Pediatric Neuroblastoma

A genomic study has revealed new insights into the pathogenesis of neuroblastoma as well as potential therapeutic targets.

Insights into the genetic drivers of the disease were identified based on data from whole-genome, whole-exome, and/or transcriptome sequencing of tumor samples.

“The comprehensive genome-wide analysis performed here allowed us to discover age-associated alterations in MYCN, TERT, PTPRD, and Ras pathway alterations, which, together with ATRX, represent the majority of common driver gene alterations in neuroblastoma,” wrote study author Samuel W. Brady, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues.

The group’s findings were published in Nature Communications.

The researchers integrated and analyzed data from 702 neuroblastomas encompassing all age and risk categories, with the goal of identifying rare driver events and age-related molecular aberrations. Among the samples, 23 were from patients who had relapsed.

The researchers found that 40% of samples had somatic alterations in known driver genes, with the most common alterations being MYCN (19%; primarily amplification), TERT (17%; structural variations [SVs]), SHANK2 (13%; SVs), PTPRD (11%; SVs and focal deletions), ALK (10%; single nucleotide variants [SNVs] and SVs), and ATRX (8%; multiple mutation types).

MYCN and TERT alterations were more common in younger children (median age of 2.3 years and 3.8 years, respectively), while ATRX alterations were more frequently seen in older patients (median age of 5.6 years).

“These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models,” the researchers wrote.

Furthermore, they found evidence to suggest the COSMIC mutational signature 18 is the most common cause of driver SNVs in neuroblastoma, including most Ras-activating and ALK variants.

Signature 18 was enriched in neuroblastomas with increased expression of mitochondrial ribosome and electron transport–associated genes, 17q gain, and MYCN amplification.

“[T]his mutagenic process, which is caused by ROS [reactive oxygen species] in other settings (though not proven in neuroblastoma), may promote evolution and heterogeneity, as many driver SNVs, such as ALK mutations, are later events in neuroblastoma,” the researchers explained.

Based on these findings, the authors concluded that neuroblastomas with 17q gain may be amenable to precision medicines, possibly through targeting altered mitochondrial function.

“[Our] findings will identify patients who might be eligible for targeted therapy and those that may be at higher risk based on a combination of genetic alterations detected by these genome-wide sequencing methods,” commented study author Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital.

The study was supported by grants from the National Cancer Institute and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. One author disclosed financial affiliations with Y-mabs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon.

SOURCE: Brady SW et al. Nat Commun. 2020 Oct 14. doi: 10.1038/s41467-020-18987-4.

A genomic study has revealed new insights into the pathogenesis of neuroblastoma as well as potential therapeutic targets.

Insights into the genetic drivers of the disease were identified based on data from whole-genome, whole-exome, and/or transcriptome sequencing of tumor samples.

“The comprehensive genome-wide analysis performed here allowed us to discover age-associated alterations in MYCN, TERT, PTPRD, and Ras pathway alterations, which, together with ATRX, represent the majority of common driver gene alterations in neuroblastoma,” wrote study author Samuel W. Brady, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues.

The group’s findings were published in Nature Communications.

The researchers integrated and analyzed data from 702 neuroblastomas encompassing all age and risk categories, with the goal of identifying rare driver events and age-related molecular aberrations. Among the samples, 23 were from patients who had relapsed.

The researchers found that 40% of samples had somatic alterations in known driver genes, with the most common alterations being MYCN (19%; primarily amplification), TERT (17%; structural variations [SVs]), SHANK2 (13%; SVs), PTPRD (11%; SVs and focal deletions), ALK (10%; single nucleotide variants [SNVs] and SVs), and ATRX (8%; multiple mutation types).

MYCN and TERT alterations were more common in younger children (median age of 2.3 years and 3.8 years, respectively), while ATRX alterations were more frequently seen in older patients (median age of 5.6 years).

“These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models,” the researchers wrote.

Furthermore, they found evidence to suggest the COSMIC mutational signature 18 is the most common cause of driver SNVs in neuroblastoma, including most Ras-activating and ALK variants.

Signature 18 was enriched in neuroblastomas with increased expression of mitochondrial ribosome and electron transport–associated genes, 17q gain, and MYCN amplification.

“[T]his mutagenic process, which is caused by ROS [reactive oxygen species] in other settings (though not proven in neuroblastoma), may promote evolution and heterogeneity, as many driver SNVs, such as ALK mutations, are later events in neuroblastoma,” the researchers explained.

Based on these findings, the authors concluded that neuroblastomas with 17q gain may be amenable to precision medicines, possibly through targeting altered mitochondrial function.

“[Our] findings will identify patients who might be eligible for targeted therapy and those that may be at higher risk based on a combination of genetic alterations detected by these genome-wide sequencing methods,” commented study author Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital.

The study was supported by grants from the National Cancer Institute and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. One author disclosed financial affiliations with Y-mabs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon.

SOURCE: Brady SW et al. Nat Commun. 2020 Oct 14. doi: 10.1038/s41467-020-18987-4.

A genomic study has revealed new insights into the pathogenesis of neuroblastoma as well as potential therapeutic targets.

Insights into the genetic drivers of the disease were identified based on data from whole-genome, whole-exome, and/or transcriptome sequencing of tumor samples.

“The comprehensive genome-wide analysis performed here allowed us to discover age-associated alterations in MYCN, TERT, PTPRD, and Ras pathway alterations, which, together with ATRX, represent the majority of common driver gene alterations in neuroblastoma,” wrote study author Samuel W. Brady, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues.

The group’s findings were published in Nature Communications.

The researchers integrated and analyzed data from 702 neuroblastomas encompassing all age and risk categories, with the goal of identifying rare driver events and age-related molecular aberrations. Among the samples, 23 were from patients who had relapsed.

The researchers found that 40% of samples had somatic alterations in known driver genes, with the most common alterations being MYCN (19%; primarily amplification), TERT (17%; structural variations [SVs]), SHANK2 (13%; SVs), PTPRD (11%; SVs and focal deletions), ALK (10%; single nucleotide variants [SNVs] and SVs), and ATRX (8%; multiple mutation types).

MYCN and TERT alterations were more common in younger children (median age of 2.3 years and 3.8 years, respectively), while ATRX alterations were more frequently seen in older patients (median age of 5.6 years).

“These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models,” the researchers wrote.

Furthermore, they found evidence to suggest the COSMIC mutational signature 18 is the most common cause of driver SNVs in neuroblastoma, including most Ras-activating and ALK variants.

Signature 18 was enriched in neuroblastomas with increased expression of mitochondrial ribosome and electron transport–associated genes, 17q gain, and MYCN amplification.

“[T]his mutagenic process, which is caused by ROS [reactive oxygen species] in other settings (though not proven in neuroblastoma), may promote evolution and heterogeneity, as many driver SNVs, such as ALK mutations, are later events in neuroblastoma,” the researchers explained.

