Neil Osterweil

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Adding ibrutinib to chemotherapy did not improve outcomes for children and young adults with relapsed or refractory mature B-cell non-Hodgkin lymphoma (B-NHL), an interim analysis of the SPARKLE trial showed.

Among 51 patients aged 1-30 years with mature B-NHL that had been diagnosed before age 18, there was no significant difference in the primary endpoint of event-free survival (EFS) between patients assigned on a 2:1 basis to receive either ibrutinib (Imbruvica) plus one of two chemotherapy regimens or to chemotherapy alone. In fact, EFS was shorter among patients assigned to ibrutinib, although a larger proportion of these patients had previously received rituximab, a known factor for poor prognosis, reported Amos Burke, MD, from Cambridge (England) University.

The trial was stopped for futility in May 2020, after a median follow-up of 17.97 months.

“Further studies are required to determine the optimal therapy for patients with relapsed, mature B-NHL, especially those who have received prior rituximab,” he said in an audio walk-through of a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a very challenging patient population because they historically have had a very poor survival rate,” commented Paul J. Galardy, MD, a pediatric hematologist/oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study.

“The field has struggled to improve outcomes for these patients in part because there are relatively few patients per year with relapsed refractory mature B-cell lymphoma due to the very effective nature of the up-front therapy. This makes new clinical trials difficult to perform,” he said.
 

Poor prognosis

Ibrutinib, an inhibitor of Bruton tyrosine kinase, is approved in the United States for treatment of marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as other indications, all in adults only. It has also been shown to have activity against B-NHL in preclinical and early human trials, Dr. Burke said.

Given the poor prognosis of children and young adults with relapsed/refractory mature B-NHL – a 2-year overall survival (OS) of 30% or less with chemoimmunotherapy – the investigators tested whether adding ibrutinib to the standard of care could improve outcomes.

They enrolled patients with relapsed/refractory B-NHL in first relapse or primarily refractory to conventional therapy, with measurable disease (greater than 1 cm) by CT, bone marrow involvement, or cerebrospinal fluid with blasts. The patients were required to have Karnofsky-Lansky performance scores of 50 or greater.

The histologies included Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt-like lymphoma, Burkitt leukemia, primary mediastinal B-cell lymphoma, and other unspecified types.

Dr. Burke reported results on 48 patients included in the May 2020 analysis, plus 3 additional patients who were enrolled between the data cutoff for the first analysis and the meeting of the independent data monitoring committee where the decision was made to stop the trial.

A total of 35 patients were randomized to receive ibrutinib with either the RICE (rituximab plus ifosfamide, carboplatin, and etoposide) or RVICI (rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) regimen. All of these patients received treatment on study.

Of the 18 patients randomized to receive either RICE or RVICI alone, 1 did not receive any cycles of chemoimmunotherapy.

At the data cutoff for the updated analysis in November 2020, 14 patients assigned to ibrutinib and 4 assigned to chemoimmunotherapy alone remained on study; no patients in either arm were still receiving therapy.

A total of 17 patients assigned to the combination arm died and 4 withdrew consent. In the chemoimmunotherapy-alone arm, 10 died and 2 withdrew consent.

In both arms, patients were treated until either completing three cycles of therapy, start of conditioning treatment prior to stem cell transplantation, disease progression, or unacceptable toxicity.

In the ibrutinib arm, the median EFS was 5.36 months, compared with 6.97 months with chemoimmunotherapy alone, translating into a hazard ratio for EFS with ibrutinib of 1.078 (nonsignificant).

The respective median overall survival was 13.44 versus 11.07 months,

Subgroup analysis showed that EFS and OS did not differ significantly by age, histology, background regimen, or central nervous system or bone marrow involvement. ­

Overall response rates were 68.6% in the ibrutinib arm, and 81.3% in the chemoimmunotherapy arm. The respective complete response rates were 8.6% and 18.8%, and partial response rates were 60% and 62.5%.

The overall treatment-emergent adverse event (TEAE) profile was similar between the treatment arms, although six patients in the ibrutinib arm versus one in the chemoimmunotherapy arm experienced a major hemorrhage. One patients in the ibrutinib arm died from pulmonary hemorrhage.

Dr. Burke noted that, although the numbers were small, the failure to see a difference in efficacy between study arms may have been caused in part by a greater number of patients assigned to ibrutinib who had received prior treatment with rituximab (85.7% vs. 56.3%).
 

Not the right partner?

“The results of this study would suggest that ibrutinib is not the right agent. This is not altogether unexpected,” Dr. Galardy said. “The benefit of ibrutinib in adults with mature B-cell lymphoma is primarily based on biological characteristics of lymphomas that develop in older individuals.”

He noted that mature B-cell lymphoma in older adults is often of the activated B-cell subtype, which frequently has mutations that make it sensitive to ibrutinib. In contrast, children, adolescents, and young adults more commonly have the germinal center B-cell subtype that doesn’t have similarly targetable mutations.

He added that, although the reasons for poor prognosis in patients with prior rituximab exposure are unclear, “it is likely that patients who have recurrent or refractory disease after therapy that included rituximab may have developed resistance to this drug. Since both arms of this study included rituximab as a component of the therapy, the patients with prior exposure to this drug may have had reduced benefit of the additional rituximab, compared with those who had not received the drug before.”

The SPARKLE trial was funded by Janssen Research & Development. Dr. Burke disclosed consultancy fees from Janssen and others. Dr. Galardy is an equity holder in Abbott and AbbVie.

Adding ibrutinib to chemotherapy did not improve outcomes for children and young adults with relapsed or refractory mature B-cell non-Hodgkin lymphoma (B-NHL), an interim analysis of the SPARKLE trial showed.

Among 51 patients aged 1-30 years with mature B-NHL that had been diagnosed before age 18, there was no significant difference in the primary endpoint of event-free survival (EFS) between patients assigned on a 2:1 basis to receive either ibrutinib (Imbruvica) plus one of two chemotherapy regimens or to chemotherapy alone. In fact, EFS was shorter among patients assigned to ibrutinib, although a larger proportion of these patients had previously received rituximab, a known factor for poor prognosis, reported Amos Burke, MD, from Cambridge (England) University.

The trial was stopped for futility in May 2020, after a median follow-up of 17.97 months.

“Further studies are required to determine the optimal therapy for patients with relapsed, mature B-NHL, especially those who have received prior rituximab,” he said in an audio walk-through of a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a very challenging patient population because they historically have had a very poor survival rate,” commented Paul J. Galardy, MD, a pediatric hematologist/oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study.

“The field has struggled to improve outcomes for these patients in part because there are relatively few patients per year with relapsed refractory mature B-cell lymphoma due to the very effective nature of the up-front therapy. This makes new clinical trials difficult to perform,” he said.
 

Poor prognosis

Ibrutinib, an inhibitor of Bruton tyrosine kinase, is approved in the United States for treatment of marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as other indications, all in adults only. It has also been shown to have activity against B-NHL in preclinical and early human trials, Dr. Burke said.

Given the poor prognosis of children and young adults with relapsed/refractory mature B-NHL – a 2-year overall survival (OS) of 30% or less with chemoimmunotherapy – the investigators tested whether adding ibrutinib to the standard of care could improve outcomes.

They enrolled patients with relapsed/refractory B-NHL in first relapse or primarily refractory to conventional therapy, with measurable disease (greater than 1 cm) by CT, bone marrow involvement, or cerebrospinal fluid with blasts. The patients were required to have Karnofsky-Lansky performance scores of 50 or greater.

The histologies included Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt-like lymphoma, Burkitt leukemia, primary mediastinal B-cell lymphoma, and other unspecified types.

Dr. Burke reported results on 48 patients included in the May 2020 analysis, plus 3 additional patients who were enrolled between the data cutoff for the first analysis and the meeting of the independent data monitoring committee where the decision was made to stop the trial.

A total of 35 patients were randomized to receive ibrutinib with either the RICE (rituximab plus ifosfamide, carboplatin, and etoposide) or RVICI (rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) regimen. All of these patients received treatment on study.

Of the 18 patients randomized to receive either RICE or RVICI alone, 1 did not receive any cycles of chemoimmunotherapy.

At the data cutoff for the updated analysis in November 2020, 14 patients assigned to ibrutinib and 4 assigned to chemoimmunotherapy alone remained on study; no patients in either arm were still receiving therapy.

A total of 17 patients assigned to the combination arm died and 4 withdrew consent. In the chemoimmunotherapy-alone arm, 10 died and 2 withdrew consent.

In both arms, patients were treated until either completing three cycles of therapy, start of conditioning treatment prior to stem cell transplantation, disease progression, or unacceptable toxicity.

In the ibrutinib arm, the median EFS was 5.36 months, compared with 6.97 months with chemoimmunotherapy alone, translating into a hazard ratio for EFS with ibrutinib of 1.078 (nonsignificant).

The respective median overall survival was 13.44 versus 11.07 months,

Subgroup analysis showed that EFS and OS did not differ significantly by age, histology, background regimen, or central nervous system or bone marrow involvement. ­

Overall response rates were 68.6% in the ibrutinib arm, and 81.3% in the chemoimmunotherapy arm. The respective complete response rates were 8.6% and 18.8%, and partial response rates were 60% and 62.5%.

The overall treatment-emergent adverse event (TEAE) profile was similar between the treatment arms, although six patients in the ibrutinib arm versus one in the chemoimmunotherapy arm experienced a major hemorrhage. One patients in the ibrutinib arm died from pulmonary hemorrhage.

Dr. Burke noted that, although the numbers were small, the failure to see a difference in efficacy between study arms may have been caused in part by a greater number of patients assigned to ibrutinib who had received prior treatment with rituximab (85.7% vs. 56.3%).
 

Not the right partner?

“The results of this study would suggest that ibrutinib is not the right agent. This is not altogether unexpected,” Dr. Galardy said. “The benefit of ibrutinib in adults with mature B-cell lymphoma is primarily based on biological characteristics of lymphomas that develop in older individuals.”

He noted that mature B-cell lymphoma in older adults is often of the activated B-cell subtype, which frequently has mutations that make it sensitive to ibrutinib. In contrast, children, adolescents, and young adults more commonly have the germinal center B-cell subtype that doesn’t have similarly targetable mutations.

He added that, although the reasons for poor prognosis in patients with prior rituximab exposure are unclear, “it is likely that patients who have recurrent or refractory disease after therapy that included rituximab may have developed resistance to this drug. Since both arms of this study included rituximab as a component of the therapy, the patients with prior exposure to this drug may have had reduced benefit of the additional rituximab, compared with those who had not received the drug before.”

The SPARKLE trial was funded by Janssen Research & Development. Dr. Burke disclosed consultancy fees from Janssen and others. Dr. Galardy is an equity holder in Abbott and AbbVie.

Adding ibrutinib to chemotherapy did not improve outcomes for children and young adults with relapsed or refractory mature B-cell non-Hodgkin lymphoma (B-NHL), an interim analysis of the SPARKLE trial showed.

Among 51 patients aged 1-30 years with mature B-NHL that had been diagnosed before age 18, there was no significant difference in the primary endpoint of event-free survival (EFS) between patients assigned on a 2:1 basis to receive either ibrutinib (Imbruvica) plus one of two chemotherapy regimens or to chemotherapy alone. In fact, EFS was shorter among patients assigned to ibrutinib, although a larger proportion of these patients had previously received rituximab, a known factor for poor prognosis, reported Amos Burke, MD, from Cambridge (England) University.

The trial was stopped for futility in May 2020, after a median follow-up of 17.97 months.

“Further studies are required to determine the optimal therapy for patients with relapsed, mature B-NHL, especially those who have received prior rituximab,” he said in an audio walk-through of a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a very challenging patient population because they historically have had a very poor survival rate,” commented Paul J. Galardy, MD, a pediatric hematologist/oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study.

