MACE.

The investigators also found that compliance with the assigned medication was greater than 99% in each study arm, allaying concerns that men assigned to the oral therapy might be less likely to faithfully take their medicine.
 

Antagonists vs. agonists

Agents such as relugolix, which are, in effect, LHRH antagonists, have several advantages over LHRH agonists, according to invited discussant Elahe Mostaghel, MD, PhD, of the VA Puget Sound Health Care System and Fred Hutchinson Cancer Research Center, both in Seattle.

“Cost and access aside, antagonists have potential benefits over agonists, each of which may be more or less important, depending on context,” she said.

Antagonists have a more rapid onset of castration, lack the flare response seen with agonists such as leuprolide, and are associated with a significant decrease in risk for MACE.

“Differences in depth and consistency of androgen suppression may also be important. LHRH antagonists may be superior to LHRH agonists in this regard, although this remains to be fully proven, while rapid testosterone recovery and oral administration may also have benefits in particular contexts,” Dr. Mostaghel said.

“It is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting,” Celestia S. Higano, MD, of the University of Washington in Seattle wrote in an editorial accompanying the HERO study in The New England Journal of Medicine.

“Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects,” Dr. Higano added.

The HERO study was supported by Myovant. Dr. Shore disclosed relationships with Myovant and other companies. Dr. Mostaghel disclosed affiliations with Context Therapeutics. Dr. Hinago disclosed grants and fees from various companies, not including Myovant.

SOURCES: Shore ND et al. ASCO 2020, Abstract 5602; N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004325.

Relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, was more effective than injectable leuprolide at maintaining castration levels of testosterone in men with advanced prostate cancer, according to investigators from the phase 3 HERO trial.

Relugolix was also associated with a significantly lower incidence of major adverse cardiovascular events (MACE), reported Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, S.C., in a presentation made as a part of the American Society of Clinical Oncology virtual scientific program. The study was published simultaneously in The New England Journal of Medicine.

“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT [androgen-deprivation therapy] in advanced prostate cancer,” Dr. Shore said. He added that a potential advantage of relugolix compared with the leutenizing hormone-releasing hormone (LHRH) agonist leuprolide is the oral agent’s adverse event profile.

“Of note, and importantly, cardiovascular mortality is the leading cause of death for patients with prostate cancer. The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors, including obesity, diabetes, hypertension, and hyperlipidemia,” Dr. Shore said.

LHRH agonists also cause an initial testosterone surge that may cause an early but transient symptom flare. In contrast, relugolix has a direct inhibitory effect on pituitary GnRH receptors, leading to suppression of both leutenizing hormone and follicle-stimulating hormone, with no testosterone flare.
 

Study details

In the HERO trial, men with advanced prostate cancer were randomized in a 2:1 ratio to receive either relugolix at a 360-mg loading dose on day 1 followed by a 120-mg oral dose once daily (n = 622) or leuprolide delivered via depot injection every 3 months (n = 308) for a total of 48 weeks.

About half of all patients in each arm had biochemical (prostate-specific antigen, or “PSA”) relapse, 23% had newly diagnosed androgen-sensitive metastatic disease, and the remaining men (26%-28%) had advanced localized disease.

Patients with a history of a MACE event – a composite of nonfatal myocardial infarction, nonfatal stroke, and death from any cause – within 6 months were excluded.

The median PSA level at baseline was 11.7 mg/mL in the relugolix arm and 9.4 ng/mL in the leuprolide arm. Respective median testosterone levels were 415.8 ng/dL and 395.9 ng/dL.

“Of note, more than 90% of men enrolled in this study had at least one cardiovascular risk factor,” Dr. Shore said. “Tobacco use and obesity were common, as were diabetes and hypertension. Fourteen percent of men reported a prior history of major adverse cardiovascular event, such as a heart attack or stroke; this is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study’s cardiovascular exclusion criteria.”
 

Efficacy

Sustained testosterone suppression to castration levels (less than 50 ng/dL) was achieved through 48 weeks in 96.7% of patients on relugolix, compared with 88.8% of men on leuprolide.

The absolute difference of 7.9% reached the statistical definitions for both noninferiority and superiority of relugolix over leuprolide (P for superiority < .001).

Mean testosterone levels on day 4 had decreased to below 50 ng/dL for relugolix and were maintained at castration levels until the end of treatment. In the leuprolide group, the mean testosterone level on day 4 was 625 ng/dL, which declined to castration levels by day 29 and remained below 50 ng/dL after the end of treatment at week 53. In contrast, testosterone levels in the relugolix arm began to recover immediately after the cessation of therapy.

Results with relugolix were significantly better than with leuprolide for the following endpoints (P < .0001 for all comparisons):

• Proportion of patients with PSA response at day 15 and confirmed at day 29 (79.4% vs. 19.8%)
• Cumulative probability of testosterone suppression to less than 50 ng/dL on day 15 (98.7% vs. 12.05%)
• Cumulative probability of profound testosterone suppression to less than 20 ng/dL on day 15 (78.38% vs. 0.98%)
• Mean follicle-stimulating hormone level at the end of week 24 (1.72 vs. 5.95 IU/L).