Based on these findings, the authors concluded that neuroblastomas with 17q gain may be amenable to precision medicines, possibly through targeting altered mitochondrial function.

“[Our] findings will identify patients who might be eligible for targeted therapy and those that may be at higher risk based on a combination of genetic alterations detected by these genome-wide sequencing methods,” commented study author Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital.

The study was supported by grants from the National Cancer Institute and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. One author disclosed financial affiliations with Y-mabs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon.

SOURCE: Brady SW et al. Nat Commun. 2020 Oct 14. doi: 10.1038/s41467-020-18987-4.

Chimeric antigen receptor natural killer T (CAR NKT) cells can expand in vivo and localize to tumors in patients with relapsed/refractory neuroblastoma, according to results of an ongoing phase 1 trial.

In one of three patients treated thus far, the CAR NKT cells induced an objective response with regression of a metastatic bone lesion.

Andras Heczey, MD, of Baylor College of Medicine, Houston, and colleagues reported outcomes for the first three patients in Nature Medicine.

The three boys – two 12-year-olds and one 6-year-old – had relapsed/refractory neuroblastoma.

NKT cells were collected from the patients, then genetically engineered to express a CAR to recognize the GD2-ganglioside expressed in neuroblastomas and also to express interleukin-15, which supports NKT cell survival. The cells were expanded and reinfused back into the patients.

The initial results suggest that CAR NKT cells can be used safely to treat neuroblastomas and perhaps other solid tumors, investigators said.
 

‘A significant advance’ if confirmed

Treating solid tumors with CAR T cells has been a challenge, in part because of inefficient trafficking into tumors.

However, NKT cells naturally migrate to tumors in response to tumor-derived chemokines, Dr. Heczey and colleagues noted. NKT cells kill macrophages associated with tumor growth and promote NK- and T-cell–mediated antitumor responses.

“We decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet – the so-called CAR – to further potentiate their capacity to destroy the tumor,” investigator Gianpietro Dotti, MD, of the University of North Carolina Lindberger Comprehensive Cancer Center in Chapel Hill, said in a press release.

Overall, the “results are very encouraging and, if confirmed in a larger cohort of patients, present a significant advance in the cell therapy field for solid tumors,” said CAR-T researcher Stephen Gottschalk, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., when asked for comment.
 

Treatment, safety, and efficacy details

NKT cells are infrequent in human peripheral blood, so the investigators stimulated the NKT cells collected from patients with alpha-galactosylceramide–pulsed irradiated peripheral blood mononuclear cells.

The final products reached a mean NKT cell purity of 95%. The proportion of cells positive for the GD2-CAR ranged from 20% to 70% across the three patients.

After lymphodepletion with cyclophosphamide/fludarabine, the patients were infused with 3 × 10⁶ CAR NKT cells/m².

The cells were well tolerated, with no dose-limiting toxicities. There were grade 3/4 adverse events, but they occurred before CAR NKT-cell infusion and were thought to be related to lymphodepletion.

NKT-cell frequency and absolute numbers increased in the peripheral blood over baseline and remained elevated at the week 4 assessment.

Two patients had stable disease at 4 weeks, but one had a partial response and a change in Curie score from 2 to 1. The patient’s SPECT- and MIBG-merged scans “revealed a dramatic reduction in the size and MIBG uptake of a bone metastasis. The patient consequently received salvage therapy and achieved a complete response that lasted approximately 6 months,” the investigators noted.

The team found higher percentages of CAR NKT cells in primary tumor and metastatic bone marrow biopsies than in peripheral blood. A high percentage of CAR NKT cells from the tumor specimen, but only a small fraction from the bone metastasis, expressed the GD2-CAR.

This research was funded by Kuur Therapeutics, Alex’s Lemonade Stand Foundation for Childhood Cancer, the American Cancer Society, Cookies for Kids’ Cancer Foundation, and the Cancer Prevention and Research Institute of Texas. Dr. Heczey, Dr. Dotti, and two other researchers are coinventors on pending patent applications for NKT cells in cancer immunotherapy that have been licensed to Kuur Therapeutics for commercial development. Dr. Gottschalk has patent applications in the fields of T-cell and/or gene therapy for cancer. He has relationships with TESSA Therapeutics, Immatics, and Tidal.

[email protected]

SOURCE: Heczey A et al. Nat Med. 2020 Oct 12. doi: 10.1038/s41591-020-1074-2.

Chimeric antigen receptor natural killer T (CAR NKT) cells can expand in vivo and localize to tumors in patients with relapsed/refractory neuroblastoma, according to results of an ongoing phase 1 trial.

In one of three patients treated thus far, the CAR NKT cells induced an objective response with regression of a metastatic bone lesion.

Andras Heczey, MD, of Baylor College of Medicine, Houston, and colleagues reported outcomes for the first three patients in Nature Medicine.

The three boys – two 12-year-olds and one 6-year-old – had relapsed/refractory neuroblastoma.

NKT cells were collected from the patients, then genetically engineered to express a CAR to recognize the GD2-ganglioside expressed in neuroblastomas and also to express interleukin-15, which supports NKT cell survival. The cells were expanded and reinfused back into the patients.

The initial results suggest that CAR NKT cells can be used safely to treat neuroblastomas and perhaps other solid tumors, investigators said.
 

‘A significant advance’ if confirmed

Treating solid tumors with CAR T cells has been a challenge, in part because of inefficient trafficking into tumors.

However, NKT cells naturally migrate to tumors in response to tumor-derived chemokines, Dr. Heczey and colleagues noted. NKT cells kill macrophages associated with tumor growth and promote NK- and T-cell–mediated antitumor responses.

“We decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet – the so-called CAR – to further potentiate their capacity to destroy the tumor,” investigator Gianpietro Dotti, MD, of the University of North Carolina Lindberger Comprehensive Cancer Center in Chapel Hill, said in a press release.

Overall, the “results are very encouraging and, if confirmed in a larger cohort of patients, present a significant advance in the cell therapy field for solid tumors,” said CAR-T researcher Stephen Gottschalk, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., when asked for comment.
 

Treatment, safety, and efficacy details

NKT cells are infrequent in human peripheral blood, so the investigators stimulated the NKT cells collected from patients with alpha-galactosylceramide–pulsed irradiated peripheral blood mononuclear cells.

The final products reached a mean NKT cell purity of 95%. The proportion of cells positive for the GD2-CAR ranged from 20% to 70% across the three patients.

After lymphodepletion with cyclophosphamide/fludarabine, the patients were infused with 3 × 10⁶ CAR NKT cells/m².

The cells were well tolerated, with no dose-limiting toxicities. There were grade 3/4 adverse events, but they occurred before CAR NKT-cell infusion and were thought to be related to lymphodepletion.