“The field has struggled to improve outcomes for these patients in part because there are relatively few patients per year with relapsed refractory mature B-cell lymphoma due to the very effective nature of the up-front therapy. This makes new clinical trials difficult to perform,” he said.
 

Poor prognosis

Ibrutinib, an inhibitor of Bruton tyrosine kinase, is approved in the United States for treatment of marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as other indications, all in adults only. It has also been shown to have activity against B-NHL in preclinical and early human trials, Dr. Burke said.

Given the poor prognosis of children and young adults with relapsed/refractory mature B-NHL – a 2-year overall survival (OS) of 30% or less with chemoimmunotherapy – the investigators tested whether adding ibrutinib to the standard of care could improve outcomes.

They enrolled patients with relapsed/refractory B-NHL in first relapse or primarily refractory to conventional therapy, with measurable disease (greater than 1 cm) by CT, bone marrow involvement, or cerebrospinal fluid with blasts. The patients were required to have Karnofsky-Lansky performance scores of 50 or greater.

The histologies included Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt-like lymphoma, Burkitt leukemia, primary mediastinal B-cell lymphoma, and other unspecified types.

Dr. Burke reported results on 48 patients included in the May 2020 analysis, plus 3 additional patients who were enrolled between the data cutoff for the first analysis and the meeting of the independent data monitoring committee where the decision was made to stop the trial.

A total of 35 patients were randomized to receive ibrutinib with either the RICE (rituximab plus ifosfamide, carboplatin, and etoposide) or RVICI (rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) regimen. All of these patients received treatment on study.

Of the 18 patients randomized to receive either RICE or RVICI alone, 1 did not receive any cycles of chemoimmunotherapy.

At the data cutoff for the updated analysis in November 2020, 14 patients assigned to ibrutinib and 4 assigned to chemoimmunotherapy alone remained on study; no patients in either arm were still receiving therapy.

A total of 17 patients assigned to the combination arm died and 4 withdrew consent. In the chemoimmunotherapy-alone arm, 10 died and 2 withdrew consent.

In both arms, patients were treated until either completing three cycles of therapy, start of conditioning treatment prior to stem cell transplantation, disease progression, or unacceptable toxicity.

In the ibrutinib arm, the median EFS was 5.36 months, compared with 6.97 months with chemoimmunotherapy alone, translating into a hazard ratio for EFS with ibrutinib of 1.078 (nonsignificant).

The respective median overall survival was 13.44 versus 11.07 months,

Subgroup analysis showed that EFS and OS did not differ significantly by age, histology, background regimen, or central nervous system or bone marrow involvement. ­

Overall response rates were 68.6% in the ibrutinib arm, and 81.3% in the chemoimmunotherapy arm. The respective complete response rates were 8.6% and 18.8%, and partial response rates were 60% and 62.5%.

The overall treatment-emergent adverse event (TEAE) profile was similar between the treatment arms, although six patients in the ibrutinib arm versus one in the chemoimmunotherapy arm experienced a major hemorrhage. One patients in the ibrutinib arm died from pulmonary hemorrhage.

Dr. Burke noted that, although the numbers were small, the failure to see a difference in efficacy between study arms may have been caused in part by a greater number of patients assigned to ibrutinib who had received prior treatment with rituximab (85.7% vs. 56.3%).
 

Not the right partner?

“The results of this study would suggest that ibrutinib is not the right agent. This is not altogether unexpected,” Dr. Galardy said. “The benefit of ibrutinib in adults with mature B-cell lymphoma is primarily based on biological characteristics of lymphomas that develop in older individuals.”

He noted that mature B-cell lymphoma in older adults is often of the activated B-cell subtype, which frequently has mutations that make it sensitive to ibrutinib. In contrast, children, adolescents, and young adults more commonly have the germinal center B-cell subtype that doesn’t have similarly targetable mutations.

He added that, although the reasons for poor prognosis in patients with prior rituximab exposure are unclear, “it is likely that patients who have recurrent or refractory disease after therapy that included rituximab may have developed resistance to this drug. Since both arms of this study included rituximab as a component of the therapy, the patients with prior exposure to this drug may have had reduced benefit of the additional rituximab, compared with those who had not received the drug before.”

The SPARKLE trial was funded by Janssen Research & Development. Dr. Burke disclosed consultancy fees from Janssen and others. Dr. Galardy is an equity holder in Abbott and AbbVie.

It’s early days, but preliminary data show that a chimeric antigen receptor T-cell therapy (CAR T) product was associated with high rates of minimal residual disease (MRD) negativity, and complete or near-complete responses in children and adolescents with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL).

Among 24 patients aged 3-20 years with relapsed or refractory B-ALL treated with the CAR T construct brexucabtagene autoleucel (KTE-X19; Tecartus), 16 had either a complete response or CR with incomplete recovery of blood counts (CRi), for a combined CR/CRi rate of 67%, reported Alan S. Wayne, MD, from Children’s Hospital Los Angeles and the University of Southern California Norris Comprehensive Cancer Center, also in Los Angeles.

“Optimized KTE-X19 formulation of 40 mL and revised toxicity management were associated with an improved risk/benefit profile,” he said in audio narration accompanying a poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

Although overall survival for children and adolescents receiving first-line therapy for B-ALL is associated with remission rates of 80% or more, the prognosis is poor following relapse, despite the availability of newer therapies such as blinatumomab (Blincyto) and inotuzumab (Besponsa), with a 1-year overall survival rate of approximately 36%, he said.

To see whether they could improve on these odds, Dr. Wayne and colleagues conducted the phase 1 Zuma-4 trial, a single-arm, open-label study in children and adolescents with relapsed/refractory B-ALL.

He reported long-term follow-up results from the study.
 

Zuma-4 details

A total of 24 patients, median age 14 (range 3 to 20) years, received the CAR T product. Four patients received the starting dose of 2 x 10⁶ CAR T per kg (these patients were enrolled per protocol for evaluation of dose-limiting toxicities).

Following the initial dosing and evaluation of safety, 11 patients were treated with a dose of 1 x 10⁶ cells per kg with a total volume of 68 mL, and 9 received 1 x 10⁶ per kg at a volume of 40 mL (the dose being used in current phase 2 trials).

The median follow-up at the time of data cutoff in September 2020 was 36.1 months.

The combined CR/CRi rate was 75% for patients treated at the starting dose, 64% for patients treated at the 1 x 10⁶ 68-mL dose, and 67% for those who received the 48-mL dose.

The respective median durations of response were 4.14 months, 10.68 months, and not reached.

All patients who had an objective response had undetectable MRD assessed by flow cytometry with a sensitivity of .01%.

The therapy served as a bridge to allogeneic transplant in 16 patients, including 2 in the initial dose group, 8 in the 68-mL group, and 6 in the 40-mL group.

Median overall survival was not reached in either of the two 1 x 10⁶–dose groups, but was 8 months in the 2 x 10⁶ group.

There were no dose-limiting toxicities seen, and the adverse event profile was consistent with that seen with the use of CAR T therapy for other malignancies.

Patients treated at either the 68-mL or 40-mL 1 x 106–dose levels received tocilizumab only for neurologic events occurring in context with the cytokine release syndrome (CRS), and were started on steroids for grade 2 or greater neurologic events.

Rates of grade 3 or greater neurologic events were 25% in the initial-dose group, 27% in the 68-mL group, and 11% in the 40-mL group. Respective rates of grade 3 or greater CRS were 75%, 27%, and 22%.

Four patients died on study, all from causes deemed unrelated to CAR T therapy: two from progressive disease, one from disseminated mucormycosis, and one from Escherichia sepsis.

Investigators are currently enrolling pediatric patients with relapsed/refractory B-ALL or non-Hodgkin lymphoma, including patients with MRD-positive disease and early relapse after first-line therapy, in phase 2 of the Zuma-4 study.
 

How long will it last?

Howard Weinstein, MD, chief of pediatric hematology/oncology at Mass General for Children in Boston, who was not involved in the study, said in an interview that the response rate and comparatively low toxicity profile look good.

“One of the challenges, though, with CAR T-cell products has been relapse – almost half of the patients who go into remission relapse. Sometimes leukemic cells change their surface properties, resulting in antigen loss, there’s T-cell exhaustion, and other postulates for relapse,” he said.

He noted that due to the high number of patients who went on to transplant, the study lacks good data on the durability of remissions.

“One of the unknowns at the moment is whether CAR T cells are sufficient to cure a high percentage of children who have had a relapse, or do you need to follow it with a bone marrow transplant,” Dr. Weinstein said.

The ZUMA-4 trial is sponsored by Kite Pharma. Dr. Wayne disclosed research funding from Kite, Servier, and Institut de Recherches Internationales. Dr. Weinstein had no relevant disclosures.

It’s early days, but preliminary data show that a chimeric antigen receptor T-cell therapy (CAR T) product was associated with high rates of minimal residual disease (MRD) negativity, and complete or near-complete responses in children and adolescents with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL).

Among 24 patients aged 3-20 years with relapsed or refractory B-ALL treated with the CAR T construct brexucabtagene autoleucel (KTE-X19; Tecartus), 16 had either a complete response or CR with incomplete recovery of blood counts (CRi), for a combined CR/CRi rate of 67%, reported Alan S. Wayne, MD, from Children’s Hospital Los Angeles and the University of Southern California Norris Comprehensive Cancer Center, also in Los Angeles.

“Optimized KTE-X19 formulation of 40 mL and revised toxicity management were associated with an improved risk/benefit profile,” he said in audio narration accompanying a poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

Although overall survival for children and adolescents receiving first-line therapy for B-ALL is associated with remission rates of 80% or more, the prognosis is poor following relapse, despite the availability of newer therapies such as blinatumomab (Blincyto) and inotuzumab (Besponsa), with a 1-year overall survival rate of approximately 36%, he said.

To see whether they could improve on these odds, Dr. Wayne and colleagues conducted the phase 1 Zuma-4 trial, a single-arm, open-label study in children and adolescents with relapsed/refractory B-ALL.

He reported long-term follow-up results from the study.
 

Zuma-4 details

A total of 24 patients, median age 14 (range 3 to 20) years, received the CAR T product. Four patients received the starting dose of 2 x 10⁶ CAR T per kg (these patients were enrolled per protocol for evaluation of dose-limiting toxicities).

Following the initial dosing and evaluation of safety, 11 patients were treated with a dose of 1 x 10⁶ cells per kg with a total volume of 68 mL, and 9 received 1 x 10⁶ per kg at a volume of 40 mL (the dose being used in current phase 2 trials).

The median follow-up at the time of data cutoff in September 2020 was 36.1 months.

The combined CR/CRi rate was 75% for patients treated at the starting dose, 64% for patients treated at the 1 x 10⁶ 68-mL dose, and 67% for those who received the 48-mL dose.

The respective median durations of response were 4.14 months, 10.68 months, and not reached.

All patients who had an objective response had undetectable MRD assessed by flow cytometry with a sensitivity of .01%.

The therapy served as a bridge to allogeneic transplant in 16 patients, including 2 in the initial dose group, 8 in the 68-mL group, and 6 in the 40-mL group.

Median overall survival was not reached in either of the two 1 x 10⁶–dose groups, but was 8 months in the 2 x 10⁶ group.

There were no dose-limiting toxicities seen, and the adverse event profile was consistent with that seen with the use of CAR T therapy for other malignancies.

Patients treated at either the 68-mL or 40-mL 1 x 106–dose levels received tocilizumab only for neurologic events occurring in context with the cytokine release syndrome (CRS), and were started on steroids for grade 2 or greater neurologic events.

Rates of grade 3 or greater neurologic events were 25% in the initial-dose group, 27% in the 68-mL group, and 11% in the 40-mL group. Respective rates of grade 3 or greater CRS were 75%, 27%, and 22%.

Four patients died on study, all from causes deemed unrelated to CAR T therapy: two from progressive disease, one from disseminated mucormycosis, and one from Escherichia sepsis.