Safety

Treatment-related adverse events occurred in 73.6% of patients treated with relugolix and 68.8% of those who received leuprolide. Grade 3 or greater adverse events occurred in 3.4% and 2.6%, respectively. The respective incidences of fatal adverse events were 1.1% and 2.9%.

At 48 weeks, MACE had occurred in 2.9% of patients on relugolix and 6.2% on leuprolide. Among men with a history of a MACE event more than 6 months before study entry, leuprolide was associated with a nearly sixfold increased risk for a new MACE.

The investigators also found that compliance with the assigned medication was greater than 99% in each study arm, allaying concerns that men assigned to the oral therapy might be less likely to faithfully take their medicine.
 

Antagonists vs. agonists

Agents such as relugolix, which are, in effect, LHRH antagonists, have several advantages over LHRH agonists, according to invited discussant Elahe Mostaghel, MD, PhD, of the VA Puget Sound Health Care System and Fred Hutchinson Cancer Research Center, both in Seattle.

“Cost and access aside, antagonists have potential benefits over agonists, each of which may be more or less important, depending on context,” she said.

Antagonists have a more rapid onset of castration, lack the flare response seen with agonists such as leuprolide, and are associated with a significant decrease in risk for MACE.

“Differences in depth and consistency of androgen suppression may also be important. LHRH antagonists may be superior to LHRH agonists in this regard, although this remains to be fully proven, while rapid testosterone recovery and oral administration may also have benefits in particular contexts,” Dr. Mostaghel said.

“It is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting,” Celestia S. Higano, MD, of the University of Washington in Seattle wrote in an editorial accompanying the HERO study in The New England Journal of Medicine.

“Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects,” Dr. Higano added.

The HERO study was supported by Myovant. Dr. Shore disclosed relationships with Myovant and other companies. Dr. Mostaghel disclosed affiliations with Context Therapeutics. Dr. Hinago disclosed grants and fees from various companies, not including Myovant.

SOURCES: Shore ND et al. ASCO 2020, Abstract 5602; N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004325.

Relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, was more effective than injectable leuprolide at maintaining castration levels of testosterone in men with advanced prostate cancer, according to investigators from the phase 3 HERO trial.

Relugolix was also associated with a significantly lower incidence of major adverse cardiovascular events (MACE), reported Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, S.C., in a presentation made as a part of the American Society of Clinical Oncology virtual scientific program. The study was published simultaneously in The New England Journal of Medicine.

“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT [androgen-deprivation therapy] in advanced prostate cancer,” Dr. Shore said. He added that a potential advantage of relugolix compared with the leutenizing hormone-releasing hormone (LHRH) agonist leuprolide is the oral agent’s adverse event profile.

“Of note, and importantly, cardiovascular mortality is the leading cause of death for patients with prostate cancer. The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors, including obesity, diabetes, hypertension, and hyperlipidemia,” Dr. Shore said.

LHRH agonists also cause an initial testosterone surge that may cause an early but transient symptom flare. In contrast, relugolix has a direct inhibitory effect on pituitary GnRH receptors, leading to suppression of both leutenizing hormone and follicle-stimulating hormone, with no testosterone flare.
 

Study details

In the HERO trial, men with advanced prostate cancer were randomized in a 2:1 ratio to receive either relugolix at a 360-mg loading dose on day 1 followed by a 120-mg oral dose once daily (n = 622) or leuprolide delivered via depot injection every 3 months (n = 308) for a total of 48 weeks.

About half of all patients in each arm had biochemical (prostate-specific antigen, or “PSA”) relapse, 23% had newly diagnosed androgen-sensitive metastatic disease, and the remaining men (26%-28%) had advanced localized disease.

Patients with a history of a MACE event – a composite of nonfatal myocardial infarction, nonfatal stroke, and death from any cause – within 6 months were excluded.

The median PSA level at baseline was 11.7 mg/mL in the relugolix arm and 9.4 ng/mL in the leuprolide arm. Respective median testosterone levels were 415.8 ng/dL and 395.9 ng/dL.

“Of note, more than 90% of men enrolled in this study had at least one cardiovascular risk factor,” Dr. Shore said. “Tobacco use and obesity were common, as were diabetes and hypertension. Fourteen percent of men reported a prior history of major adverse cardiovascular event, such as a heart attack or stroke; this is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study’s cardiovascular exclusion criteria.”
 

Efficacy

Sustained testosterone suppression to castration levels (less than 50 ng/dL) was achieved through 48 weeks in 96.7% of patients on relugolix, compared with 88.8% of men on leuprolide.

The absolute difference of 7.9% reached the statistical definitions for both noninferiority and superiority of relugolix over leuprolide (P for superiority < .001).

Mean testosterone levels on day 4 had decreased to below 50 ng/dL for relugolix and were maintained at castration levels until the end of treatment. In the leuprolide group, the mean testosterone level on day 4 was 625 ng/dL, which declined to castration levels by day 29 and remained below 50 ng/dL after the end of treatment at week 53. In contrast, testosterone levels in the relugolix arm began to recover immediately after the cessation of therapy.