NKT-cell frequency and absolute numbers increased in the peripheral blood over baseline and remained elevated at the week 4 assessment.

Two patients had stable disease at 4 weeks, but one had a partial response and a change in Curie score from 2 to 1. The patient’s SPECT- and MIBG-merged scans “revealed a dramatic reduction in the size and MIBG uptake of a bone metastasis. The patient consequently received salvage therapy and achieved a complete response that lasted approximately 6 months,” the investigators noted.

The team found higher percentages of CAR NKT cells in primary tumor and metastatic bone marrow biopsies than in peripheral blood. A high percentage of CAR NKT cells from the tumor specimen, but only a small fraction from the bone metastasis, expressed the GD2-CAR.

This research was funded by Kuur Therapeutics, Alex’s Lemonade Stand Foundation for Childhood Cancer, the American Cancer Society, Cookies for Kids’ Cancer Foundation, and the Cancer Prevention and Research Institute of Texas. Dr. Heczey, Dr. Dotti, and two other researchers are coinventors on pending patent applications for NKT cells in cancer immunotherapy that have been licensed to Kuur Therapeutics for commercial development. Dr. Gottschalk has patent applications in the fields of T-cell and/or gene therapy for cancer. He has relationships with TESSA Therapeutics, Immatics, and Tidal.

[email protected]

SOURCE: Heczey A et al. Nat Med. 2020 Oct 12. doi: 10.1038/s41591-020-1074-2.

Chimeric antigen receptor natural killer T (CAR NKT) cells can expand in vivo and localize to tumors in patients with relapsed/refractory neuroblastoma, according to results of an ongoing phase 1 trial.

In one of three patients treated thus far, the CAR NKT cells induced an objective response with regression of a metastatic bone lesion.

Andras Heczey, MD, of Baylor College of Medicine, Houston, and colleagues reported outcomes for the first three patients in Nature Medicine.

The three boys – two 12-year-olds and one 6-year-old – had relapsed/refractory neuroblastoma.

NKT cells were collected from the patients, then genetically engineered to express a CAR to recognize the GD2-ganglioside expressed in neuroblastomas and also to express interleukin-15, which supports NKT cell survival. The cells were expanded and reinfused back into the patients.

The initial results suggest that CAR NKT cells can be used safely to treat neuroblastomas and perhaps other solid tumors, investigators said.
 

‘A significant advance’ if confirmed

Treating solid tumors with CAR T cells has been a challenge, in part because of inefficient trafficking into tumors.

However, NKT cells naturally migrate to tumors in response to tumor-derived chemokines, Dr. Heczey and colleagues noted. NKT cells kill macrophages associated with tumor growth and promote NK- and T-cell–mediated antitumor responses.

“We decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet – the so-called CAR – to further potentiate their capacity to destroy the tumor,” investigator Gianpietro Dotti, MD, of the University of North Carolina Lindberger Comprehensive Cancer Center in Chapel Hill, said in a press release.

Overall, the “results are very encouraging and, if confirmed in a larger cohort of patients, present a significant advance in the cell therapy field for solid tumors,” said CAR-T researcher Stephen Gottschalk, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., when asked for comment.
 

Treatment, safety, and efficacy details

NKT cells are infrequent in human peripheral blood, so the investigators stimulated the NKT cells collected from patients with alpha-galactosylceramide–pulsed irradiated peripheral blood mononuclear cells.

The final products reached a mean NKT cell purity of 95%. The proportion of cells positive for the GD2-CAR ranged from 20% to 70% across the three patients.

After lymphodepletion with cyclophosphamide/fludarabine, the patients were infused with 3 × 10⁶ CAR NKT cells/m².

The cells were well tolerated, with no dose-limiting toxicities. There were grade 3/4 adverse events, but they occurred before CAR NKT-cell infusion and were thought to be related to lymphodepletion.

NKT-cell frequency and absolute numbers increased in the peripheral blood over baseline and remained elevated at the week 4 assessment.

Two patients had stable disease at 4 weeks, but one had a partial response and a change in Curie score from 2 to 1. The patient’s SPECT- and MIBG-merged scans “revealed a dramatic reduction in the size and MIBG uptake of a bone metastasis. The patient consequently received salvage therapy and achieved a complete response that lasted approximately 6 months,” the investigators noted.

The team found higher percentages of CAR NKT cells in primary tumor and metastatic bone marrow biopsies than in peripheral blood. A high percentage of CAR NKT cells from the tumor specimen, but only a small fraction from the bone metastasis, expressed the GD2-CAR.

This research was funded by Kuur Therapeutics, Alex’s Lemonade Stand Foundation for Childhood Cancer, the American Cancer Society, Cookies for Kids’ Cancer Foundation, and the Cancer Prevention and Research Institute of Texas. Dr. Heczey, Dr. Dotti, and two other researchers are coinventors on pending patent applications for NKT cells in cancer immunotherapy that have been licensed to Kuur Therapeutics for commercial development. Dr. Gottschalk has patent applications in the fields of T-cell and/or gene therapy for cancer. He has relationships with TESSA Therapeutics, Immatics, and Tidal.

[email protected]

SOURCE: Heczey A et al. Nat Med. 2020 Oct 12. doi: 10.1038/s41591-020-1074-2.

For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.

Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.

“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.

But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.

Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.

Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.

For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.

Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.

Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.

A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.

As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).

The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.

A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.

The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.

SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.

For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.

Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.

“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.

But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.

Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.

Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.

For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.

Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.

Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.

A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.

As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).

The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.

A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.

The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.

SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.

For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.

Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.

“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.

But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.

Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.

Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.

For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.

Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.

Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.

A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.

As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).

The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.

A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.

The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.

SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.

Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.

The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.

Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.

He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?

The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.

After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:

• larotrectinib (targeting NTRK fusions).
• erdafitinib (targeting FGFR1/2/3/4).
• tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
• LY3023414 (targeting the PI3K/MTOR pathway).
• selumetinib (targeting the MAPK pathway).
• ensartinib (targeting ALK or ROS1).
• vemurafenib (targeting BRAF V600 mutations).
• olaparib (targeting defects in DNA damage repair).
• palbociclib (targeting alterations in cell cycle genes).
• ulixertinib (targeting MAPK pathway mutations).

Early results

From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.

The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).

A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.

“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.

Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.

Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.

“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”

The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.

[email protected]

SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.

Entrectinib demonstrated “very promising” antitumor activity in children and adolescents with recurrent or refractory solid tumors, according to an investigator involved in a phase 1/1b trial.

Twelve of 29 patients enrolled in the trial have responded to entrectinib. All responders had fusions in genes targeted by the drug – NTRK1/2/3 (TRKA/B/C), ROS1, or ALK – or an ALK mutation.

Details of this study are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Giles W. Robinson, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., discussed the study during a press briefing in advance of the meeting.