Investigators are currently enrolling pediatric patients with relapsed/refractory B-ALL or non-Hodgkin lymphoma, including patients with MRD-positive disease and early relapse after first-line therapy, in phase 2 of the Zuma-4 study.
 

How long will it last?

Howard Weinstein, MD, chief of pediatric hematology/oncology at Mass General for Children in Boston, who was not involved in the study, said in an interview that the response rate and comparatively low toxicity profile look good.

“One of the challenges, though, with CAR T-cell products has been relapse – almost half of the patients who go into remission relapse. Sometimes leukemic cells change their surface properties, resulting in antigen loss, there’s T-cell exhaustion, and other postulates for relapse,” he said.

He noted that due to the high number of patients who went on to transplant, the study lacks good data on the durability of remissions.

“One of the unknowns at the moment is whether CAR T cells are sufficient to cure a high percentage of children who have had a relapse, or do you need to follow it with a bone marrow transplant,” Dr. Weinstein said.

The ZUMA-4 trial is sponsored by Kite Pharma. Dr. Wayne disclosed research funding from Kite, Servier, and Institut de Recherches Internationales. Dr. Weinstein had no relevant disclosures.

It’s early days, but preliminary data show that a chimeric antigen receptor T-cell therapy (CAR T) product was associated with high rates of minimal residual disease (MRD) negativity, and complete or near-complete responses in children and adolescents with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL).

Among 24 patients aged 3-20 years with relapsed or refractory B-ALL treated with the CAR T construct brexucabtagene autoleucel (KTE-X19; Tecartus), 16 had either a complete response or CR with incomplete recovery of blood counts (CRi), for a combined CR/CRi rate of 67%, reported Alan S. Wayne, MD, from Children’s Hospital Los Angeles and the University of Southern California Norris Comprehensive Cancer Center, also in Los Angeles.

“Optimized KTE-X19 formulation of 40 mL and revised toxicity management were associated with an improved risk/benefit profile,” he said in audio narration accompanying a poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

Although overall survival for children and adolescents receiving first-line therapy for B-ALL is associated with remission rates of 80% or more, the prognosis is poor following relapse, despite the availability of newer therapies such as blinatumomab (Blincyto) and inotuzumab (Besponsa), with a 1-year overall survival rate of approximately 36%, he said.

To see whether they could improve on these odds, Dr. Wayne and colleagues conducted the phase 1 Zuma-4 trial, a single-arm, open-label study in children and adolescents with relapsed/refractory B-ALL.

He reported long-term follow-up results from the study.
 

Zuma-4 details

A total of 24 patients, median age 14 (range 3 to 20) years, received the CAR T product. Four patients received the starting dose of 2 x 10⁶ CAR T per kg (these patients were enrolled per protocol for evaluation of dose-limiting toxicities).

Following the initial dosing and evaluation of safety, 11 patients were treated with a dose of 1 x 10⁶ cells per kg with a total volume of 68 mL, and 9 received 1 x 10⁶ per kg at a volume of 40 mL (the dose being used in current phase 2 trials).

The median follow-up at the time of data cutoff in September 2020 was 36.1 months.

The combined CR/CRi rate was 75% for patients treated at the starting dose, 64% for patients treated at the 1 x 10⁶ 68-mL dose, and 67% for those who received the 48-mL dose.

The respective median durations of response were 4.14 months, 10.68 months, and not reached.

All patients who had an objective response had undetectable MRD assessed by flow cytometry with a sensitivity of .01%.

The therapy served as a bridge to allogeneic transplant in 16 patients, including 2 in the initial dose group, 8 in the 68-mL group, and 6 in the 40-mL group.

Median overall survival was not reached in either of the two 1 x 10⁶–dose groups, but was 8 months in the 2 x 10⁶ group.

There were no dose-limiting toxicities seen, and the adverse event profile was consistent with that seen with the use of CAR T therapy for other malignancies.

Patients treated at either the 68-mL or 40-mL 1 x 106–dose levels received tocilizumab only for neurologic events occurring in context with the cytokine release syndrome (CRS), and were started on steroids for grade 2 or greater neurologic events.

Rates of grade 3 or greater neurologic events were 25% in the initial-dose group, 27% in the 68-mL group, and 11% in the 40-mL group. Respective rates of grade 3 or greater CRS were 75%, 27%, and 22%.

Four patients died on study, all from causes deemed unrelated to CAR T therapy: two from progressive disease, one from disseminated mucormycosis, and one from Escherichia sepsis.

Investigators are currently enrolling pediatric patients with relapsed/refractory B-ALL or non-Hodgkin lymphoma, including patients with MRD-positive disease and early relapse after first-line therapy, in phase 2 of the Zuma-4 study.
 

How long will it last?

Howard Weinstein, MD, chief of pediatric hematology/oncology at Mass General for Children in Boston, who was not involved in the study, said in an interview that the response rate and comparatively low toxicity profile look good.

“One of the challenges, though, with CAR T-cell products has been relapse – almost half of the patients who go into remission relapse. Sometimes leukemic cells change their surface properties, resulting in antigen loss, there’s T-cell exhaustion, and other postulates for relapse,” he said.

He noted that due to the high number of patients who went on to transplant, the study lacks good data on the durability of remissions.

“One of the unknowns at the moment is whether CAR T cells are sufficient to cure a high percentage of children who have had a relapse, or do you need to follow it with a bone marrow transplant,” Dr. Weinstein said.

The ZUMA-4 trial is sponsored by Kite Pharma. Dr. Wayne disclosed research funding from Kite, Servier, and Institut de Recherches Internationales. Dr. Weinstein had no relevant disclosures.

Do your patients think that getting COVID-19 is fully protective against subsequent reinfection? Tell it to the Marines.

A study of U.S. Marine recruits on their way to boot camp at Parris Island, S.C., showed that those who were seropositive at baseline, indicating prior exposure to SARS-CoV-2, remained at some risk for reinfection. They had about one-fifth the risk of subsequent infection, compared with seronegative recruits during basic training, but reinfections did occur.

The study, by Stuart C. Sealfon, MD, of Icahn School of Medicine at Mount Sinai in New York, and colleagues, was published in The Lancet Respiratory Medicine.

“Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection,” they wrote.

An infectious disease specialist who was not involved in the study said that the findings provide further evidence about the level of immunity acquired after an infection.

“It’s quite clear that reinfections do occur, they are of public health importance, and they’re something we need to be mindful of in terms of advising patients about whether a prior infection protects them from reinfection,” Mark Siedner, MD, MPH, a clinician and researcher in the division of infectious diseases at Massachusetts General Hospital, Boston, said in an interview.

The study results reinforce that “not all antibodies are the same,” said Sachin Gupta, MD, an attending physician in pulmonary and critical care medicine at Alameda Health System in Oakland, Calif. “We’re seeing still that 10% of folks who have antibodies can get infected again,” he said in an interview.

CHARM initiative

Dr. Sealfon and colleagues presented an analysis of data from the ironically named CHARM (COVID-19 Health Action Response for Marines) prospective study.

CHARM included U.S. Marine recruits, most of them male, aged 18-20 years, who were instructed to follow a 2-week unsupervised quarantine at home, after which they reported to a Marine-supervised facility for an additional 2-week quarantine.

At baseline, participants were tested for SARS-CoV-2 immunoglobulin G (IgG) seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein enzyme-linked immunosorbent assay (ELISA).

The recruits filled out questionnaires asking them to report any of 14 specific COVID-19–related symptoms or any other unspecified symptom, as well as demographic information, risk factors, and a brief medical history.

Investigators tested recruits for SARS-CoV-2 infection by polymerase chain reaction (PCR) assay at weeks 0, 1, and 2 of quarantine, and any who had positive PCR results during quarantine were excluded.

Participants who had three negative swab PCR results during quarantine and a baseline serology test at the beginning of the supervised quarantine period – either seronegative or seropositive – then went on to enjoy their basic training at the Marine Corps Recruit Depot, Parris Island, S.C.

The participants were followed prospectively with PCR tests at weeks 2, 4, and 6 in both the seropositive and seronegative groups, and sera were obtained at the same time.
 

Holes in immunologic armor

Full data were available for a total of 189 participants who were seropositive and 2,247 who were seronegative at enrollment.

In all, 19 of 189 seropositive recruits (10%) had at least one PCR test positive for SARS-CoV-2 infection during the 6-week follow-up period. This translated into an incidence of 1.1 cases per person-year.

Of the 2,247 participants seronegative at baseline, 1,079 tested positive (6.2 cases per person-year; incidence rate ratio 0.18).

It appeared that antibodies provided some protection for seropositive recruits, as evidenced by a higher likelihood of infection among those with lower baseline full-length spike protein IgG titers than in those with higher baseline titers (hazard ratio 0.4, P < .001).

Among the seropositive participants who did acquire a second SARS-CoV-2 infection, viral loads in mid-turbinate nasal swabs were about 10-fold lower than in seronegative recruits who acquired infections during follow-up.

“This finding suggests that some reinfected individuals could have a similar capacity to transmit infection as those who are infected for the first time. The rate at which reinfection occurs after vaccines and natural immunity is important for estimating the proportion of the population that needs to be vaccinated to suppress the pandemic,” the investigators wrote.

Baseline neutralizing antibody titers were detected in 45 of the first 54 seropositive recruits who remained PCR negative throughout follow-up, but also in 6 of 19 seropositive participants who became infected during the 6 weeks of observation.
 

Lessons

Both Dr. Siedner and Dr. Gupta agreed with the authors that the risks for reinfection that were observed in young, physically fit people may differ for other populations, such as women (only 10% of seropositive recruits and 8% of seronegative recruits were female), older patients, or those who are immunocompromised.

Given that the adjusted odds ratio for reinfection in this study was nearly identical to that of a recent British study comparing infection rates between seropositive and seronegative health care workers, the risk of reinfection for other young adults and for the general population may be similar, Dr. Sealfon and colleagues wrote.

Adding to the challenge of reaching herd immunity is the observation that some patients who have recovered from COVID-19 are skeptical about the need for further protection.

“There are patients who feel like vaccination is of low benefit to them, and I think these are the same people who would be hesitant to get the vaccine anyway,” Dr. Gupta said.

Although no vaccine is perfect – the vaccine failure rate from the mRNA-based vaccines from Moderna and Pfizer/Biontech is about 5% – the protections they afford are unmistakable, Dr. Siedner said.

“I think it’s important to make the distinction that most postvaccination infections by and large have been very mild,” he said. “In people with normal immune systems, we have not seen an onslaught of postvaccination infections requiring hospitalization. Even if people do get infected after vaccination, the vaccines protect people from severe infection, and that’s what we want them to do.”

The investigators stated, “Young adults, of whom a high proportion are asymptomatically infected and become seropositive in the absence of known infection, can be an important source of transmission to more vulnerable populations. Evaluating the protection against subsequent SARS-CoV-2 infection conferred by seropositivity in young adults is important for determining the need for vaccinating previously infected individuals in this age group.”

The study was funded by the Defense Health Agency and Defense Advanced Research Projects Agency. Dr. Sealfon, Dr. Siedner, and Dr. Gupta have no conflicts of interest to report. Dr. Gupta is a member of the editorial advisory board for this publication.

Do your patients think that getting COVID-19 is fully protective against subsequent reinfection? Tell it to the Marines.

A study of U.S. Marine recruits on their way to boot camp at Parris Island, S.C., showed that those who were seropositive at baseline, indicating prior exposure to SARS-CoV-2, remained at some risk for reinfection. They had about one-fifth the risk of subsequent infection, compared with seronegative recruits during basic training, but reinfections did occur.

The study, by Stuart C. Sealfon, MD, of Icahn School of Medicine at Mount Sinai in New York, and colleagues, was published in The Lancet Respiratory Medicine.

“Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection,” they wrote.

An infectious disease specialist who was not involved in the study said that the findings provide further evidence about the level of immunity acquired after an infection.

“It’s quite clear that reinfections do occur, they are of public health importance, and they’re something we need to be mindful of in terms of advising patients about whether a prior infection protects them from reinfection,” Mark Siedner, MD, MPH, a clinician and researcher in the division of infectious diseases at Massachusetts General Hospital, Boston, said in an interview.

The study results reinforce that “not all antibodies are the same,” said Sachin Gupta, MD, an attending physician in pulmonary and critical care medicine at Alameda Health System in Oakland, Calif. “We’re seeing still that 10% of folks who have antibodies can get infected again,” he said in an interview.

CHARM initiative

Dr. Sealfon and colleagues presented an analysis of data from the ironically named CHARM (COVID-19 Health Action Response for Marines) prospective study.

CHARM included U.S. Marine recruits, most of them male, aged 18-20 years, who were instructed to follow a 2-week unsupervised quarantine at home, after which they reported to a Marine-supervised facility for an additional 2-week quarantine.

At baseline, participants were tested for SARS-CoV-2 immunoglobulin G (IgG) seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein enzyme-linked immunosorbent assay (ELISA).

The recruits filled out questionnaires asking them to report any of 14 specific COVID-19–related symptoms or any other unspecified symptom, as well as demographic information, risk factors, and a brief medical history.

Investigators tested recruits for SARS-CoV-2 infection by polymerase chain reaction (PCR) assay at weeks 0, 1, and 2 of quarantine, and any who had positive PCR results during quarantine were excluded.

Participants who had three negative swab PCR results during quarantine and a baseline serology test at the beginning of the supervised quarantine period – either seronegative or seropositive – then went on to enjoy their basic training at the Marine Corps Recruit Depot, Parris Island, S.C.

The participants were followed prospectively with PCR tests at weeks 2, 4, and 6 in both the seropositive and seronegative groups, and sera were obtained at the same time.
 

Holes in immunologic armor

Full data were available for a total of 189 participants who were seropositive and 2,247 who were seronegative at enrollment.

In all, 19 of 189 seropositive recruits (10%) had at least one PCR test positive for SARS-CoV-2 infection during the 6-week follow-up period. This translated into an incidence of 1.1 cases per person-year.

Of the 2,247 participants seronegative at baseline, 1,079 tested positive (6.2 cases per person-year; incidence rate ratio 0.18).

It appeared that antibodies provided some protection for seropositive recruits, as evidenced by a higher likelihood of infection among those with lower baseline full-length spike protein IgG titers than in those with higher baseline titers (hazard ratio 0.4, P < .001).

Among the seropositive participants who did acquire a second SARS-CoV-2 infection, viral loads in mid-turbinate nasal swabs were about 10-fold lower than in seronegative recruits who acquired infections during follow-up.

“This finding suggests that some reinfected individuals could have a similar capacity to transmit infection as those who are infected for the first time. The rate at which reinfection occurs after vaccines and natural immunity is important for estimating the proportion of the population that needs to be vaccinated to suppress the pandemic,” the investigators wrote.

Baseline neutralizing antibody titers were detected in 45 of the first 54 seropositive recruits who remained PCR negative throughout follow-up, but also in 6 of 19 seropositive participants who became infected during the 6 weeks of observation.
 

Lessons

Both Dr. Siedner and Dr. Gupta agreed with the authors that the risks for reinfection that were observed in young, physically fit people may differ for other populations, such as women (only 10% of seropositive recruits and 8% of seronegative recruits were female), older patients, or those who are immunocompromised.

Given that the adjusted odds ratio for reinfection in this study was nearly identical to that of a recent British study comparing infection rates between seropositive and seronegative health care workers, the risk of reinfection for other young adults and for the general population may be similar, Dr. Sealfon and colleagues wrote.

Adding to the challenge of reaching herd immunity is the observation that some patients who have recovered from COVID-19 are skeptical about the need for further protection.

“There are patients who feel like vaccination is of low benefit to them, and I think these are the same people who would be hesitant to get the vaccine anyway,” Dr. Gupta said.

Although no vaccine is perfect – the vaccine failure rate from the mRNA-based vaccines from Moderna and Pfizer/Biontech is about 5% – the protections they afford are unmistakable, Dr. Siedner said.

“I think it’s important to make the distinction that most postvaccination infections by and large have been very mild,” he said. “In people with normal immune systems, we have not seen an onslaught of postvaccination infections requiring hospitalization. Even if people do get infected after vaccination, the vaccines protect people from severe infection, and that’s what we want them to do.”

The investigators stated, “Young adults, of whom a high proportion are asymptomatically infected and become seropositive in the absence of known infection, can be an important source of transmission to more vulnerable populations. Evaluating the protection against subsequent SARS-CoV-2 infection conferred by seropositivity in young adults is important for determining the need for vaccinating previously infected individuals in this age group.”

The study was funded by the Defense Health Agency and Defense Advanced Research Projects Agency. Dr. Sealfon, Dr. Siedner, and Dr. Gupta have no conflicts of interest to report. Dr. Gupta is a member of the editorial advisory board for this publication.

Do your patients think that getting COVID-19 is fully protective against subsequent reinfection? Tell it to the Marines.

A study of U.S. Marine recruits on their way to boot camp at Parris Island, S.C., showed that those who were seropositive at baseline, indicating prior exposure to SARS-CoV-2, remained at some risk for reinfection. They had about one-fifth the risk of subsequent infection, compared with seronegative recruits during basic training, but reinfections did occur.

The study, by Stuart C. Sealfon, MD, of Icahn School of Medicine at Mount Sinai in New York, and colleagues, was published in The Lancet Respiratory Medicine.

“Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection,” they wrote.

An infectious disease specialist who was not involved in the study said that the findings provide further evidence about the level of immunity acquired after an infection.

“It’s quite clear that reinfections do occur, they are of public health importance, and they’re something we need to be mindful of in terms of advising patients about whether a prior infection protects them from reinfection,” Mark Siedner, MD, MPH, a clinician and researcher in the division of infectious diseases at Massachusetts General Hospital, Boston, said in an interview.

The study results reinforce that “not all antibodies are the same,” said Sachin Gupta, MD, an attending physician in pulmonary and critical care medicine at Alameda Health System in Oakland, Calif. “We’re seeing still that 10% of folks who have antibodies can get infected again,” he said in an interview.

CHARM initiative

Dr. Sealfon and colleagues presented an analysis of data from the ironically named CHARM (COVID-19 Health Action Response for Marines) prospective study.

CHARM included U.S. Marine recruits, most of them male, aged 18-20 years, who were instructed to follow a 2-week unsupervised quarantine at home, after which they reported to a Marine-supervised facility for an additional 2-week quarantine.

At baseline, participants were tested for SARS-CoV-2 immunoglobulin G (IgG) seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein enzyme-linked immunosorbent assay (ELISA).

The recruits filled out questionnaires asking them to report any of 14 specific COVID-19–related symptoms or any other unspecified symptom, as well as demographic information, risk factors, and a brief medical history.

Investigators tested recruits for SARS-CoV-2 infection by polymerase chain reaction (PCR) assay at weeks 0, 1, and 2 of quarantine, and any who had positive PCR results during quarantine were excluded.

Participants who had three negative swab PCR results during quarantine and a baseline serology test at the beginning of the supervised quarantine period – either seronegative or seropositive – then went on to enjoy their basic training at the Marine Corps Recruit Depot, Parris Island, S.C.

The participants were followed prospectively with PCR tests at weeks 2, 4, and 6 in both the seropositive and seronegative groups, and sera were obtained at the same time.
 

Holes in immunologic armor

Full data were available for a total of 189 participants who were seropositive and 2,247 who were seronegative at enrollment.

In all, 19 of 189 seropositive recruits (10%) had at least one PCR test positive for SARS-CoV-2 infection during the 6-week follow-up period. This translated into an incidence of 1.1 cases per person-year.

Of the 2,247 participants seronegative at baseline, 1,079 tested positive (6.2 cases per person-year; incidence rate ratio 0.18).

It appeared that antibodies provided some protection for seropositive recruits, as evidenced by a higher likelihood of infection among those with lower baseline full-length spike protein IgG titers than in those with higher baseline titers (hazard ratio 0.4, P < .001).

Among the seropositive participants who did acquire a second SARS-CoV-2 infection, viral loads in mid-turbinate nasal swabs were about 10-fold lower than in seronegative recruits who acquired infections during follow-up.

“This finding suggests that some reinfected individuals could have a similar capacity to transmit infection as those who are infected for the first time. The rate at which reinfection occurs after vaccines and natural immunity is important for estimating the proportion of the population that needs to be vaccinated to suppress the pandemic,” the investigators wrote.

Baseline neutralizing antibody titers were detected in 45 of the first 54 seropositive recruits who remained PCR negative throughout follow-up, but also in 6 of 19 seropositive participants who became infected during the 6 weeks of observation.
 

Lessons

Both Dr. Siedner and Dr. Gupta agreed with the authors that the risks for reinfection that were observed in young, physically fit people may differ for other populations, such as women (only 10% of seropositive recruits and 8% of seronegative recruits were female), older patients, or those who are immunocompromised.

Given that the adjusted odds ratio for reinfection in this study was nearly identical to that of a recent British study comparing infection rates between seropositive and seronegative health care workers, the risk of reinfection for other young adults and for the general population may be similar, Dr. Sealfon and colleagues wrote.

Adding to the challenge of reaching herd immunity is the observation that some patients who have recovered from COVID-19 are skeptical about the need for further protection.

“There are patients who feel like vaccination is of low benefit to them, and I think these are the same people who would be hesitant to get the vaccine anyway,” Dr. Gupta said.

Although no vaccine is perfect – the vaccine failure rate from the mRNA-based vaccines from Moderna and Pfizer/Biontech is about 5% – the protections they afford are unmistakable, Dr. Siedner said.

“I think it’s important to make the distinction that most postvaccination infections by and large have been very mild,” he said. “In people with normal immune systems, we have not seen an onslaught of postvaccination infections requiring hospitalization. Even if people do get infected after vaccination, the vaccines protect people from severe infection, and that’s what we want them to do.”

The investigators stated, “Young adults, of whom a high proportion are asymptomatically infected and become seropositive in the absence of known infection, can be an important source of transmission to more vulnerable populations. Evaluating the protection against subsequent SARS-CoV-2 infection conferred by seropositivity in young adults is important for determining the need for vaccinating previously infected individuals in this age group.”

The study was funded by the Defense Health Agency and Defense Advanced Research Projects Agency. Dr. Sealfon, Dr. Siedner, and Dr. Gupta have no conflicts of interest to report. Dr. Gupta is a member of the editorial advisory board for this publication.

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab.

The new analysis shows benefit even in patients with high-risk disease.

The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs. 13.4 months for patients on sorafenib (P = .0009).

Jennifer J. Knox, MD, of Princess Margaret Cancer Centre at the University of Toronto, said that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.

“As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival,” she said.

Dr. Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT009).
 

Benefit seen also in high-risk group

At the meeting, Dr. Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).

High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Dr. Finn noted. 

In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.

The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Dr. Finn said. 

Median progression-free survival (PFS) among high-risk patients was 5.4 months vs. 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.

“The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population,” he said.

However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment related, Dr. Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.

Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs. one in the sorafenib arm.

Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.

In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Dr. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.
 

What’s next?

In her discussion, Dr. Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with tyrosine kinase inhibitors alone.

“There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients,” she said.

“This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis,” Dr. Knox summarized.

The IMBRave150 trial is sponsored by F. Hoffmann–La Roche. Dr. Finn disclosed consulting activities for F. Hoffmann–La Roche, and institutional grant/research support from Roche and others. Dr. Knox disclosed grant/research support from F. Hoffmann–La Roche and others, and consulting for Merck, Pfizer, and Esai.