Results with relugolix were significantly better than with leuprolide for the following endpoints (P < .0001 for all comparisons):

• Proportion of patients with PSA response at day 15 and confirmed at day 29 (79.4% vs. 19.8%)
• Cumulative probability of testosterone suppression to less than 50 ng/dL on day 15 (98.7% vs. 12.05%)
• Cumulative probability of profound testosterone suppression to less than 20 ng/dL on day 15 (78.38% vs. 0.98%)
• Mean follicle-stimulating hormone level at the end of week 24 (1.72 vs. 5.95 IU/L).

Safety

Treatment-related adverse events occurred in 73.6% of patients treated with relugolix and 68.8% of those who received leuprolide. Grade 3 or greater adverse events occurred in 3.4% and 2.6%, respectively. The respective incidences of fatal adverse events were 1.1% and 2.9%.

At 48 weeks, MACE had occurred in 2.9% of patients on relugolix and 6.2% on leuprolide. Among men with a history of a MACE event more than 6 months before study entry, leuprolide was associated with a nearly sixfold increased risk for a new MACE.

The investigators also found that compliance with the assigned medication was greater than 99% in each study arm, allaying concerns that men assigned to the oral therapy might be less likely to faithfully take their medicine.
 

Antagonists vs. agonists

Agents such as relugolix, which are, in effect, LHRH antagonists, have several advantages over LHRH agonists, according to invited discussant Elahe Mostaghel, MD, PhD, of the VA Puget Sound Health Care System and Fred Hutchinson Cancer Research Center, both in Seattle.

“Cost and access aside, antagonists have potential benefits over agonists, each of which may be more or less important, depending on context,” she said.

Antagonists have a more rapid onset of castration, lack the flare response seen with agonists such as leuprolide, and are associated with a significant decrease in risk for MACE.

“Differences in depth and consistency of androgen suppression may also be important. LHRH antagonists may be superior to LHRH agonists in this regard, although this remains to be fully proven, while rapid testosterone recovery and oral administration may also have benefits in particular contexts,” Dr. Mostaghel said.

“It is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting,” Celestia S. Higano, MD, of the University of Washington in Seattle wrote in an editorial accompanying the HERO study in The New England Journal of Medicine.

“Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects,” Dr. Higano added.

The HERO study was supported by Myovant. Dr. Shore disclosed relationships with Myovant and other companies. Dr. Mostaghel disclosed affiliations with Context Therapeutics. Dr. Hinago disclosed grants and fees from various companies, not including Myovant.

SOURCES: Shore ND et al. ASCO 2020, Abstract 5602; N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004325.

Frontline pembrolizumab doubled progression-free survival (PFS), when compared with chemotherapy, among patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer in the KEYNOTE-177 study.

The median PFS was 16.5 months for patients who received pembrolizumab and 8.2 months for those who received investigators’ choice of chemotherapy (one of six regimens).

“In the past, no medical treatment has shown such difference in terms of improvement of PFS in metastatic colorectal cancer,” said study investigator Thierry André, MD, of Hôpital Saint Antoine in Paris.

“Today, this study demonstrates that the majority of the 5% of patients with metastatic colorectal cancer selected by MSI-high status benefited greatly from anti–PD-1 [programmed death-1] pembrolizumab, compared with standard of care,” he added.

Dr. André discussed the study in a press briefing prior to his presentation of the data as part of the American Society of Clinical Oncology virtual scientific program.

“I think this is setting a new standard of care,” said Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center in Houston. Dr. Overman, the invited discussant, commented on the KEYNOTE-177 study in an interview prior to the presentation.

Dr. Overman noted that, although the overall response rate was higher with pembrolizumab, the rate of progressive disease was higher in the pembrolizumab arm than in the chemotherapy arm. Progressive disease was the best response in 29.4% of patients on pembrolizumab and 12.3% of patients on chemotherapy.

“The only area where I think the question on pembrolizumab is still open would be in the group of patients where we’re saying ‘I care about the near future – this patient has so many symptoms and so much disease burden that I care what happens in the short term,’” Dr. Overman said. He added that, for this subgroup of patients, chemotherapy or pembrolizumab in combination with another immunotherapy, such as ipilimumab, might be more appropriate.
 

KEYNOTE-177 details

Investigators enrolled 307 patients with confirmed, untreated MSI-H/dMMR metastatic colorectal cancer and good performance status (Eastern Cooperative Oncology Group performance status 0 or 1).

Patients were randomized to pembrolizumab at 200 mg every 3 weeks for up to 35 cycles (n = 153) or to the investigators’ choice of chemotherapy (n = 154). Chemotherapy regimens were modified FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) alone or in combination with either bevacizumab or cetuximab, or FOLFIRI (leucovorin, fluorouracil, irinotecan) alone or in combination with either bevacizumab or cetuximab.

Patients assigned to the chemotherapy arm were allowed to cross over to pembrolizumab for up to 35 cycles if they had disease progression confirmed by central review.

PFS is a coprimary endpoint with overall survival. The trial was deemed to be successful if either of the coprimary endpoints was met. Overall survival results are not yet available.