“Entrectinib is an oral and potent inhibitor of the TRKA/B/C, ROS1, and ALK proteins, but it also penetrates into the brain to reach tumors in the brain and spine, which can be a hard area to get drugs to,” Dr. Robinson explained.

“Promising clinical activity was initially seen in the adult solid tumor patients with target rearrangements, and it was encouraging to see these patients also had responses when the tumors were located in their brains. And what got us really excited as pediatric oncologists was that a variety of pediatric cancers harbor these fusions and mutations within certain tumors.”

With this in mind, Dr. Robinson and colleagues conducted a phase 1/1b study (NCT02650401) of entrectinib in 29 patients with recurrent or refractory solid tumors, including central nervous system (CNS) tumors.

The patients’ median age was 7 years (range, 0-20 years), and roughly half of them were male (n = 15). Patients were diagnosed with neuroblastoma (n = 16), high-grade glioma (n = 5), inflammatory myofibroblastic tumors (n = 3), infantile fibrosarcoma (n = 2), CNS embryonal tumor (n = 1), melanoma (n = 1), and synovial sarcoma (n = 1).

In the dose-finding portion of the trial, patients received entrectinib at 250 mg/m² (n = 3), 400 mg/m² (n = 3), 550 mg/m² (n = 7), or 750 mg/m² (n = 3).

In the phase 1b portion, patients received entrectinib at 550 mg/m² (n = 7) – the recommended dose – or 400 mg/m² (n = 6) if they were unable to swallow intact capsules.

Dr. Robinson said entrectinib was “quite well tolerated” overall, but he did not present any data on adverse events. He did say dose-limiting toxicities included fatigue, elevated creatinine levels, dysgeusia resulting in loss of taste, weight gain, and, in one patient, pulmonary edema.

“Entrectinib produced striking, rapid, and durable responses in all children with refractory CNS and solid tumors that actually harbored these fusions in NTRK1/2/3, ROS1, or ALK,” Dr. Robinson said. “It also produced a significant response in one ALK-mutated neuroblastoma patient. [N]o responses were seen in tumors lacking aberrations in the target kinases.”

In all, 12 patients responded. The three complete responders had an ALK F1174L mutation, an ALK fusion, and an NTRK fusion, respectively. Five partial responders had NTRK fusions, three had ROS1 fusions, and one had an ALK fusion.

Three responders discontinued treatment. Ten patients were still receiving entrectinib at last follow-up, and 11 patients had died.

Progression-free survival was significantly longer among patients who had fusions than among those who did not (P less than .0001).

“To sum up, entrectinib really is very promising,” Dr. Robinson said. “It has very promising antitumor activity and progression-free survival but [only] in patients with target gene fusions.”

Dr. Robinson said this trial is ongoing, but it is now limited to patients with fusions targeted by entrectinib.

The trial is sponsored by Hoffman-La Roche Ltd. and supported by Alex’s Lemonade Stand Center of Excellence. Dr. Robinson has relationships with Lilly, Genentech/Roche, and Novartis.

[email protected]

SOURCE: Robinson GW et al. ASCO 2019. Abstract 10009.

Entrectinib demonstrated “very promising” antitumor activity in children and adolescents with recurrent or refractory solid tumors, according to an investigator involved in a phase 1/1b trial.

Twelve of 29 patients enrolled in the trial have responded to entrectinib. All responders had fusions in genes targeted by the drug – NTRK1/2/3 (TRKA/B/C), ROS1, or ALK – or an ALK mutation.

Details of this study are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Giles W. Robinson, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., discussed the study during a press briefing in advance of the meeting.

“Entrectinib is an oral and potent inhibitor of the TRKA/B/C, ROS1, and ALK proteins, but it also penetrates into the brain to reach tumors in the brain and spine, which can be a hard area to get drugs to,” Dr. Robinson explained.

“Promising clinical activity was initially seen in the adult solid tumor patients with target rearrangements, and it was encouraging to see these patients also had responses when the tumors were located in their brains. And what got us really excited as pediatric oncologists was that a variety of pediatric cancers harbor these fusions and mutations within certain tumors.”

With this in mind, Dr. Robinson and colleagues conducted a phase 1/1b study (NCT02650401) of entrectinib in 29 patients with recurrent or refractory solid tumors, including central nervous system (CNS) tumors.

The patients’ median age was 7 years (range, 0-20 years), and roughly half of them were male (n = 15). Patients were diagnosed with neuroblastoma (n = 16), high-grade glioma (n = 5), inflammatory myofibroblastic tumors (n = 3), infantile fibrosarcoma (n = 2), CNS embryonal tumor (n = 1), melanoma (n = 1), and synovial sarcoma (n = 1).

In the dose-finding portion of the trial, patients received entrectinib at 250 mg/m² (n = 3), 400 mg/m² (n = 3), 550 mg/m² (n = 7), or 750 mg/m² (n = 3).

In the phase 1b portion, patients received entrectinib at 550 mg/m² (n = 7) – the recommended dose – or 400 mg/m² (n = 6) if they were unable to swallow intact capsules.

Dr. Robinson said entrectinib was “quite well tolerated” overall, but he did not present any data on adverse events. He did say dose-limiting toxicities included fatigue, elevated creatinine levels, dysgeusia resulting in loss of taste, weight gain, and, in one patient, pulmonary edema.

“Entrectinib produced striking, rapid, and durable responses in all children with refractory CNS and solid tumors that actually harbored these fusions in NTRK1/2/3, ROS1, or ALK,” Dr. Robinson said. “It also produced a significant response in one ALK-mutated neuroblastoma patient. [N]o responses were seen in tumors lacking aberrations in the target kinases.”

In all, 12 patients responded. The three complete responders had an ALK F1174L mutation, an ALK fusion, and an NTRK fusion, respectively. Five partial responders had NTRK fusions, three had ROS1 fusions, and one had an ALK fusion.

Three responders discontinued treatment. Ten patients were still receiving entrectinib at last follow-up, and 11 patients had died.

Progression-free survival was significantly longer among patients who had fusions than among those who did not (P less than .0001).

“To sum up, entrectinib really is very promising,” Dr. Robinson said. “It has very promising antitumor activity and progression-free survival but [only] in patients with target gene fusions.”

Dr. Robinson said this trial is ongoing, but it is now limited to patients with fusions targeted by entrectinib.

The trial is sponsored by Hoffman-La Roche Ltd. and supported by Alex’s Lemonade Stand Center of Excellence. Dr. Robinson has relationships with Lilly, Genentech/Roche, and Novartis.

[email protected]

SOURCE: Robinson GW et al. ASCO 2019. Abstract 10009.

Entrectinib demonstrated “very promising” antitumor activity in children and adolescents with recurrent or refractory solid tumors, according to an investigator involved in a phase 1/1b trial.