A version of this article first appeared on Medscape.com.

Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab.

The new analysis shows benefit even in patients with high-risk disease.

The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs. 13.4 months for patients on sorafenib (P = .0009).

Jennifer J. Knox, MD, of Princess Margaret Cancer Centre at the University of Toronto, said that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.

“As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival,” she said.

Dr. Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT009).
 

Benefit seen also in high-risk group

At the meeting, Dr. Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).

High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Dr. Finn noted. 

In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.

The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Dr. Finn said. 

Median progression-free survival (PFS) among high-risk patients was 5.4 months vs. 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.

“The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population,” he said.

However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment related, Dr. Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.

Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs. one in the sorafenib arm.

Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.

In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Dr. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.
 

What’s next?

In her discussion, Dr. Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with tyrosine kinase inhibitors alone.

“There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients,” she said.

“This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis,” Dr. Knox summarized.

The IMBRave150 trial is sponsored by F. Hoffmann–La Roche. Dr. Finn disclosed consulting activities for F. Hoffmann–La Roche, and institutional grant/research support from Roche and others. Dr. Knox disclosed grant/research support from F. Hoffmann–La Roche and others, and consulting for Merck, Pfizer, and Esai.

A version of this article first appeared on Medscape.com.

Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab.

The new analysis shows benefit even in patients with high-risk disease.

The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs. 13.4 months for patients on sorafenib (P = .0009).

Jennifer J. Knox, MD, of Princess Margaret Cancer Centre at the University of Toronto, said that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.

“As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival,” she said.

Dr. Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT009).
 

Benefit seen also in high-risk group

At the meeting, Dr. Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).

High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Dr. Finn noted. 

In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.

The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Dr. Finn said. 

Median progression-free survival (PFS) among high-risk patients was 5.4 months vs. 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.

“The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population,” he said.

However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment related, Dr. Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.

Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs. one in the sorafenib arm.

Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.

In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Dr. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.
 

What’s next?

In her discussion, Dr. Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with tyrosine kinase inhibitors alone.

“There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients,” she said.

“This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis,” Dr. Knox summarized.

The IMBRave150 trial is sponsored by F. Hoffmann–La Roche. Dr. Finn disclosed consulting activities for F. Hoffmann–La Roche, and institutional grant/research support from Roche and others. Dr. Knox disclosed grant/research support from F. Hoffmann–La Roche and others, and consulting for Merck, Pfizer, and Esai.

A version of this article first appeared on Medscape.com.

Hopes for a new category of agents recently hailed as “a triumph of drug discovery” have been dimmed somewhat by new data showing many types of acquired resistance.

KRAS is one of the most frequently mutated oncogenes in human cancer and has long been thought “undruggable” – but novel drugs acting specifically on the KRAS G12C mutation have shown promise in clinical trials.

Early results with the experimental KRAS inhibitors sotorasib and adagrasib were deemed promising, but new data presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB002) have splashed cold water on that enthusiasm.

The efficacy of these new drugs looks to be threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Mark M. Awad, MD, PhD, from the Dana-Farber Cancer Institute in Boston, reported data from 30 patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) bearing the KRAS G12C mutation who had disease progression while being treated with adagrasib in clinical trials. Investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to adagrasib in these patients.

“Diverse mechanisms confer resistance to the KRAS G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” Dr. Awad said in a mini-symposium presentation.

“Several cases displayed multiple resistance mechanisms, and novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” he said.

Inactivating KRAS

The KRAS G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form.

But the mutation has been considered too tough to target because of the KRAS gene’s strong binding affinity for guanosine triphosphate, an essential building block of RNA synthesis, and by a lack of accessible drug-binding sites.

Sotorasib and adagrasib are small-molecule, specific, and irreversible inhibitors of KRAS that interact with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drugs inhibit oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

Multiple mutations, histologic transformations

Dr. Awad and colleagues studied biopsy samples and circulating tumor DNA (ctDNA) from 30 patients both at baseline and after administration of adagrasib monotherapy. The patients all had initial responses to the drug but then experienced disease progression.

The investigators used mutagenesis screens to identify mechanisms of resistance to KRAS G12C inhibitors.

The 30 patients included 23 with NSCLC and 7 with CRC. Eighteen had unknown mechanisms of resistance, and putative resistance mechanisms were identified in the other 12 patients. Of this latter group, seven appeared to have single resistance mechanisms, and five had multiple mechanisms of resistance.

One patient with NSCLC who had radiographic evidence of response followed by progression was found to have had a novel KRAS Y96C mutation, and three had novel KRAS mutations in other gene regions, with multiple concurrent alterations in genes implicated in other forms of cancer, such as PTEN, BRAF, and MAP2K1.

The investigators also identified amplifications of the KRAS G12C allele, and MET.

In two patients, NSCLC underwent histologic transformation from adenocarcinoma at baseline to squamous cell carcinoma at the time of acquired resistance to the drug. No genomic resistance mechanisms were detected in either of these patients, Dr. Awad said.

“In several cases, we see multiple mechanisms or co-occurring alterations in each individual patient, with the suggestion that perhaps the multiple mutations or resistance mechanism may be more common in the colorectal population, particularly with acquired gene fusions, than in the lung cancer population, although larger datasets will be needed to confirm this observation,” he said.
 

Does duration of response matter?

In the question-and-answer session following his presentation, Dr. Awad was asked about clinical responses in the patients who developed resistance.

“In this initial reporting of resistance mechanisms we did not overlay or report out the clinical outcomes, including the durations of response or the time to disease progression, in part because this is an ongoing clinical trial, and those data will be reported in full at a later time,” Dr. Awad replied. “But I think it will be really important to identify whether patients are more likely to develop resistance earlier versus later or have different resistance mechanisms.”

Dr. Awad commented further that the resistance to adagrasib appeared to be acquired. “These resistance mutations were not detected to the level of detection at the baseline samples. So presumably they may be present at some low levels at the time of initial diagnosis, or they emerge over the course of therapy,” he said.

“Many of the resistance mechanisms appear to be more subclonal, occurring at an allele fraction lower than the original KRAS G12C mutation, which we know is the clonal event in the entire population of the cancer, and I think when we’re seeing these multiple resistance mechanisms emerging, they are potentially each representing different subclones that can develop simultaneously,” he added.

Adagrasib trials are supported by Mirati Therapeutics. Dr. Awad disclosed consulting for Mirati and others, and institutional research support from several different companies.

A version of this article first appeared on Medscape.com.

Hopes for a new category of agents recently hailed as “a triumph of drug discovery” have been dimmed somewhat by new data showing many types of acquired resistance.

KRAS is one of the most frequently mutated oncogenes in human cancer and has long been thought “undruggable” – but novel drugs acting specifically on the KRAS G12C mutation have shown promise in clinical trials.

Early results with the experimental KRAS inhibitors sotorasib and adagrasib were deemed promising, but new data presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB002) have splashed cold water on that enthusiasm.

The efficacy of these new drugs looks to be threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Mark M. Awad, MD, PhD, from the Dana-Farber Cancer Institute in Boston, reported data from 30 patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) bearing the KRAS G12C mutation who had disease progression while being treated with adagrasib in clinical trials. Investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to adagrasib in these patients.

“Diverse mechanisms confer resistance to the KRAS G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” Dr. Awad said in a mini-symposium presentation.

“Several cases displayed multiple resistance mechanisms, and novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” he said.

Inactivating KRAS

The KRAS G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form.

But the mutation has been considered too tough to target because of the KRAS gene’s strong binding affinity for guanosine triphosphate, an essential building block of RNA synthesis, and by a lack of accessible drug-binding sites.

Sotorasib and adagrasib are small-molecule, specific, and irreversible inhibitors of KRAS that interact with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drugs inhibit oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

Multiple mutations, histologic transformations

Dr. Awad and colleagues studied biopsy samples and circulating tumor DNA (ctDNA) from 30 patients both at baseline and after administration of adagrasib monotherapy. The patients all had initial responses to the drug but then experienced disease progression.

The investigators used mutagenesis screens to identify mechanisms of resistance to KRAS G12C inhibitors.

The 30 patients included 23 with NSCLC and 7 with CRC. Eighteen had unknown mechanisms of resistance, and putative resistance mechanisms were identified in the other 12 patients. Of this latter group, seven appeared to have single resistance mechanisms, and five had multiple mechanisms of resistance.

One patient with NSCLC who had radiographic evidence of response followed by progression was found to have had a novel KRAS Y96C mutation, and three had novel KRAS mutations in other gene regions, with multiple concurrent alterations in genes implicated in other forms of cancer, such as PTEN, BRAF, and MAP2K1.

The investigators also identified amplifications of the KRAS G12C allele, and MET.

In two patients, NSCLC underwent histologic transformation from adenocarcinoma at baseline to squamous cell carcinoma at the time of acquired resistance to the drug. No genomic resistance mechanisms were detected in either of these patients, Dr. Awad said.

“In several cases, we see multiple mechanisms or co-occurring alterations in each individual patient, with the suggestion that perhaps the multiple mutations or resistance mechanism may be more common in the colorectal population, particularly with acquired gene fusions, than in the lung cancer population, although larger datasets will be needed to confirm this observation,” he said.
 

Does duration of response matter?

In the question-and-answer session following his presentation, Dr. Awad was asked about clinical responses in the patients who developed resistance.

“In this initial reporting of resistance mechanisms we did not overlay or report out the clinical outcomes, including the durations of response or the time to disease progression, in part because this is an ongoing clinical trial, and those data will be reported in full at a later time,” Dr. Awad replied. “But I think it will be really important to identify whether patients are more likely to develop resistance earlier versus later or have different resistance mechanisms.”

Dr. Awad commented further that the resistance to adagrasib appeared to be acquired. “These resistance mutations were not detected to the level of detection at the baseline samples. So presumably they may be present at some low levels at the time of initial diagnosis, or they emerge over the course of therapy,” he said.

“Many of the resistance mechanisms appear to be more subclonal, occurring at an allele fraction lower than the original KRAS G12C mutation, which we know is the clonal event in the entire population of the cancer, and I think when we’re seeing these multiple resistance mechanisms emerging, they are potentially each representing different subclones that can develop simultaneously,” he added.

Adagrasib trials are supported by Mirati Therapeutics. Dr. Awad disclosed consulting for Mirati and others, and institutional research support from several different companies.

A version of this article first appeared on Medscape.com.

Hopes for a new category of agents recently hailed as “a triumph of drug discovery” have been dimmed somewhat by new data showing many types of acquired resistance.

KRAS is one of the most frequently mutated oncogenes in human cancer and has long been thought “undruggable” – but novel drugs acting specifically on the KRAS G12C mutation have shown promise in clinical trials.

Early results with the experimental KRAS inhibitors sotorasib and adagrasib were deemed promising, but new data presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB002) have splashed cold water on that enthusiasm.

The efficacy of these new drugs looks to be threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Mark M. Awad, MD, PhD, from the Dana-Farber Cancer Institute in Boston, reported data from 30 patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) bearing the KRAS G12C mutation who had disease progression while being treated with adagrasib in clinical trials. Investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to adagrasib in these patients.

“Diverse mechanisms confer resistance to the KRAS G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” Dr. Awad said in a mini-symposium presentation.

“Several cases displayed multiple resistance mechanisms, and novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” he said.

Inactivating KRAS

The KRAS G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form.

But the mutation has been considered too tough to target because of the KRAS gene’s strong binding affinity for guanosine triphosphate, an essential building block of RNA synthesis, and by a lack of accessible drug-binding sites.

Sotorasib and adagrasib are small-molecule, specific, and irreversible inhibitors of KRAS that interact with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drugs inhibit oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

Multiple mutations, histologic transformations

Dr. Awad and colleagues studied biopsy samples and circulating tumor DNA (ctDNA) from 30 patients both at baseline and after administration of adagrasib monotherapy. The patients all had initial responses to the drug but then experienced disease progression.