The median PFS was 16.5 months with pembrolizumab and 8.2 months with chemotherapy (hazard ratio, 0.60; P = .0002). The 12-month PFS rates were 55% and 37%, respectively. The 24-month PFS rates were 48% and 19%, respectively.

Overall response rates were 43.8% with pembrolizumab, consisting of 11.1% complete responses and 32.7% partial responses. The overall response rate with chemotherapy was 33.1%, consisting of 3.9% complete responses and 29.2% partial responses.

In all, 20.9% of patients on pembrolizumab and 42.2% of those on chemotherapy had stable disease. Rates of progressive disease were 29.4% and 12.3%, respectively.

The median duration of response was not reached in the pembrolizumab arm and was 10.6 months in the chemotherapy arm. At 2 years, 83% of patients treated with pembrolizumab and 35% treated with chemotherapy had ongoing responses.

Grade 3 or greater treatment-related adverse events occurred in 22% of patients on pembrolizumab and 66% on chemotherapy.

Immune-mediated adverse events and infusion reactions were more common with pembrolizumab than with chemotherapy (31% and 13%, respectively). Adverse events that were common with chemotherapy included gastrointestinal events, fatigue, neutropenia, and peripheral sensory neuropathy.

The study was funded by Merck. Dr. André disclosed relationships with multiple companies, including MSD Oncology. Dr. Overman disclosed consulting activities with various companies, not including Merck.

SOURCE: André T et al. ASCO 2020, Abstract LBA4.

Frontline pembrolizumab doubled progression-free survival (PFS), when compared with chemotherapy, among patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer in the KEYNOTE-177 study.

The median PFS was 16.5 months for patients who received pembrolizumab and 8.2 months for those who received investigators’ choice of chemotherapy (one of six regimens).

“In the past, no medical treatment has shown such difference in terms of improvement of PFS in metastatic colorectal cancer,” said study investigator Thierry André, MD, of Hôpital Saint Antoine in Paris.

“Today, this study demonstrates that the majority of the 5% of patients with metastatic colorectal cancer selected by MSI-high status benefited greatly from anti–PD-1 [programmed death-1] pembrolizumab, compared with standard of care,” he added.

Dr. André discussed the study in a press briefing prior to his presentation of the data as part of the American Society of Clinical Oncology virtual scientific program.

“I think this is setting a new standard of care,” said Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center in Houston. Dr. Overman, the invited discussant, commented on the KEYNOTE-177 study in an interview prior to the presentation.

Dr. Overman noted that, although the overall response rate was higher with pembrolizumab, the rate of progressive disease was higher in the pembrolizumab arm than in the chemotherapy arm. Progressive disease was the best response in 29.4% of patients on pembrolizumab and 12.3% of patients on chemotherapy.

“The only area where I think the question on pembrolizumab is still open would be in the group of patients where we’re saying ‘I care about the near future – this patient has so many symptoms and so much disease burden that I care what happens in the short term,’” Dr. Overman said. He added that, for this subgroup of patients, chemotherapy or pembrolizumab in combination with another immunotherapy, such as ipilimumab, might be more appropriate.
 

KEYNOTE-177 details

Investigators enrolled 307 patients with confirmed, untreated MSI-H/dMMR metastatic colorectal cancer and good performance status (Eastern Cooperative Oncology Group performance status 0 or 1).

Patients were randomized to pembrolizumab at 200 mg every 3 weeks for up to 35 cycles (n = 153) or to the investigators’ choice of chemotherapy (n = 154). Chemotherapy regimens were modified FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) alone or in combination with either bevacizumab or cetuximab, or FOLFIRI (leucovorin, fluorouracil, irinotecan) alone or in combination with either bevacizumab or cetuximab.

Patients assigned to the chemotherapy arm were allowed to cross over to pembrolizumab for up to 35 cycles if they had disease progression confirmed by central review.

PFS is a coprimary endpoint with overall survival. The trial was deemed to be successful if either of the coprimary endpoints was met. Overall survival results are not yet available.

The median PFS was 16.5 months with pembrolizumab and 8.2 months with chemotherapy (hazard ratio, 0.60; P = .0002). The 12-month PFS rates were 55% and 37%, respectively. The 24-month PFS rates were 48% and 19%, respectively.

Overall response rates were 43.8% with pembrolizumab, consisting of 11.1% complete responses and 32.7% partial responses. The overall response rate with chemotherapy was 33.1%, consisting of 3.9% complete responses and 29.2% partial responses.

In all, 20.9% of patients on pembrolizumab and 42.2% of those on chemotherapy had stable disease. Rates of progressive disease were 29.4% and 12.3%, respectively.

The median duration of response was not reached in the pembrolizumab arm and was 10.6 months in the chemotherapy arm. At 2 years, 83% of patients treated with pembrolizumab and 35% treated with chemotherapy had ongoing responses.

Grade 3 or greater treatment-related adverse events occurred in 22% of patients on pembrolizumab and 66% on chemotherapy.

Immune-mediated adverse events and infusion reactions were more common with pembrolizumab than with chemotherapy (31% and 13%, respectively). Adverse events that were common with chemotherapy included gastrointestinal events, fatigue, neutropenia, and peripheral sensory neuropathy.