Twelve of 29 patients enrolled in the trial have responded to entrectinib. All responders had fusions in genes targeted by the drug – NTRK1/2/3 (TRKA/B/C), ROS1, or ALK – or an ALK mutation.

Details of this study are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Giles W. Robinson, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., discussed the study during a press briefing in advance of the meeting.

“Entrectinib is an oral and potent inhibitor of the TRKA/B/C, ROS1, and ALK proteins, but it also penetrates into the brain to reach tumors in the brain and spine, which can be a hard area to get drugs to,” Dr. Robinson explained.

“Promising clinical activity was initially seen in the adult solid tumor patients with target rearrangements, and it was encouraging to see these patients also had responses when the tumors were located in their brains. And what got us really excited as pediatric oncologists was that a variety of pediatric cancers harbor these fusions and mutations within certain tumors.”

With this in mind, Dr. Robinson and colleagues conducted a phase 1/1b study (NCT02650401) of entrectinib in 29 patients with recurrent or refractory solid tumors, including central nervous system (CNS) tumors.

The patients’ median age was 7 years (range, 0-20 years), and roughly half of them were male (n = 15). Patients were diagnosed with neuroblastoma (n = 16), high-grade glioma (n = 5), inflammatory myofibroblastic tumors (n = 3), infantile fibrosarcoma (n = 2), CNS embryonal tumor (n = 1), melanoma (n = 1), and synovial sarcoma (n = 1).

In the dose-finding portion of the trial, patients received entrectinib at 250 mg/m² (n = 3), 400 mg/m² (n = 3), 550 mg/m² (n = 7), or 750 mg/m² (n = 3).

In the phase 1b portion, patients received entrectinib at 550 mg/m² (n = 7) – the recommended dose – or 400 mg/m² (n = 6) if they were unable to swallow intact capsules.

Dr. Robinson said entrectinib was “quite well tolerated” overall, but he did not present any data on adverse events. He did say dose-limiting toxicities included fatigue, elevated creatinine levels, dysgeusia resulting in loss of taste, weight gain, and, in one patient, pulmonary edema.

“Entrectinib produced striking, rapid, and durable responses in all children with refractory CNS and solid tumors that actually harbored these fusions in NTRK1/2/3, ROS1, or ALK,” Dr. Robinson said. “It also produced a significant response in one ALK-mutated neuroblastoma patient. [N]o responses were seen in tumors lacking aberrations in the target kinases.”

In all, 12 patients responded. The three complete responders had an ALK F1174L mutation, an ALK fusion, and an NTRK fusion, respectively. Five partial responders had NTRK fusions, three had ROS1 fusions, and one had an ALK fusion.

Three responders discontinued treatment. Ten patients were still receiving entrectinib at last follow-up, and 11 patients had died.

Progression-free survival was significantly longer among patients who had fusions than among those who did not (P less than .0001).

“To sum up, entrectinib really is very promising,” Dr. Robinson said. “It has very promising antitumor activity and progression-free survival but [only] in patients with target gene fusions.”

Dr. Robinson said this trial is ongoing, but it is now limited to patients with fusions targeted by entrectinib.

The trial is sponsored by Hoffman-La Roche Ltd. and supported by Alex’s Lemonade Stand Center of Excellence. Dr. Robinson has relationships with Lilly, Genentech/Roche, and Novartis.

[email protected]

SOURCE: Robinson GW et al. ASCO 2019. Abstract 10009.

Telomere maintenance mechanisms, RAS mutations, and p53 mutations can be used to mechanistically classify clinical phenotypes of neuroblastoma, according to investigators.

Genomic analysis of neuroblastomas showed that the aforementioned markers were strongly associated with outcome and other disease characteristics, reported Sandra Ackermann, MD, of the department of experimental pediatric oncology at the University Children’s Hospital of Cologne (Germany), and her colleagues.

Although previous studies have shown relationships between genetic alterations and behavior of neuroblastomas, “to date, these genomic data have not produced a coherent model of pathogenesis that can explain the extremely divergent clinical phenotypes of neuroblastoma,” the investigators wrote in Science.

The present study involved genomic sequencing of 416 pretreatment neuroblastomas, with tests for telomere maintenance mechanisms, RAS-pathway mutations, and p53-pathway mutations.

Based on existing data, the investigators first devised a panel based on 17 genes related to the RAS pathway (11 genes included ALK) and 6 related to the p53 pathway. In 198 cases, 28 tested positive for RAS- or p53-pathway abnormalities (17.8%). Positivity was more common in high-risk tumors than non–high-risk tumors (21.3% vs. 13.3%; P = .048), and in both risk groups, positivity was associated with poor outcome (hazard ratio, 2.056; P = .001).

However, because clinical courses varied widely among non–high-risk patients with RAS/p53 mutations, the investigators recognized that a piece of the puzzle was missing. They hypothesized that telomere maintenance mechanisms could also be playing a role. Following several intervening experiments, the investigators devised telomere maintenance mechanism testing, defined by MYCN amplification or TERT rearrangements, elevated TERT expression if negative for these abnormalities, or presence of ALT-associated promyelocytic leukemia nuclear bodies. Subsequent testing revealed that positivity for these parameters was associated with a HR of 5.184 (P less than .001), thereby confirming that telomere maintenance mechanisms could independently predict survival.

“Together, our findings demonstrate that the divergent clinical phenotypes of human neuroblastoma are driven by molecular alterations affecting telomere maintenance and RAS or p53 pathways, suggesting a mechanistic classification of this malignancy,” the authors concluded.

The proposed classification scheme also includes associations with other genetic features (tumor cell ploidy, segmental copy number alterations, MYCN/TERT/ATRX alterations, and gene expression favorability) and clinical characteristics (stage of disease and age at diagnosis).

The study was funded by the German Cancer Aid, the German Ministry of Science and Education, the MYC-NET, the Deutsche Forschungsgemeinschaft, the Berlin Institute of Health, the European Union, and others. One coauthor reported financial relationships with Biogazelle and pxlence, and another reported consulting fees from NEO New Oncology.

SOURCE: Ackermann S et al. Science. 2018 Dec 7. doi: 10.1126/science.aat6768.

Telomere maintenance mechanisms, RAS mutations, and p53 mutations can be used to mechanistically classify clinical phenotypes of neuroblastoma, according to investigators.

Genomic analysis of neuroblastomas showed that the aforementioned markers were strongly associated with outcome and other disease characteristics, reported Sandra Ackermann, MD, of the department of experimental pediatric oncology at the University Children’s Hospital of Cologne (Germany), and her colleagues.

Although previous studies have shown relationships between genetic alterations and behavior of neuroblastomas, “to date, these genomic data have not produced a coherent model of pathogenesis that can explain the extremely divergent clinical phenotypes of neuroblastoma,” the investigators wrote in Science.

The present study involved genomic sequencing of 416 pretreatment neuroblastomas, with tests for telomere maintenance mechanisms, RAS-pathway mutations, and p53-pathway mutations.