The investigators used mutagenesis screens to identify mechanisms of resistance to KRAS G12C inhibitors.

The 30 patients included 23 with NSCLC and 7 with CRC. Eighteen had unknown mechanisms of resistance, and putative resistance mechanisms were identified in the other 12 patients. Of this latter group, seven appeared to have single resistance mechanisms, and five had multiple mechanisms of resistance.

One patient with NSCLC who had radiographic evidence of response followed by progression was found to have had a novel KRAS Y96C mutation, and three had novel KRAS mutations in other gene regions, with multiple concurrent alterations in genes implicated in other forms of cancer, such as PTEN, BRAF, and MAP2K1.

The investigators also identified amplifications of the KRAS G12C allele, and MET.

In two patients, NSCLC underwent histologic transformation from adenocarcinoma at baseline to squamous cell carcinoma at the time of acquired resistance to the drug. No genomic resistance mechanisms were detected in either of these patients, Dr. Awad said.

“In several cases, we see multiple mechanisms or co-occurring alterations in each individual patient, with the suggestion that perhaps the multiple mutations or resistance mechanism may be more common in the colorectal population, particularly with acquired gene fusions, than in the lung cancer population, although larger datasets will be needed to confirm this observation,” he said.
 

Does duration of response matter?

In the question-and-answer session following his presentation, Dr. Awad was asked about clinical responses in the patients who developed resistance.

“In this initial reporting of resistance mechanisms we did not overlay or report out the clinical outcomes, including the durations of response or the time to disease progression, in part because this is an ongoing clinical trial, and those data will be reported in full at a later time,” Dr. Awad replied. “But I think it will be really important to identify whether patients are more likely to develop resistance earlier versus later or have different resistance mechanisms.”

Dr. Awad commented further that the resistance to adagrasib appeared to be acquired. “These resistance mutations were not detected to the level of detection at the baseline samples. So presumably they may be present at some low levels at the time of initial diagnosis, or they emerge over the course of therapy,” he said.

“Many of the resistance mechanisms appear to be more subclonal, occurring at an allele fraction lower than the original KRAS G12C mutation, which we know is the clonal event in the entire population of the cancer, and I think when we’re seeing these multiple resistance mechanisms emerging, they are potentially each representing different subclones that can develop simultaneously,” he added.

Adagrasib trials are supported by Mirati Therapeutics. Dr. Awad disclosed consulting for Mirati and others, and institutional research support from several different companies.

A version of this article first appeared on Medscape.com.

An experimental immunotherapy that contains a genetically altered version of herpes simplex virus type 1 (HSV-1) was associated with a doubling in median overall survival for children and adolescents with recurrent or progressive high-grade gliomas.

This is a rapidly fatal form of brain cancer. Among historical control patients, the median overall survival was only 5.3 months.

The new results show a median overall survival of 12.2 months.

They come from a phase 1 trial conducted in 12 patients aged 7-18 years who had high-grade gliomas. All of the patients received the experimental therapy, dubbed G207, which was infused directly into the brain tumors.

“In our secondary objectives, we saw promising overall survival data ... [and] we saw that G207 turned immunologically ‘cold’ tumors to ‘hot,’ ” said lead investigator Gregory K. Friedman, MD, from the University of Alabama at Birmingham.

Dr. Friedman presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT018). The study was also published simultaneously online in the New England Journal of Medicine.

Although the number of patients in the study was small, the data from this early trial look promising, commented Howard Kaufman, MD, director of the Oncolytic Virus Research Laboratory at Massachusetts General Hospital, Boston, who was not involved in the study.

“This is just a horrendous disease that hasn’t really responded to anything, so seeing some signs of benefit as well as a pretty tolerable safety profile is a very important observation that I think merits further investigation,” he said in an interview.
 

Engineered virus

G207 is an oncolytic form of HSV-1 created through genetic engineering in which a neurovirulence gene was deleted and viral nucleotide reductase was disabled. The engineered mutations prevent HSV-1 from infecting normal cells while allowing the virus to replicate in tumor cells.

The oncolytic virus product can be inoculated directly into tumors to circumvent the blood-brain barrier, and it preferentially infects neural tissue, making it ideal for treating brain tumors, the investigators explain.

One example of this type of product is already on the market. Talimogene laherparepvec is an oncolytic HSV-1 therapy that was approved in 2015 by the Food and Drug Administration for local treatment (i.e., injection directly into the skin lesion) of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery.

In their article, Dr. Friedman and colleagues summarized some of the data with G207 that “provided a strong rationale for conducting a trial involving children and adolescents.

“In addition to infecting and lysing tumor cells directly, G207 can reverse tumor immune evasion, increase cross-presentation of tumor antigens, and promote an antitumor immune response even in the absence of virus permissivity,” they wrote. “A single radiation dose enhances G207 efficacy in animal models by increasing viral replication and spread.”

In preclinical studies using tumor xenografts, pediatric brain tumors were 11-fold more sensitive to G207, compared with glioblastomas in adults.

The researchers hypothesized that intratumoral G207 would increase the amount of tumor-infiltrating lymphocytes and thereby convert immunologically “cold” pediatric brain tumors to “hot” and “inflamed” tumors.
 

Phase 1 trial

The phase 1 trial included four dose cohorts of children and adolescents with a pathologically proven malignant supratentorial brain tumor of at least 1 cm in diameter that had progressed after surgery, radiotherapy, or chemotherapy.

There were three patients in each dose cohort. One cohort received 107 plaque-forming units, the second received 108 PFU, the third received 107 PFU with 5 Gy of radiation, and the fourth received 108 PFU with 5 Gy radiation.

The patients first underwent stereotactic placement of up to four intratumoral catheters. The next day, they underwent infusion of the assigned PFU doses by controlled-rate infusion over 6 hours.

For the patients who received radiation, 5 Gy were administered to the gross tumor volume within 24 hours following G207 administration.

Among the 12 patients, tumors included 10 glioblastomas, one anaplastic astrocytoma, and one high-grade glioma not otherwise specified.

Responses (radiographic, neuropathologic, or clinical) occurred in 11 of the 12 patients.

Four patients were still alive 18 months after treatment, “which exceeds the life expectancy for newly diagnosed patients,” Dr. Friedman noted. Most patients die within 1 year of being diagnosed with pediatric glioma.

The investigators also found evidence to suggest that survival may be improved for patients who experience seroconversion after exposure to HSV-1 in comparison to patients with HSV-1 antibodies from prior HSV-1 infection. The median overall survival was 18.3 months for patients who experienced seroconversion, compared with 5.1 months for three patients who, at baseline, had IgG antibodies to HSV-1.

No dose-limiting toxicities or serious adverse events attributable to G207 occurred. There were 20 grade 1 adverse events that were potentially related to G207.

There was no evidence of peripheral G207 shedding or viremia, the investigators reported.
 

Radiation effect?

Commenting on the results in an interview, Dr. Kaufman noted that the sample size (12 patients) in this study was too small to determine whether the radiation received by patients in two of the four cohorts had any additive effect.

“Whether to move forward with virus alone or to add the radiation remains an open question that I don’t think was adequately answered,” he said.

Regarding the evidence suggesting that survival was better among patients who did not have antibodies to HSV-1 at baseline, Dr. Kaufman said, “We’ve looked at that in the melanoma population but haven’t seen any correlation there, so that’s interesting.”

The finding could be related to the fact that this was a pediatric population, or it could be related to the location of the tumors in the brain.

“It’s an interesting finding, and it suggests that, in future studies, they might want to select patients who are HSV seronegative up front,” he said.

Dr. Friedman and colleagues are currently planning a phase 2 trial of G207 with 5 Gy of radiation for children and adolescents with recurrent or progressive high-grade gliomas.

The study was supported by grants from the FDA, the National Institutes of Health, Cannonball Kids’ Cancer Foundation, the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, St. Baldrick’s Foundation, the Department of Defense, the Andrew McDonough B+ Foundation, and the Kaul Pediatric Research Institute; by NIH/National Cancer Institute Cancer Center support grants to the University of Alabama at Birmingham and to the Memorial Sloan Kettering Cancer Center; and by Kelsie’s Crew, Eli’s Block Party Childhood Cancer Foundation, the Eli Jackson Foundation, Jaxon’s FROG Foundation, Battle for a Cure Foundation, and Sandcastle Kids. Dr. Friedman has received grants/support from the organizations listed above, as well as from Eli Lilly and Pfizer. Dr. Kaufman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An experimental immunotherapy that contains a genetically altered version of herpes simplex virus type 1 (HSV-1) was associated with a doubling in median overall survival for children and adolescents with recurrent or progressive high-grade gliomas.

This is a rapidly fatal form of brain cancer. Among historical control patients, the median overall survival was only 5.3 months.

The new results show a median overall survival of 12.2 months.

They come from a phase 1 trial conducted in 12 patients aged 7-18 years who had high-grade gliomas. All of the patients received the experimental therapy, dubbed G207, which was infused directly into the brain tumors.

“In our secondary objectives, we saw promising overall survival data ... [and] we saw that G207 turned immunologically ‘cold’ tumors to ‘hot,’ ” said lead investigator Gregory K. Friedman, MD, from the University of Alabama at Birmingham.

Dr. Friedman presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT018). The study was also published simultaneously online in the New England Journal of Medicine.

Although the number of patients in the study was small, the data from this early trial look promising, commented Howard Kaufman, MD, director of the Oncolytic Virus Research Laboratory at Massachusetts General Hospital, Boston, who was not involved in the study.

“This is just a horrendous disease that hasn’t really responded to anything, so seeing some signs of benefit as well as a pretty tolerable safety profile is a very important observation that I think merits further investigation,” he said in an interview.
 

Engineered virus

G207 is an oncolytic form of HSV-1 created through genetic engineering in which a neurovirulence gene was deleted and viral nucleotide reductase was disabled. The engineered mutations prevent HSV-1 from infecting normal cells while allowing the virus to replicate in tumor cells.

The oncolytic virus product can be inoculated directly into tumors to circumvent the blood-brain barrier, and it preferentially infects neural tissue, making it ideal for treating brain tumors, the investigators explain.

One example of this type of product is already on the market. Talimogene laherparepvec is an oncolytic HSV-1 therapy that was approved in 2015 by the Food and Drug Administration for local treatment (i.e., injection directly into the skin lesion) of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery.

In their article, Dr. Friedman and colleagues summarized some of the data with G207 that “provided a strong rationale for conducting a trial involving children and adolescents.

“In addition to infecting and lysing tumor cells directly, G207 can reverse tumor immune evasion, increase cross-presentation of tumor antigens, and promote an antitumor immune response even in the absence of virus permissivity,” they wrote. “A single radiation dose enhances G207 efficacy in animal models by increasing viral replication and spread.”

In preclinical studies using tumor xenografts, pediatric brain tumors were 11-fold more sensitive to G207, compared with glioblastomas in adults.

The researchers hypothesized that intratumoral G207 would increase the amount of tumor-infiltrating lymphocytes and thereby convert immunologically “cold” pediatric brain tumors to “hot” and “inflamed” tumors.
 

Phase 1 trial

The phase 1 trial included four dose cohorts of children and adolescents with a pathologically proven malignant supratentorial brain tumor of at least 1 cm in diameter that had progressed after surgery, radiotherapy, or chemotherapy.

There were three patients in each dose cohort. One cohort received 107 plaque-forming units, the second received 108 PFU, the third received 107 PFU with 5 Gy of radiation, and the fourth received 108 PFU with 5 Gy radiation.

The patients first underwent stereotactic placement of up to four intratumoral catheters. The next day, they underwent infusion of the assigned PFU doses by controlled-rate infusion over 6 hours.

For the patients who received radiation, 5 Gy were administered to the gross tumor volume within 24 hours following G207 administration.