The study was funded by Merck. Dr. André disclosed relationships with multiple companies, including MSD Oncology. Dr. Overman disclosed consulting activities with various companies, not including Merck.

SOURCE: André T et al. ASCO 2020, Abstract LBA4.

Frontline pembrolizumab doubled progression-free survival (PFS), when compared with chemotherapy, among patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer in the KEYNOTE-177 study.

The median PFS was 16.5 months for patients who received pembrolizumab and 8.2 months for those who received investigators’ choice of chemotherapy (one of six regimens).

“In the past, no medical treatment has shown such difference in terms of improvement of PFS in metastatic colorectal cancer,” said study investigator Thierry André, MD, of Hôpital Saint Antoine in Paris.

“Today, this study demonstrates that the majority of the 5% of patients with metastatic colorectal cancer selected by MSI-high status benefited greatly from anti–PD-1 [programmed death-1] pembrolizumab, compared with standard of care,” he added.

Dr. André discussed the study in a press briefing prior to his presentation of the data as part of the American Society of Clinical Oncology virtual scientific program.

“I think this is setting a new standard of care,” said Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center in Houston. Dr. Overman, the invited discussant, commented on the KEYNOTE-177 study in an interview prior to the presentation.

Dr. Overman noted that, although the overall response rate was higher with pembrolizumab, the rate of progressive disease was higher in the pembrolizumab arm than in the chemotherapy arm. Progressive disease was the best response in 29.4% of patients on pembrolizumab and 12.3% of patients on chemotherapy.

“The only area where I think the question on pembrolizumab is still open would be in the group of patients where we’re saying ‘I care about the near future – this patient has so many symptoms and so much disease burden that I care what happens in the short term,’” Dr. Overman said. He added that, for this subgroup of patients, chemotherapy or pembrolizumab in combination with another immunotherapy, such as ipilimumab, might be more appropriate.
 

KEYNOTE-177 details

Investigators enrolled 307 patients with confirmed, untreated MSI-H/dMMR metastatic colorectal cancer and good performance status (Eastern Cooperative Oncology Group performance status 0 or 1).

Patients were randomized to pembrolizumab at 200 mg every 3 weeks for up to 35 cycles (n = 153) or to the investigators’ choice of chemotherapy (n = 154). Chemotherapy regimens were modified FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) alone or in combination with either bevacizumab or cetuximab, or FOLFIRI (leucovorin, fluorouracil, irinotecan) alone or in combination with either bevacizumab or cetuximab.

Patients assigned to the chemotherapy arm were allowed to cross over to pembrolizumab for up to 35 cycles if they had disease progression confirmed by central review.

PFS is a coprimary endpoint with overall survival. The trial was deemed to be successful if either of the coprimary endpoints was met. Overall survival results are not yet available.

The median PFS was 16.5 months with pembrolizumab and 8.2 months with chemotherapy (hazard ratio, 0.60; P = .0002). The 12-month PFS rates were 55% and 37%, respectively. The 24-month PFS rates were 48% and 19%, respectively.

Overall response rates were 43.8% with pembrolizumab, consisting of 11.1% complete responses and 32.7% partial responses. The overall response rate with chemotherapy was 33.1%, consisting of 3.9% complete responses and 29.2% partial responses.

In all, 20.9% of patients on pembrolizumab and 42.2% of those on chemotherapy had stable disease. Rates of progressive disease were 29.4% and 12.3%, respectively.

The median duration of response was not reached in the pembrolizumab arm and was 10.6 months in the chemotherapy arm. At 2 years, 83% of patients treated with pembrolizumab and 35% treated with chemotherapy had ongoing responses.

Grade 3 or greater treatment-related adverse events occurred in 22% of patients on pembrolizumab and 66% on chemotherapy.

Immune-mediated adverse events and infusion reactions were more common with pembrolizumab than with chemotherapy (31% and 13%, respectively). Adverse events that were common with chemotherapy included gastrointestinal events, fatigue, neutropenia, and peripheral sensory neuropathy.

The study was funded by Merck. Dr. André disclosed relationships with multiple companies, including MSD Oncology. Dr. Overman disclosed consulting activities with various companies, not including Merck.

SOURCE: André T et al. ASCO 2020, Abstract LBA4.

Adding pembrolizumab to standard chemotherapy significantly improved progression-free survival for patients with metastatic triple-negative breast cancer, but only if their tumors were enriched with comparatively high levels of the target programmed death ligand-1 (PD-L1), results of the KEYNOTE 355 trial showed.

Among 843 patients with triple-negative breast cancer (TNBC) randomized to receive either investigator’s choice of chemotherapy plus pembrolizumab (Keytruda) or placebo, patients whose tumors had a PD-L1 combined positive score (CPS) of 10 or higher had a median progression-free survival (PFS) of 9.7 months when treated with pembrolizumab and chemotherapy, compared with 5.6 months among patients treated with chemotherapy and placebo, reported Javier Cortes, MD, PhD, from the Vall d´Hebron Institute of Oncology in Madrid and Barcelona.