Based on existing data, the investigators first devised a panel based on 17 genes related to the RAS pathway (11 genes included ALK) and 6 related to the p53 pathway. In 198 cases, 28 tested positive for RAS- or p53-pathway abnormalities (17.8%). Positivity was more common in high-risk tumors than non–high-risk tumors (21.3% vs. 13.3%; P = .048), and in both risk groups, positivity was associated with poor outcome (hazard ratio, 2.056; P = .001).

However, because clinical courses varied widely among non–high-risk patients with RAS/p53 mutations, the investigators recognized that a piece of the puzzle was missing. They hypothesized that telomere maintenance mechanisms could also be playing a role. Following several intervening experiments, the investigators devised telomere maintenance mechanism testing, defined by MYCN amplification or TERT rearrangements, elevated TERT expression if negative for these abnormalities, or presence of ALT-associated promyelocytic leukemia nuclear bodies. Subsequent testing revealed that positivity for these parameters was associated with a HR of 5.184 (P less than .001), thereby confirming that telomere maintenance mechanisms could independently predict survival.

“Together, our findings demonstrate that the divergent clinical phenotypes of human neuroblastoma are driven by molecular alterations affecting telomere maintenance and RAS or p53 pathways, suggesting a mechanistic classification of this malignancy,” the authors concluded.

The proposed classification scheme also includes associations with other genetic features (tumor cell ploidy, segmental copy number alterations, MYCN/TERT/ATRX alterations, and gene expression favorability) and clinical characteristics (stage of disease and age at diagnosis).

The study was funded by the German Cancer Aid, the German Ministry of Science and Education, the MYC-NET, the Deutsche Forschungsgemeinschaft, the Berlin Institute of Health, the European Union, and others. One coauthor reported financial relationships with Biogazelle and pxlence, and another reported consulting fees from NEO New Oncology.

SOURCE: Ackermann S et al. Science. 2018 Dec 7. doi: 10.1126/science.aat6768.

Telomere maintenance mechanisms, RAS mutations, and p53 mutations can be used to mechanistically classify clinical phenotypes of neuroblastoma, according to investigators.

Genomic analysis of neuroblastomas showed that the aforementioned markers were strongly associated with outcome and other disease characteristics, reported Sandra Ackermann, MD, of the department of experimental pediatric oncology at the University Children’s Hospital of Cologne (Germany), and her colleagues.

Although previous studies have shown relationships between genetic alterations and behavior of neuroblastomas, “to date, these genomic data have not produced a coherent model of pathogenesis that can explain the extremely divergent clinical phenotypes of neuroblastoma,” the investigators wrote in Science.

The present study involved genomic sequencing of 416 pretreatment neuroblastomas, with tests for telomere maintenance mechanisms, RAS-pathway mutations, and p53-pathway mutations.

Based on existing data, the investigators first devised a panel based on 17 genes related to the RAS pathway (11 genes included ALK) and 6 related to the p53 pathway. In 198 cases, 28 tested positive for RAS- or p53-pathway abnormalities (17.8%). Positivity was more common in high-risk tumors than non–high-risk tumors (21.3% vs. 13.3%; P = .048), and in both risk groups, positivity was associated with poor outcome (hazard ratio, 2.056; P = .001).

However, because clinical courses varied widely among non–high-risk patients with RAS/p53 mutations, the investigators recognized that a piece of the puzzle was missing. They hypothesized that telomere maintenance mechanisms could also be playing a role. Following several intervening experiments, the investigators devised telomere maintenance mechanism testing, defined by MYCN amplification or TERT rearrangements, elevated TERT expression if negative for these abnormalities, or presence of ALT-associated promyelocytic leukemia nuclear bodies. Subsequent testing revealed that positivity for these parameters was associated with a HR of 5.184 (P less than .001), thereby confirming that telomere maintenance mechanisms could independently predict survival.

“Together, our findings demonstrate that the divergent clinical phenotypes of human neuroblastoma are driven by molecular alterations affecting telomere maintenance and RAS or p53 pathways, suggesting a mechanistic classification of this malignancy,” the authors concluded.

The proposed classification scheme also includes associations with other genetic features (tumor cell ploidy, segmental copy number alterations, MYCN/TERT/ATRX alterations, and gene expression favorability) and clinical characteristics (stage of disease and age at diagnosis).

The study was funded by the German Cancer Aid, the German Ministry of Science and Education, the MYC-NET, the Deutsche Forschungsgemeinschaft, the Berlin Institute of Health, the European Union, and others. One coauthor reported financial relationships with Biogazelle and pxlence, and another reported consulting fees from NEO New Oncology.

SOURCE: Ackermann S et al. Science. 2018 Dec 7. doi: 10.1126/science.aat6768.

PITTSBURGH – Genetic analysis of circulating free DNA (cfDNA) from pediatric solid tumors can noninvasively identify somatic mutations and copy number alterations that could be used to identify therapeutic targets, investigators reported.

An analysis of tumor specimens and plasma samples from children with neuroblastoma, osteosarcoma, and Wilms tumor revealed in cfDNA both somatic mutations and copy number alterations that had already been detected in the solid tumors, and new, potentially targetable mutations, reported Prachi Kothari, DO, and her colleagues from Memorial Sloan Kettering Cancer Center in New York.

Neil Osterweil/MDedge News

“Circulating free DNA is much less invasive than a tumor biopsy, and you can do it throughout the patient’s entire timeline of treatment, so you get real-time information or after they relapse to see what’s going on if you’re not able to get a tumor biopsy,” Dr. Kothari said at annual meeting of the American Society of Pediatric Hematology/Oncology.

So-called “liquid biopsy” using cfDNA has been used for molecular profiling of adults malignancies, but there are few data on its use in pediatric tumors, Dr. Kothari said.

To see whether the technique could provide useful clinical information for the management of pediatric tumors, the investigators examined tumor samples taken at diagnosis or at the time of disease progression from 15 patients with neuroblastoma, 10 with osteosarcoma, and 5 with Wilms tumor. They analyzed the tumor samples using targeted next-generation sequencing (NGS), and cfDNA using three different genomic analysis techniques, including NGS, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), and shallow whole genome sequencing.

For each of the tumor types studies, cfDNA analysis with the MSK-IMPACT platform identified key drivers of malignancy, including MYCN, ALK, and ATRX in neuroblastoma; CDKN2A and MDM2 in osteosarcoma; and DICER1 and AMER1 in Wilms tumor.

The cfDNA samples also revealed somatic mutations and copy number alterations previously reported in the tumors of 8 of the 15 patients with neuroblastoma, as well as potentially targetable new mutations in 6 of the 15 patients, including NRAS, MLL2, ARID1B, and IDH2.