Among the 12 patients, tumors included 10 glioblastomas, one anaplastic astrocytoma, and one high-grade glioma not otherwise specified.

Responses (radiographic, neuropathologic, or clinical) occurred in 11 of the 12 patients.

Four patients were still alive 18 months after treatment, “which exceeds the life expectancy for newly diagnosed patients,” Dr. Friedman noted. Most patients die within 1 year of being diagnosed with pediatric glioma.

The investigators also found evidence to suggest that survival may be improved for patients who experience seroconversion after exposure to HSV-1 in comparison to patients with HSV-1 antibodies from prior HSV-1 infection. The median overall survival was 18.3 months for patients who experienced seroconversion, compared with 5.1 months for three patients who, at baseline, had IgG antibodies to HSV-1.

No dose-limiting toxicities or serious adverse events attributable to G207 occurred. There were 20 grade 1 adverse events that were potentially related to G207.

There was no evidence of peripheral G207 shedding or viremia, the investigators reported.
 

Radiation effect?

Commenting on the results in an interview, Dr. Kaufman noted that the sample size (12 patients) in this study was too small to determine whether the radiation received by patients in two of the four cohorts had any additive effect.

“Whether to move forward with virus alone or to add the radiation remains an open question that I don’t think was adequately answered,” he said.

Regarding the evidence suggesting that survival was better among patients who did not have antibodies to HSV-1 at baseline, Dr. Kaufman said, “We’ve looked at that in the melanoma population but haven’t seen any correlation there, so that’s interesting.”

The finding could be related to the fact that this was a pediatric population, or it could be related to the location of the tumors in the brain.

“It’s an interesting finding, and it suggests that, in future studies, they might want to select patients who are HSV seronegative up front,” he said.

Dr. Friedman and colleagues are currently planning a phase 2 trial of G207 with 5 Gy of radiation for children and adolescents with recurrent or progressive high-grade gliomas.

The study was supported by grants from the FDA, the National Institutes of Health, Cannonball Kids’ Cancer Foundation, the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, St. Baldrick’s Foundation, the Department of Defense, the Andrew McDonough B+ Foundation, and the Kaul Pediatric Research Institute; by NIH/National Cancer Institute Cancer Center support grants to the University of Alabama at Birmingham and to the Memorial Sloan Kettering Cancer Center; and by Kelsie’s Crew, Eli’s Block Party Childhood Cancer Foundation, the Eli Jackson Foundation, Jaxon’s FROG Foundation, Battle for a Cure Foundation, and Sandcastle Kids. Dr. Friedman has received grants/support from the organizations listed above, as well as from Eli Lilly and Pfizer. Dr. Kaufman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An experimental immunotherapy that contains a genetically altered version of herpes simplex virus type 1 (HSV-1) was associated with a doubling in median overall survival for children and adolescents with recurrent or progressive high-grade gliomas.

This is a rapidly fatal form of brain cancer. Among historical control patients, the median overall survival was only 5.3 months.

The new results show a median overall survival of 12.2 months.

They come from a phase 1 trial conducted in 12 patients aged 7-18 years who had high-grade gliomas. All of the patients received the experimental therapy, dubbed G207, which was infused directly into the brain tumors.

“In our secondary objectives, we saw promising overall survival data ... [and] we saw that G207 turned immunologically ‘cold’ tumors to ‘hot,’ ” said lead investigator Gregory K. Friedman, MD, from the University of Alabama at Birmingham.

Dr. Friedman presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT018). The study was also published simultaneously online in the New England Journal of Medicine.

Although the number of patients in the study was small, the data from this early trial look promising, commented Howard Kaufman, MD, director of the Oncolytic Virus Research Laboratory at Massachusetts General Hospital, Boston, who was not involved in the study.

“This is just a horrendous disease that hasn’t really responded to anything, so seeing some signs of benefit as well as a pretty tolerable safety profile is a very important observation that I think merits further investigation,” he said in an interview.
 

Engineered virus

G207 is an oncolytic form of HSV-1 created through genetic engineering in which a neurovirulence gene was deleted and viral nucleotide reductase was disabled. The engineered mutations prevent HSV-1 from infecting normal cells while allowing the virus to replicate in tumor cells.

The oncolytic virus product can be inoculated directly into tumors to circumvent the blood-brain barrier, and it preferentially infects neural tissue, making it ideal for treating brain tumors, the investigators explain.

One example of this type of product is already on the market. Talimogene laherparepvec is an oncolytic HSV-1 therapy that was approved in 2015 by the Food and Drug Administration for local treatment (i.e., injection directly into the skin lesion) of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery.

In their article, Dr. Friedman and colleagues summarized some of the data with G207 that “provided a strong rationale for conducting a trial involving children and adolescents.

“In addition to infecting and lysing tumor cells directly, G207 can reverse tumor immune evasion, increase cross-presentation of tumor antigens, and promote an antitumor immune response even in the absence of virus permissivity,” they wrote. “A single radiation dose enhances G207 efficacy in animal models by increasing viral replication and spread.”

In preclinical studies using tumor xenografts, pediatric brain tumors were 11-fold more sensitive to G207, compared with glioblastomas in adults.

The researchers hypothesized that intratumoral G207 would increase the amount of tumor-infiltrating lymphocytes and thereby convert immunologically “cold” pediatric brain tumors to “hot” and “inflamed” tumors.
 

Phase 1 trial

The phase 1 trial included four dose cohorts of children and adolescents with a pathologically proven malignant supratentorial brain tumor of at least 1 cm in diameter that had progressed after surgery, radiotherapy, or chemotherapy.

There were three patients in each dose cohort. One cohort received 107 plaque-forming units, the second received 108 PFU, the third received 107 PFU with 5 Gy of radiation, and the fourth received 108 PFU with 5 Gy radiation.

The patients first underwent stereotactic placement of up to four intratumoral catheters. The next day, they underwent infusion of the assigned PFU doses by controlled-rate infusion over 6 hours.

For the patients who received radiation, 5 Gy were administered to the gross tumor volume within 24 hours following G207 administration.

Among the 12 patients, tumors included 10 glioblastomas, one anaplastic astrocytoma, and one high-grade glioma not otherwise specified.

Responses (radiographic, neuropathologic, or clinical) occurred in 11 of the 12 patients.

Four patients were still alive 18 months after treatment, “which exceeds the life expectancy for newly diagnosed patients,” Dr. Friedman noted. Most patients die within 1 year of being diagnosed with pediatric glioma.

The investigators also found evidence to suggest that survival may be improved for patients who experience seroconversion after exposure to HSV-1 in comparison to patients with HSV-1 antibodies from prior HSV-1 infection. The median overall survival was 18.3 months for patients who experienced seroconversion, compared with 5.1 months for three patients who, at baseline, had IgG antibodies to HSV-1.

No dose-limiting toxicities or serious adverse events attributable to G207 occurred. There were 20 grade 1 adverse events that were potentially related to G207.

There was no evidence of peripheral G207 shedding or viremia, the investigators reported.
 

Radiation effect?

Commenting on the results in an interview, Dr. Kaufman noted that the sample size (12 patients) in this study was too small to determine whether the radiation received by patients in two of the four cohorts had any additive effect.

“Whether to move forward with virus alone or to add the radiation remains an open question that I don’t think was adequately answered,” he said.

Regarding the evidence suggesting that survival was better among patients who did not have antibodies to HSV-1 at baseline, Dr. Kaufman said, “We’ve looked at that in the melanoma population but haven’t seen any correlation there, so that’s interesting.”

The finding could be related to the fact that this was a pediatric population, or it could be related to the location of the tumors in the brain.

“It’s an interesting finding, and it suggests that, in future studies, they might want to select patients who are HSV seronegative up front,” he said.

Dr. Friedman and colleagues are currently planning a phase 2 trial of G207 with 5 Gy of radiation for children and adolescents with recurrent or progressive high-grade gliomas.

The study was supported by grants from the FDA, the National Institutes of Health, Cannonball Kids’ Cancer Foundation, the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, St. Baldrick’s Foundation, the Department of Defense, the Andrew McDonough B+ Foundation, and the Kaul Pediatric Research Institute; by NIH/National Cancer Institute Cancer Center support grants to the University of Alabama at Birmingham and to the Memorial Sloan Kettering Cancer Center; and by Kelsie’s Crew, Eli’s Block Party Childhood Cancer Foundation, the Eli Jackson Foundation, Jaxon’s FROG Foundation, Battle for a Cure Foundation, and Sandcastle Kids. Dr. Friedman has received grants/support from the organizations listed above, as well as from Eli Lilly and Pfizer. Dr. Kaufman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.

However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.

Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.

Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.

This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.

This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.

“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.

Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).

The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.

The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
 

Change in trial design

Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.

However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).

“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.

Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”

She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.

“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
 

CheckMate 816 particulars

CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.

Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.

Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.

In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.

Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).

In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
 

Safety similar

“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.

The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.

Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.

Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.

The investigators are continuing to assess event-free survival and overall survival.

CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.

A version of this article first appeared on Medscape.com.

Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.

However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.

Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.

Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.

This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.

This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.

“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.

Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).

The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.

The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
 

Change in trial design

Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.

However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).

“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.

Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”

She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.

“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
 

CheckMate 816 particulars

CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.

Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.

Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.

In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.

Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).

In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
 

Safety similar

“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.

The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.

Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.

Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.

The investigators are continuing to assess event-free survival and overall survival.

CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.

A version of this article first appeared on Medscape.com.

Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.

However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.

Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.

Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.

This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.

This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.

“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.

Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).

The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.

The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
 

Change in trial design

Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.

However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).

“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.

Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”

She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.

“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
 

CheckMate 816 particulars

CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.

Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.

Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.

In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.

Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).

In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
 

Safety similar

“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.

The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.

Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.

Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.

The investigators are continuing to assess event-free survival and overall survival.

CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.

A version of this article first appeared on Medscape.com.

The combination of ixabepilone and bevacizumab demonstrated efficacy in patients with platinum-resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer in a phase 2 trial.

The median progression-free survival (PFS) was 5.5 months for patients randomized to receive ixabepilone and bevacizumab, versus 2.2 months for patients assigned to ixabepilone alone (P < .001). The median overall survival (OS) was 10 months and 6 months, respectively (P = .006), although the trial was underpowered to detect OS differences.

These results were presented in a late-breaking abstract session at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11570).

“Therapeutic options for platinum- and taxane-resistant ovarian cancer are limited, and, unfortunately, median overall survival in this population is only approximately 12 months. It’s obvious that additional treatment strategies are warranted,” Dana M. Roque, MD, of the University of Maryland in Baltimore, said when presenting the results.
 

Study rationale and details

Dr. Roque explained that ixabepilone is an epothilone B analog that may retain activity in patients with taxane-resistant disease. She and her colleagues previously found, in a retrospective study, that ixabepilone, with or without bevacizumab, showed “promising” activity with acceptable toxicity in patients with recurrent uterine or ovarian/primary peritoneal/fallopian tube cancers.

At SGO 2021, Dr. Roque reported results of a prospective, phase 2 trial of 76 patients randomized to ixabepilone alone or in combination with bevacizumab.

Patients with measurable recurrent or persistent platinum-resistant or refractory epithelial nonmucinous ovarian, fallopian tube, or primary peritoneal cancers were enrolled. The patients had to have received at least three prior cycles of paclitaxel, but there was no upper limit on prior lines of therapy, including bevacizumab.

After stratification by prior bevacizumab and study site, the patients were randomly assigned to either ixabepilone monotherapy at a dose of 20 mg/m² on days 1, 8, and 15 of every 28-day cycle (n = 37), or the same dose of ixabepilone plus bevacizumab at 10 mg/kg on days 1 and 15 every 28 days (n = 39).

Most patients in each arm – 78% in the monotherapy arm and 87% in the combination arm – had serous tumors, with the remaining patients having carcinosarcomas or other, unspecified histologies.
 