However, among patients with CPS between 1 and 10, there was no significant difference in PFS between the treatment arms, he said in a presentation made as a part of the 2020 American Society of Clinical Oncology virtual scientific program.

“The inclusion of taxanes and a known taxane/platinum–based regimen permits assessment of the clinical benefit of pembro in combination with several routinely used chemo partners. A trend toward improved efficacy with PD-L1 enrichment was observed in patients treated with pembro plus chemo. The improvement in progression-free survival with chemotherapy and pembrolizumab was observed across patient subgroups,” said Dr. Cortes.

In the KEYNOTE-522 study, adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive TNBC would have a pathologic complete response and sustained clinical benefit.

KEYNOTE-355 examined whether pembrolizumab in combination with chemotherapy could provide additional benefit over chemotherapy alone in patients with previously untreated locally recurrent inoperable or metastatic TNBC.

Patients with previously untreated metastatic triple-negative breast cancer who had at least 6 months between definite surgery or last dose of adjuvant chemotherapy (whichever came last) and first disease recurrence were stratified by study chemotherapy received, tumor PD-L1 expression at baseline, and prior treatment with the same class of chemotherapy in the neoadjuvant and/or adjuvant setting.

The patients were then randomized in a 2:1 ratio to pembrolizumab plus chemotherapy based on the investigator’s choice of nab-paclitaxel, paclitaxel, or carboplatin-gemcitabine (562 patients) or to chemotherapy alone (281).

Pembrolizumab and placebo were administered in a double-blind fashion for up to 35 doses. Chemotherapy was given at the investigator’s discretion according to local guidelines. This trial was not powered or designed to compare differential efficacy of the various chemotherapy regimens, Dr. Cortes noted.

The trial had dual primary endpoints of PFS in patients with PD-L1–positive tumors (CPS > 10 and > 1) and in the intention-to-treat population, and overall survival both in PD-L1-positive patients and the ITT population. Overall survival results will be reported at a later date.

As noted before, the primary endpoint was met in the population of patients with CPS higher than 10, with median PFS of 9.7 among those receiving pembrolizumab versus 5.6 months among those receiving placebo, and an estimated 1 year PFS of 39.1% versus 23% for controls, translating into a hazard ratio for progression on pembrolizumab of 0.65 (P = .0012).

In the patients with CPS higher than 1, however, the median PFS was 7.6 months with pembrolizumab compared with 5.6 months with placebo, translating into a hazard ratio of 0.74. However, the results did not meet the prespecified boundary for significance. Because of this, the statistical significance in the ITT population was not tested.

“In patients with PD-L1 CPS 10 or higher tumors, the benefit of pembro/chemo on progression-free survival was generally consistent across most predefined subgroups, including eight geographic regions, ECOG performance status, on-study chemo, and prior treatment with the same class of chemo,” Dr. Cortes said.

Treatment-related adverse events occurred in 96.3% of the patients on pembrolizumab and 95% of patients on placebo. Grade 3 or greater adverse events occurred in 68.1% versus 66.9%, respectively. Two patients in the pembrolizumab arm died from a treatment-related event. There were no treatment-related deaths in the placebo arm.

The most common events were those typically associated with chemotherapy, including anemia, neutropenia, nausea, alopecia, fatigue, decreased neutrophil counts, and elevated liver transaminases. Immune-mediated adverse events of any grade occurred in 25.6% of patients in the pembrolizumab arm versus 6% of controls; none of these events were fatal.

“What is clear in this study is that again we’re seeing efficacy of pembrolizumab in combination with chemotherapy increases with increases in CPS,” according to the invited discussant Catherine M. Kelly, MB, BCh, from University College Dublin and Mater Misericordiae University Hospital in Dublin.

“The results from today’s KEYNOTE-355 appear consistent in terms of progression-free survival. However, it is ‘watch this space’ until we get overall survival data before we can make any further comparisons,” she added.

Questions that still need to be answered include which is the best test for measuring PD-L1, whether patients with CPS of 1 or more but less than 10 benefit from the treatment, which of the available chemotherapy regimens is the best partner for pembrolizumab, how to treat patients who don’t respond to the combination, and what are the implications for PD-1/PD-L1 inhibitors in late-stage disease if they are approved in the neoadjuvant or adjuvant setting, Dr. Kelly said.

The study was funded by Merck. Dr. Cortes disclosed honoraria from, a consulting/advisory role for, and institutional research funding from Merck and others. Dr. Kelly disclosed honoraria from MSD Oncology and others, and travel expenses from Pfizer and Roche.

SOURCE: Cortes J et al. ASCO 2020, Abstract 1000.

Adding pembrolizumab to standard chemotherapy significantly improved progression-free survival for patients with metastatic triple-negative breast cancer, but only if their tumors were enriched with comparatively high levels of the target programmed death ligand-1 (PD-L1), results of the KEYNOTE 355 trial showed.

Among 843 patients with triple-negative breast cancer (TNBC) randomized to receive either investigator’s choice of chemotherapy plus pembrolizumab (Keytruda) or placebo, patients whose tumors had a PD-L1 combined positive score (CPS) of 10 or higher had a median progression-free survival (PFS) of 9.7 months when treated with pembrolizumab and chemotherapy, compared with 5.6 months among patients treated with chemotherapy and placebo, reported Javier Cortes, MD, PhD, from the Vall d´Hebron Institute of Oncology in Madrid and Barcelona.