In 5 of the 10 patients with osteosarcoma, cfDNA detected mutations that had been seen in the tumor samples, including mutations in ATRX and NOTCH3, and copy number alterations such as CDK4 amplification,

Of the five patients with Wilms tumors, cfDNA analysis was performed on two samples, one of which showed the same mutation as the tumor. Additionally, for the three patients without tumor analysis, cfDNA showed recurrent driver mutations such as AMER1 and DICER1.

SOURCE: Kothari P et al. ASPHO 2018. Abstract #809.

PITTSBURGH – Genetic analysis of circulating free DNA (cfDNA) from pediatric solid tumors can noninvasively identify somatic mutations and copy number alterations that could be used to identify therapeutic targets, investigators reported.

An analysis of tumor specimens and plasma samples from children with neuroblastoma, osteosarcoma, and Wilms tumor revealed in cfDNA both somatic mutations and copy number alterations that had already been detected in the solid tumors, and new, potentially targetable mutations, reported Prachi Kothari, DO, and her colleagues from Memorial Sloan Kettering Cancer Center in New York.

Neil Osterweil/MDedge News

“Circulating free DNA is much less invasive than a tumor biopsy, and you can do it throughout the patient’s entire timeline of treatment, so you get real-time information or after they relapse to see what’s going on if you’re not able to get a tumor biopsy,” Dr. Kothari said at annual meeting of the American Society of Pediatric Hematology/Oncology.

So-called “liquid biopsy” using cfDNA has been used for molecular profiling of adults malignancies, but there are few data on its use in pediatric tumors, Dr. Kothari said.

To see whether the technique could provide useful clinical information for the management of pediatric tumors, the investigators examined tumor samples taken at diagnosis or at the time of disease progression from 15 patients with neuroblastoma, 10 with osteosarcoma, and 5 with Wilms tumor. They analyzed the tumor samples using targeted next-generation sequencing (NGS), and cfDNA using three different genomic analysis techniques, including NGS, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), and shallow whole genome sequencing.

For each of the tumor types studies, cfDNA analysis with the MSK-IMPACT platform identified key drivers of malignancy, including MYCN, ALK, and ATRX in neuroblastoma; CDKN2A and MDM2 in osteosarcoma; and DICER1 and AMER1 in Wilms tumor.

The cfDNA samples also revealed somatic mutations and copy number alterations previously reported in the tumors of 8 of the 15 patients with neuroblastoma, as well as potentially targetable new mutations in 6 of the 15 patients, including NRAS, MLL2, ARID1B, and IDH2.

In 5 of the 10 patients with osteosarcoma, cfDNA detected mutations that had been seen in the tumor samples, including mutations in ATRX and NOTCH3, and copy number alterations such as CDK4 amplification,

Of the five patients with Wilms tumors, cfDNA analysis was performed on two samples, one of which showed the same mutation as the tumor. Additionally, for the three patients without tumor analysis, cfDNA showed recurrent driver mutations such as AMER1 and DICER1.

SOURCE: Kothari P et al. ASPHO 2018. Abstract #809.

PITTSBURGH – Genetic analysis of circulating free DNA (cfDNA) from pediatric solid tumors can noninvasively identify somatic mutations and copy number alterations that could be used to identify therapeutic targets, investigators reported.

An analysis of tumor specimens and plasma samples from children with neuroblastoma, osteosarcoma, and Wilms tumor revealed in cfDNA both somatic mutations and copy number alterations that had already been detected in the solid tumors, and new, potentially targetable mutations, reported Prachi Kothari, DO, and her colleagues from Memorial Sloan Kettering Cancer Center in New York.

Neil Osterweil/MDedge News

“Circulating free DNA is much less invasive than a tumor biopsy, and you can do it throughout the patient’s entire timeline of treatment, so you get real-time information or after they relapse to see what’s going on if you’re not able to get a tumor biopsy,” Dr. Kothari said at annual meeting of the American Society of Pediatric Hematology/Oncology.

So-called “liquid biopsy” using cfDNA has been used for molecular profiling of adults malignancies, but there are few data on its use in pediatric tumors, Dr. Kothari said.

To see whether the technique could provide useful clinical information for the management of pediatric tumors, the investigators examined tumor samples taken at diagnosis or at the time of disease progression from 15 patients with neuroblastoma, 10 with osteosarcoma, and 5 with Wilms tumor. They analyzed the tumor samples using targeted next-generation sequencing (NGS), and cfDNA using three different genomic analysis techniques, including NGS, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), and shallow whole genome sequencing.

For each of the tumor types studies, cfDNA analysis with the MSK-IMPACT platform identified key drivers of malignancy, including MYCN, ALK, and ATRX in neuroblastoma; CDKN2A and MDM2 in osteosarcoma; and DICER1 and AMER1 in Wilms tumor.

The cfDNA samples also revealed somatic mutations and copy number alterations previously reported in the tumors of 8 of the 15 patients with neuroblastoma, as well as potentially targetable new mutations in 6 of the 15 patients, including NRAS, MLL2, ARID1B, and IDH2.

In 5 of the 10 patients with osteosarcoma, cfDNA detected mutations that had been seen in the tumor samples, including mutations in ATRX and NOTCH3, and copy number alterations such as CDK4 amplification,

Of the five patients with Wilms tumors, cfDNA analysis was performed on two samples, one of which showed the same mutation as the tumor. Additionally, for the three patients without tumor analysis, cfDNA showed recurrent driver mutations such as AMER1 and DICER1.

SOURCE: Kothari P et al. ASPHO 2018. Abstract #809.

PITTSBURGH – Call it the CAR of the future – an investigational chimeric antigen receptor–T cell construct targeted against an antigen highly expressed on pediatric solid tumors has shown promising efficacy in preclinical studies.

Investigators found that the antigen, labeled B7-H3, was expressed on 84% of microarrays of pediatric solid tumors. More importantly, a single dose of CAR targeted to B7-H3 caused complete regression of osteosarcoma and Ewing sarcoma xenografts and improved survival over an untransduced, CD19-targeted CAR in mice, Robbie Majzner, MD, reported at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Neil Osterweil/MDedge News

In contrast, B7-H3 is highly expressed on many different pediatric solid tumors, including rhabdomyosarcoma (95% of tumors stained), Ewing sarcoma (89%), Wilms tumor (100%), neuroblastoma (82%), ganglioneuroblastoma and ganglioneuroma (53%), medulloblastoma (96%), glioblastoma multiforme (84%), and diffuse intrinsic pontine glioma (100%).

To see whether CAR T therapy might have better efficacy than checkpoint inhibitors in this population, the investigators created a B7-H3 CAR using the B7-H3 tumor–specific monoclonal antibody MGA271, which has been shown to be safe in both adults and children in early clinical trials.