Efficacy and safety

The overall response rate was 33% with the combination and 8% with ixabepilone monotherapy. There were no correlations between TUBB3 staining and either responses or durable disease control.

As noted before, PFS and OS were significantly better with the combination. Neither PFS nor OS were influenced by prior bevacizumab use, heavy pretreatment, poor performance status, nonserous histology, or age.

Dose-limiting toxicities with the combination included peripheral neuropathy, neutropenia, and fatigue. There was one bowel perforation in a patient on the combination.

Patients assigned to the combination were significantly more likely to experience hypertension (36% vs. 8%, P = .005) and peripheral neuropathy (51% vs. 19%, P = .004). However, there were no differences in serious adverse events between the treatment arms.

Dr. Roque acknowledged that this study was limited by incomplete immunohistochemistry data, a lack of stratification by extent of prior taxane exposure in the recurrent setting, a lack of a bevacizumab control arm, and underpowering to detect OS differences.
 

Comparison with AURELIA

Dr. Roque and the invited discussant, Thomas J. Herzog, MD, of the University of Cincinnati Cancer Center in Ohio, both compared results of the current trial to results from the AURELIA trial, in which patients with platinum-resistant ovarian cancers were randomized to chemotherapy with or without bevacizumab.

According to AURELIA data published in 2014, the ORR with the bevacizumab-chemotherapy combination was 27%, compared with 33% with ixabepilone-bevacizumab in the current trial. The median PFS was 6.7 months and 5.5 months, respectively, and the median OS was 16.6 months and 10 months, respectively.

An analysis of AURELIA data published in 2015 suggested that outcomes were even better for patients who received paclitaxel plus bevacizumab. This group had an ORR of 53.3%, a median PFS of 10.4 months, and a median OS of 22.4 months.

Though the current study’s results don’t appear to measure up to results from AURELIA, Dr. Herzog called the current study “very exciting.”

“The efficacy looks very promising,” he said. “They even showed efficacy for OS that looked very interesting, even though that was underpowered.”

Dr. Herzog did note the lack of a companion diagnostic because the TUBB3 staining did not correlate with response. He also said the trial was limited by the lack of a bevacizumab control arm. Furthermore, because of the relatively small sample size in the combination group (n = 39), the lower bound of the confidence interval for ORR includes response rates typically seen with conventional therapies.

“I do think that the combination does make sense biologically, so I’d like to see more data on that,” he concluded.

The trial was sponsored by Yale University, with study drug supplied by R-Pharm-US. Dr. Roque reported no conflicts of interest. Dr. Herzog disclosed serving as a scientific advisor to several companies, including Genentech, maker of bevacizumab.

The combination of ixabepilone and bevacizumab demonstrated efficacy in patients with platinum-resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer in a phase 2 trial.

The median progression-free survival (PFS) was 5.5 months for patients randomized to receive ixabepilone and bevacizumab, versus 2.2 months for patients assigned to ixabepilone alone (P < .001). The median overall survival (OS) was 10 months and 6 months, respectively (P = .006), although the trial was underpowered to detect OS differences.

These results were presented in a late-breaking abstract session at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11570).

“Therapeutic options for platinum- and taxane-resistant ovarian cancer are limited, and, unfortunately, median overall survival in this population is only approximately 12 months. It’s obvious that additional treatment strategies are warranted,” Dana M. Roque, MD, of the University of Maryland in Baltimore, said when presenting the results.
 

Study rationale and details

Dr. Roque explained that ixabepilone is an epothilone B analog that may retain activity in patients with taxane-resistant disease. She and her colleagues previously found, in a retrospective study, that ixabepilone, with or without bevacizumab, showed “promising” activity with acceptable toxicity in patients with recurrent uterine or ovarian/primary peritoneal/fallopian tube cancers.

At SGO 2021, Dr. Roque reported results of a prospective, phase 2 trial of 76 patients randomized to ixabepilone alone or in combination with bevacizumab.

Patients with measurable recurrent or persistent platinum-resistant or refractory epithelial nonmucinous ovarian, fallopian tube, or primary peritoneal cancers were enrolled. The patients had to have received at least three prior cycles of paclitaxel, but there was no upper limit on prior lines of therapy, including bevacizumab.

After stratification by prior bevacizumab and study site, the patients were randomly assigned to either ixabepilone monotherapy at a dose of 20 mg/m² on days 1, 8, and 15 of every 28-day cycle (n = 37), or the same dose of ixabepilone plus bevacizumab at 10 mg/kg on days 1 and 15 every 28 days (n = 39).

Most patients in each arm – 78% in the monotherapy arm and 87% in the combination arm – had serous tumors, with the remaining patients having carcinosarcomas or other, unspecified histologies.
 

Efficacy and safety

The overall response rate was 33% with the combination and 8% with ixabepilone monotherapy. There were no correlations between TUBB3 staining and either responses or durable disease control.

As noted before, PFS and OS were significantly better with the combination. Neither PFS nor OS were influenced by prior bevacizumab use, heavy pretreatment, poor performance status, nonserous histology, or age.

Dose-limiting toxicities with the combination included peripheral neuropathy, neutropenia, and fatigue. There was one bowel perforation in a patient on the combination.

Patients assigned to the combination were significantly more likely to experience hypertension (36% vs. 8%, P = .005) and peripheral neuropathy (51% vs. 19%, P = .004). However, there were no differences in serious adverse events between the treatment arms.

Dr. Roque acknowledged that this study was limited by incomplete immunohistochemistry data, a lack of stratification by extent of prior taxane exposure in the recurrent setting, a lack of a bevacizumab control arm, and underpowering to detect OS differences.
 

Comparison with AURELIA

Dr. Roque and the invited discussant, Thomas J. Herzog, MD, of the University of Cincinnati Cancer Center in Ohio, both compared results of the current trial to results from the AURELIA trial, in which patients with platinum-resistant ovarian cancers were randomized to chemotherapy with or without bevacizumab.

According to AURELIA data published in 2014, the ORR with the bevacizumab-chemotherapy combination was 27%, compared with 33% with ixabepilone-bevacizumab in the current trial. The median PFS was 6.7 months and 5.5 months, respectively, and the median OS was 16.6 months and 10 months, respectively.

An analysis of AURELIA data published in 2015 suggested that outcomes were even better for patients who received paclitaxel plus bevacizumab. This group had an ORR of 53.3%, a median PFS of 10.4 months, and a median OS of 22.4 months.

Though the current study’s results don’t appear to measure up to results from AURELIA, Dr. Herzog called the current study “very exciting.”

“The efficacy looks very promising,” he said. “They even showed efficacy for OS that looked very interesting, even though that was underpowered.”

Dr. Herzog did note the lack of a companion diagnostic because the TUBB3 staining did not correlate with response. He also said the trial was limited by the lack of a bevacizumab control arm. Furthermore, because of the relatively small sample size in the combination group (n = 39), the lower bound of the confidence interval for ORR includes response rates typically seen with conventional therapies.

“I do think that the combination does make sense biologically, so I’d like to see more data on that,” he concluded.

The trial was sponsored by Yale University, with study drug supplied by R-Pharm-US. Dr. Roque reported no conflicts of interest. Dr. Herzog disclosed serving as a scientific advisor to several companies, including Genentech, maker of bevacizumab.

The combination of ixabepilone and bevacizumab demonstrated efficacy in patients with platinum-resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer in a phase 2 trial.

The median progression-free survival (PFS) was 5.5 months for patients randomized to receive ixabepilone and bevacizumab, versus 2.2 months for patients assigned to ixabepilone alone (P < .001). The median overall survival (OS) was 10 months and 6 months, respectively (P = .006), although the trial was underpowered to detect OS differences.

These results were presented in a late-breaking abstract session at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11570).

“Therapeutic options for platinum- and taxane-resistant ovarian cancer are limited, and, unfortunately, median overall survival in this population is only approximately 12 months. It’s obvious that additional treatment strategies are warranted,” Dana M. Roque, MD, of the University of Maryland in Baltimore, said when presenting the results.
 

Study rationale and details

Dr. Roque explained that ixabepilone is an epothilone B analog that may retain activity in patients with taxane-resistant disease. She and her colleagues previously found, in a retrospective study, that ixabepilone, with or without bevacizumab, showed “promising” activity with acceptable toxicity in patients with recurrent uterine or ovarian/primary peritoneal/fallopian tube cancers.

At SGO 2021, Dr. Roque reported results of a prospective, phase 2 trial of 76 patients randomized to ixabepilone alone or in combination with bevacizumab.

Patients with measurable recurrent or persistent platinum-resistant or refractory epithelial nonmucinous ovarian, fallopian tube, or primary peritoneal cancers were enrolled. The patients had to have received at least three prior cycles of paclitaxel, but there was no upper limit on prior lines of therapy, including bevacizumab.

After stratification by prior bevacizumab and study site, the patients were randomly assigned to either ixabepilone monotherapy at a dose of 20 mg/m² on days 1, 8, and 15 of every 28-day cycle (n = 37), or the same dose of ixabepilone plus bevacizumab at 10 mg/kg on days 1 and 15 every 28 days (n = 39).

Most patients in each arm – 78% in the monotherapy arm and 87% in the combination arm – had serous tumors, with the remaining patients having carcinosarcomas or other, unspecified histologies.
 

Efficacy and safety

The overall response rate was 33% with the combination and 8% with ixabepilone monotherapy. There were no correlations between TUBB3 staining and either responses or durable disease control.

As noted before, PFS and OS were significantly better with the combination. Neither PFS nor OS were influenced by prior bevacizumab use, heavy pretreatment, poor performance status, nonserous histology, or age.

Dose-limiting toxicities with the combination included peripheral neuropathy, neutropenia, and fatigue. There was one bowel perforation in a patient on the combination.

Patients assigned to the combination were significantly more likely to experience hypertension (36% vs. 8%, P = .005) and peripheral neuropathy (51% vs. 19%, P = .004). However, there were no differences in serious adverse events between the treatment arms.

Dr. Roque acknowledged that this study was limited by incomplete immunohistochemistry data, a lack of stratification by extent of prior taxane exposure in the recurrent setting, a lack of a bevacizumab control arm, and underpowering to detect OS differences.
 

Comparison with AURELIA

Dr. Roque and the invited discussant, Thomas J. Herzog, MD, of the University of Cincinnati Cancer Center in Ohio, both compared results of the current trial to results from the AURELIA trial, in which patients with platinum-resistant ovarian cancers were randomized to chemotherapy with or without bevacizumab.

According to AURELIA data published in 2014, the ORR with the bevacizumab-chemotherapy combination was 27%, compared with 33% with ixabepilone-bevacizumab in the current trial. The median PFS was 6.7 months and 5.5 months, respectively, and the median OS was 16.6 months and 10 months, respectively.

An analysis of AURELIA data published in 2015 suggested that outcomes were even better for patients who received paclitaxel plus bevacizumab. This group had an ORR of 53.3%, a median PFS of 10.4 months, and a median OS of 22.4 months.

Though the current study’s results don’t appear to measure up to results from AURELIA, Dr. Herzog called the current study “very exciting.”

“The efficacy looks very promising,” he said. “They even showed efficacy for OS that looked very interesting, even though that was underpowered.”

Dr. Herzog did note the lack of a companion diagnostic because the TUBB3 staining did not correlate with response. He also said the trial was limited by the lack of a bevacizumab control arm. Furthermore, because of the relatively small sample size in the combination group (n = 39), the lower bound of the confidence interval for ORR includes response rates typically seen with conventional therapies.

“I do think that the combination does make sense biologically, so I’d like to see more data on that,” he concluded.

The trial was sponsored by Yale University, with study drug supplied by R-Pharm-US. Dr. Roque reported no conflicts of interest. Dr. Herzog disclosed serving as a scientific advisor to several companies, including Genentech, maker of bevacizumab.