However, among patients with CPS between 1 and 10, there was no significant difference in PFS between the treatment arms, he said in a presentation made as a part of the 2020 American Society of Clinical Oncology virtual scientific program.

“The inclusion of taxanes and a known taxane/platinum–based regimen permits assessment of the clinical benefit of pembro in combination with several routinely used chemo partners. A trend toward improved efficacy with PD-L1 enrichment was observed in patients treated with pembro plus chemo. The improvement in progression-free survival with chemotherapy and pembrolizumab was observed across patient subgroups,” said Dr. Cortes.

In the KEYNOTE-522 study, adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive TNBC would have a pathologic complete response and sustained clinical benefit.

KEYNOTE-355 examined whether pembrolizumab in combination with chemotherapy could provide additional benefit over chemotherapy alone in patients with previously untreated locally recurrent inoperable or metastatic TNBC.

Patients with previously untreated metastatic triple-negative breast cancer who had at least 6 months between definite surgery or last dose of adjuvant chemotherapy (whichever came last) and first disease recurrence were stratified by study chemotherapy received, tumor PD-L1 expression at baseline, and prior treatment with the same class of chemotherapy in the neoadjuvant and/or adjuvant setting.

The patients were then randomized in a 2:1 ratio to pembrolizumab plus chemotherapy based on the investigator’s choice of nab-paclitaxel, paclitaxel, or carboplatin-gemcitabine (562 patients) or to chemotherapy alone (281).

Pembrolizumab and placebo were administered in a double-blind fashion for up to 35 doses. Chemotherapy was given at the investigator’s discretion according to local guidelines. This trial was not powered or designed to compare differential efficacy of the various chemotherapy regimens, Dr. Cortes noted.

The trial had dual primary endpoints of PFS in patients with PD-L1–positive tumors (CPS > 10 and > 1) and in the intention-to-treat population, and overall survival both in PD-L1-positive patients and the ITT population. Overall survival results will be reported at a later date.

As noted before, the primary endpoint was met in the population of patients with CPS higher than 10, with median PFS of 9.7 among those receiving pembrolizumab versus 5.6 months among those receiving placebo, and an estimated 1 year PFS of 39.1% versus 23% for controls, translating into a hazard ratio for progression on pembrolizumab of 0.65 (P = .0012).

In the patients with CPS higher than 1, however, the median PFS was 7.6 months with pembrolizumab compared with 5.6 months with placebo, translating into a hazard ratio of 0.74. However, the results did not meet the prespecified boundary for significance. Because of this, the statistical significance in the ITT population was not tested.

“In patients with PD-L1 CPS 10 or higher tumors, the benefit of pembro/chemo on progression-free survival was generally consistent across most predefined subgroups, including eight geographic regions, ECOG performance status, on-study chemo, and prior treatment with the same class of chemo,” Dr. Cortes said.

Treatment-related adverse events occurred in 96.3% of the patients on pembrolizumab and 95% of patients on placebo. Grade 3 or greater adverse events occurred in 68.1% versus 66.9%, respectively. Two patients in the pembrolizumab arm died from a treatment-related event. There were no treatment-related deaths in the placebo arm.

The most common events were those typically associated with chemotherapy, including anemia, neutropenia, nausea, alopecia, fatigue, decreased neutrophil counts, and elevated liver transaminases. Immune-mediated adverse events of any grade occurred in 25.6% of patients in the pembrolizumab arm versus 6% of controls; none of these events were fatal.

“What is clear in this study is that again we’re seeing efficacy of pembrolizumab in combination with chemotherapy increases with increases in CPS,” according to the invited discussant Catherine M. Kelly, MB, BCh, from University College Dublin and Mater Misericordiae University Hospital in Dublin.

“The results from today’s KEYNOTE-355 appear consistent in terms of progression-free survival. However, it is ‘watch this space’ until we get overall survival data before we can make any further comparisons,” she added.

Questions that still need to be answered include which is the best test for measuring PD-L1, whether patients with CPS of 1 or more but less than 10 benefit from the treatment, which of the available chemotherapy regimens is the best partner for pembrolizumab, how to treat patients who don’t respond to the combination, and what are the implications for PD-1/PD-L1 inhibitors in late-stage disease if they are approved in the neoadjuvant or adjuvant setting, Dr. Kelly said.

The study was funded by Merck. Dr. Cortes disclosed honoraria from, a consulting/advisory role for, and institutional research funding from Merck and others. Dr. Kelly disclosed honoraria from MSD Oncology and others, and travel expenses from Pfizer and Roche.

SOURCE: Cortes J et al. ASCO 2020, Abstract 1000.

Adding pembrolizumab to standard chemotherapy significantly improved progression-free survival for patients with metastatic triple-negative breast cancer, but only if their tumors were enriched with comparatively high levels of the target programmed death ligand-1 (PD-L1), results of the KEYNOTE 355 trial showed.