In human tumor xenograft models of osteosarcoma, all mice who received a single dose of the B7-H3 CAR survived at least 70 days after tumor engraftment, whereas all control mice, who received the CD19 CAR, died by day 60 (P = .0067). Similarly, in a model of Ewing sarcoma, all mice treated with B7-H3 survived at least 100 days, whereas all controls were dead by day 50 (P = .0015).

The B7-H3 construct also showed good activity against a model of medulloblastoma, showing that it was capable of crossing the blood-brain barrier.

Since B7-H3 has been reported to be expressed on both myeloid and lymphoid leukemia cells, the investigators also tested the CAR against a murine model of leukemia generated by injection of K562, a well-characterized line of myeloid leukemia cells.

“While we found some increase in survival in the mice that received the B7-H3 CAR T cells, compared to mice that received untransduced CAR T cells, this clearly is not as effective as in our solid tumor models,” Dr. Majzner said.

Going back to the cell line, they discovered that expression of B7-H3 was considerably lower in the K562 cells than in either the osteosarcoma or medulloblastoma cell lines used in their other models.

They found that both in vitro and in vivo, high levels of B7-H3 expression were necessary to provoke the immune system into releasing cytokines necessary for an adequate antitumor response.

The investigators are currently planning clinical trials using the B7-H3 CAR T-cell construct in patients with solid tumors.

The work is supported by the Sarcoma Alliance for Research through Collaboration, the St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.

SOURCE: Majzner RG et al. ASPHO 2018, Abstract #PS2003.

PITTSBURGH – Call it the CAR of the future – an investigational chimeric antigen receptor–T cell construct targeted against an antigen highly expressed on pediatric solid tumors has shown promising efficacy in preclinical studies.

Investigators found that the antigen, labeled B7-H3, was expressed on 84% of microarrays of pediatric solid tumors. More importantly, a single dose of CAR targeted to B7-H3 caused complete regression of osteosarcoma and Ewing sarcoma xenografts and improved survival over an untransduced, CD19-targeted CAR in mice, Robbie Majzner, MD, reported at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Neil Osterweil/MDedge News

In contrast, B7-H3 is highly expressed on many different pediatric solid tumors, including rhabdomyosarcoma (95% of tumors stained), Ewing sarcoma (89%), Wilms tumor (100%), neuroblastoma (82%), ganglioneuroblastoma and ganglioneuroma (53%), medulloblastoma (96%), glioblastoma multiforme (84%), and diffuse intrinsic pontine glioma (100%).

To see whether CAR T therapy might have better efficacy than checkpoint inhibitors in this population, the investigators created a B7-H3 CAR using the B7-H3 tumor–specific monoclonal antibody MGA271, which has been shown to be safe in both adults and children in early clinical trials.

In human tumor xenograft models of osteosarcoma, all mice who received a single dose of the B7-H3 CAR survived at least 70 days after tumor engraftment, whereas all control mice, who received the CD19 CAR, died by day 60 (P = .0067). Similarly, in a model of Ewing sarcoma, all mice treated with B7-H3 survived at least 100 days, whereas all controls were dead by day 50 (P = .0015).

The B7-H3 construct also showed good activity against a model of medulloblastoma, showing that it was capable of crossing the blood-brain barrier.

Since B7-H3 has been reported to be expressed on both myeloid and lymphoid leukemia cells, the investigators also tested the CAR against a murine model of leukemia generated by injection of K562, a well-characterized line of myeloid leukemia cells.

“While we found some increase in survival in the mice that received the B7-H3 CAR T cells, compared to mice that received untransduced CAR T cells, this clearly is not as effective as in our solid tumor models,” Dr. Majzner said.

Going back to the cell line, they discovered that expression of B7-H3 was considerably lower in the K562 cells than in either the osteosarcoma or medulloblastoma cell lines used in their other models.

They found that both in vitro and in vivo, high levels of B7-H3 expression were necessary to provoke the immune system into releasing cytokines necessary for an adequate antitumor response.

The investigators are currently planning clinical trials using the B7-H3 CAR T-cell construct in patients with solid tumors.

The work is supported by the Sarcoma Alliance for Research through Collaboration, the St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.

SOURCE: Majzner RG et al. ASPHO 2018, Abstract #PS2003.

PITTSBURGH – Call it the CAR of the future – an investigational chimeric antigen receptor–T cell construct targeted against an antigen highly expressed on pediatric solid tumors has shown promising efficacy in preclinical studies.

Investigators found that the antigen, labeled B7-H3, was expressed on 84% of microarrays of pediatric solid tumors. More importantly, a single dose of CAR targeted to B7-H3 caused complete regression of osteosarcoma and Ewing sarcoma xenografts and improved survival over an untransduced, CD19-targeted CAR in mice, Robbie Majzner, MD, reported at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Neil Osterweil/MDedge News

In contrast, B7-H3 is highly expressed on many different pediatric solid tumors, including rhabdomyosarcoma (95% of tumors stained), Ewing sarcoma (89%), Wilms tumor (100%), neuroblastoma (82%), ganglioneuroblastoma and ganglioneuroma (53%), medulloblastoma (96%), glioblastoma multiforme (84%), and diffuse intrinsic pontine glioma (100%).

To see whether CAR T therapy might have better efficacy than checkpoint inhibitors in this population, the investigators created a B7-H3 CAR using the B7-H3 tumor–specific monoclonal antibody MGA271, which has been shown to be safe in both adults and children in early clinical trials.

In human tumor xenograft models of osteosarcoma, all mice who received a single dose of the B7-H3 CAR survived at least 70 days after tumor engraftment, whereas all control mice, who received the CD19 CAR, died by day 60 (P = .0067). Similarly, in a model of Ewing sarcoma, all mice treated with B7-H3 survived at least 100 days, whereas all controls were dead by day 50 (P = .0015).

The B7-H3 construct also showed good activity against a model of medulloblastoma, showing that it was capable of crossing the blood-brain barrier.

Since B7-H3 has been reported to be expressed on both myeloid and lymphoid leukemia cells, the investigators also tested the CAR against a murine model of leukemia generated by injection of K562, a well-characterized line of myeloid leukemia cells.

“While we found some increase in survival in the mice that received the B7-H3 CAR T cells, compared to mice that received untransduced CAR T cells, this clearly is not as effective as in our solid tumor models,” Dr. Majzner said.

Going back to the cell line, they discovered that expression of B7-H3 was considerably lower in the K562 cells than in either the osteosarcoma or medulloblastoma cell lines used in their other models.

They found that both in vitro and in vivo, high levels of B7-H3 expression were necessary to provoke the immune system into releasing cytokines necessary for an adequate antitumor response.

The investigators are currently planning clinical trials using the B7-H3 CAR T-cell construct in patients with solid tumors.

The work is supported by the Sarcoma Alliance for Research through Collaboration, the St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.

SOURCE: Majzner RG et al. ASPHO 2018, Abstract #PS2003.