Among 843 patients with triple-negative breast cancer (TNBC) randomized to receive either investigator’s choice of chemotherapy plus pembrolizumab (Keytruda) or placebo, patients whose tumors had a PD-L1 combined positive score (CPS) of 10 or higher had a median progression-free survival (PFS) of 9.7 months when treated with pembrolizumab and chemotherapy, compared with 5.6 months among patients treated with chemotherapy and placebo, reported Javier Cortes, MD, PhD, from the Vall d´Hebron Institute of Oncology in Madrid and Barcelona.

However, among patients with CPS between 1 and 10, there was no significant difference in PFS between the treatment arms, he said in a presentation made as a part of the 2020 American Society of Clinical Oncology virtual scientific program.

“The inclusion of taxanes and a known taxane/platinum–based regimen permits assessment of the clinical benefit of pembro in combination with several routinely used chemo partners. A trend toward improved efficacy with PD-L1 enrichment was observed in patients treated with pembro plus chemo. The improvement in progression-free survival with chemotherapy and pembrolizumab was observed across patient subgroups,” said Dr. Cortes.

In the KEYNOTE-522 study, adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive TNBC would have a pathologic complete response and sustained clinical benefit.

KEYNOTE-355 examined whether pembrolizumab in combination with chemotherapy could provide additional benefit over chemotherapy alone in patients with previously untreated locally recurrent inoperable or metastatic TNBC.

Patients with previously untreated metastatic triple-negative breast cancer who had at least 6 months between definite surgery or last dose of adjuvant chemotherapy (whichever came last) and first disease recurrence were stratified by study chemotherapy received, tumor PD-L1 expression at baseline, and prior treatment with the same class of chemotherapy in the neoadjuvant and/or adjuvant setting.

The patients were then randomized in a 2:1 ratio to pembrolizumab plus chemotherapy based on the investigator’s choice of nab-paclitaxel, paclitaxel, or carboplatin-gemcitabine (562 patients) or to chemotherapy alone (281).

Pembrolizumab and placebo were administered in a double-blind fashion for up to 35 doses. Chemotherapy was given at the investigator’s discretion according to local guidelines. This trial was not powered or designed to compare differential efficacy of the various chemotherapy regimens, Dr. Cortes noted.

The trial had dual primary endpoints of PFS in patients with PD-L1–positive tumors (CPS > 10 and > 1) and in the intention-to-treat population, and overall survival both in PD-L1-positive patients and the ITT population. Overall survival results will be reported at a later date.

As noted before, the primary endpoint was met in the population of patients with CPS higher than 10, with median PFS of 9.7 among those receiving pembrolizumab versus 5.6 months among those receiving placebo, and an estimated 1 year PFS of 39.1% versus 23% for controls, translating into a hazard ratio for progression on pembrolizumab of 0.65 (P = .0012).

In the patients with CPS higher than 1, however, the median PFS was 7.6 months with pembrolizumab compared with 5.6 months with placebo, translating into a hazard ratio of 0.74. However, the results did not meet the prespecified boundary for significance. Because of this, the statistical significance in the ITT population was not tested.

“In patients with PD-L1 CPS 10 or higher tumors, the benefit of pembro/chemo on progression-free survival was generally consistent across most predefined subgroups, including eight geographic regions, ECOG performance status, on-study chemo, and prior treatment with the same class of chemo,” Dr. Cortes said.

Treatment-related adverse events occurred in 96.3% of the patients on pembrolizumab and 95% of patients on placebo. Grade 3 or greater adverse events occurred in 68.1% versus 66.9%, respectively. Two patients in the pembrolizumab arm died from a treatment-related event. There were no treatment-related deaths in the placebo arm.

The most common events were those typically associated with chemotherapy, including anemia, neutropenia, nausea, alopecia, fatigue, decreased neutrophil counts, and elevated liver transaminases. Immune-mediated adverse events of any grade occurred in 25.6% of patients in the pembrolizumab arm versus 6% of controls; none of these events were fatal.

“What is clear in this study is that again we’re seeing efficacy of pembrolizumab in combination with chemotherapy increases with increases in CPS,” according to the invited discussant Catherine M. Kelly, MB, BCh, from University College Dublin and Mater Misericordiae University Hospital in Dublin.

“The results from today’s KEYNOTE-355 appear consistent in terms of progression-free survival. However, it is ‘watch this space’ until we get overall survival data before we can make any further comparisons,” she added.

Questions that still need to be answered include which is the best test for measuring PD-L1, whether patients with CPS of 1 or more but less than 10 benefit from the treatment, which of the available chemotherapy regimens is the best partner for pembrolizumab, how to treat patients who don’t respond to the combination, and what are the implications for PD-1/PD-L1 inhibitors in late-stage disease if they are approved in the neoadjuvant or adjuvant setting, Dr. Kelly said.

The study was funded by Merck. Dr. Cortes disclosed honoraria from, a consulting/advisory role for, and institutional research funding from Merck and others. Dr. Kelly disclosed honoraria from MSD Oncology and others, and travel expenses from Pfizer and Roche.

SOURCE: Cortes J et al. ASCO 2020, Abstract 1000.