CNS/Brain Cancer

Adding intraoperative radiotherapy to the standard of care for patients with newly diagnosed glioblastoma appear to offer improved local control and survival, compared with those of historical controls without major adverse events, according to authors of a pooled analysis.

Among 51 patients who underwent tumor resection followed by intraoperative radiotherapy (IORT), standard adjuvant chemoradiotherapy, and chemotherapy maintenance, the estimated 2-year overall survival (OS) rate was 38.7%, compared with 26.5% at 2 years for patients who had received external beam radiotherapy (EBRT) and concomitant plus adjuvant temozolomide in a multinational phase 3 trial, reported Gustavo Sarria, MD, from University Medical Center Mannheim (Germany) and colleagues.

The median local progression-free survival (L-PFS) at a median follow-up of 18 months was 16 months, and the median distant PFS (D-PFS) was 30 months, indicating effective delay of tumor recurrence in a substantial proportion of patients.

“Intraoperative radiotherapy does not require extra radiation to travel through healthy tissue as compared to EBRT, thus allowing for local dose escalation at the site of most likely recurrence,” they wrote in Radiotherapy and Oncology.

The investigators performed a retrospective analysis of data on a total of 51 patients with a median age of 55 years who were treated with IORT and standard of care at five centers in Germany, Perum, and China. The patients all underwent brain surgery followed by a single IORT application at doses ranging from 10 to 40 Gy, with low-energy (50-kV) x-rays.

Following surgery, all patients received 60-Gy intensity-modulated or volumetric-modulated arc (IMRT-VMAT) EBRT and concomitant temozolomide chemotherapy followed by maintenance temozolomide.

At a median follow-up of 18 months the median OS was 18 months, median overall PFS was 11.4 months, median L-PFS (new lesions 1 cm or less from the tumor cavity border) was 16 months, and median D-PFS (new lesions more than 1 cm from the tumor cavity border) was 30 months.

The estimated Kaplan-Meier 1-, 2-, and 3-year OS rates were 79.5%, 38.7%, and 25.6%, respectively. The estimated median PFS over the same time points was 46.2%, 29.4%, and 5.9. The 1-, 2-, and 3-year estimated L-PFS was 60.9%, 37.9%, and 12.6%, and D-FPS rates were 76.7%, 65.0%, and 39.0% respectively.

In slightly more than one-third of the cases (35.3%), the first progression occurred locally. Grade 1 radionecrosis occurred in 7.8% of patients, and 17.6% had grade 3 radionecrosis. There were no grade 4 toxicities reported, and no treatment-related deaths.

The investigators noted that IORT added to standard of care is being tested against standard care alone in a multinational phase 3 randomized trial (NCT02685605).

The authors did not receive outside funding for the study. Dr. Sarria reported Grants from Carl Zeiss Meditec outside the submitted work.

SOURCE: Sarria G et al. J Rad Oncol. 2019 Oct 16. doi: 10.1016/j.radonc.2019.09.023.

Adding intraoperative radiotherapy to the standard of care for patients with newly diagnosed glioblastoma appear to offer improved local control and survival, compared with those of historical controls without major adverse events, according to authors of a pooled analysis.

Among 51 patients who underwent tumor resection followed by intraoperative radiotherapy (IORT), standard adjuvant chemoradiotherapy, and chemotherapy maintenance, the estimated 2-year overall survival (OS) rate was 38.7%, compared with 26.5% at 2 years for patients who had received external beam radiotherapy (EBRT) and concomitant plus adjuvant temozolomide in a multinational phase 3 trial, reported Gustavo Sarria, MD, from University Medical Center Mannheim (Germany) and colleagues.

The median local progression-free survival (L-PFS) at a median follow-up of 18 months was 16 months, and the median distant PFS (D-PFS) was 30 months, indicating effective delay of tumor recurrence in a substantial proportion of patients.

“Intraoperative radiotherapy does not require extra radiation to travel through healthy tissue as compared to EBRT, thus allowing for local dose escalation at the site of most likely recurrence,” they wrote in Radiotherapy and Oncology.

The investigators performed a retrospective analysis of data on a total of 51 patients with a median age of 55 years who were treated with IORT and standard of care at five centers in Germany, Perum, and China. The patients all underwent brain surgery followed by a single IORT application at doses ranging from 10 to 40 Gy, with low-energy (50-kV) x-rays.

Following surgery, all patients received 60-Gy intensity-modulated or volumetric-modulated arc (IMRT-VMAT) EBRT and concomitant temozolomide chemotherapy followed by maintenance temozolomide.

At a median follow-up of 18 months the median OS was 18 months, median overall PFS was 11.4 months, median L-PFS (new lesions 1 cm or less from the tumor cavity border) was 16 months, and median D-PFS (new lesions more than 1 cm from the tumor cavity border) was 30 months.

The estimated Kaplan-Meier 1-, 2-, and 3-year OS rates were 79.5%, 38.7%, and 25.6%, respectively. The estimated median PFS over the same time points was 46.2%, 29.4%, and 5.9. The 1-, 2-, and 3-year estimated L-PFS was 60.9%, 37.9%, and 12.6%, and D-FPS rates were 76.7%, 65.0%, and 39.0% respectively.

In slightly more than one-third of the cases (35.3%), the first progression occurred locally. Grade 1 radionecrosis occurred in 7.8% of patients, and 17.6% had grade 3 radionecrosis. There were no grade 4 toxicities reported, and no treatment-related deaths.

The investigators noted that IORT added to standard of care is being tested against standard care alone in a multinational phase 3 randomized trial (NCT02685605).

The authors did not receive outside funding for the study. Dr. Sarria reported Grants from Carl Zeiss Meditec outside the submitted work.

SOURCE: Sarria G et al. J Rad Oncol. 2019 Oct 16. doi: 10.1016/j.radonc.2019.09.023.

Adding intraoperative radiotherapy to the standard of care for patients with newly diagnosed glioblastoma appear to offer improved local control and survival, compared with those of historical controls without major adverse events, according to authors of a pooled analysis.

Among 51 patients who underwent tumor resection followed by intraoperative radiotherapy (IORT), standard adjuvant chemoradiotherapy, and chemotherapy maintenance, the estimated 2-year overall survival (OS) rate was 38.7%, compared with 26.5% at 2 years for patients who had received external beam radiotherapy (EBRT) and concomitant plus adjuvant temozolomide in a multinational phase 3 trial, reported Gustavo Sarria, MD, from University Medical Center Mannheim (Germany) and colleagues.

The median local progression-free survival (L-PFS) at a median follow-up of 18 months was 16 months, and the median distant PFS (D-PFS) was 30 months, indicating effective delay of tumor recurrence in a substantial proportion of patients.

“Intraoperative radiotherapy does not require extra radiation to travel through healthy tissue as compared to EBRT, thus allowing for local dose escalation at the site of most likely recurrence,” they wrote in Radiotherapy and Oncology.

The investigators performed a retrospective analysis of data on a total of 51 patients with a median age of 55 years who were treated with IORT and standard of care at five centers in Germany, Perum, and China. The patients all underwent brain surgery followed by a single IORT application at doses ranging from 10 to 40 Gy, with low-energy (50-kV) x-rays.

Following surgery, all patients received 60-Gy intensity-modulated or volumetric-modulated arc (IMRT-VMAT) EBRT and concomitant temozolomide chemotherapy followed by maintenance temozolomide.

At a median follow-up of 18 months the median OS was 18 months, median overall PFS was 11.4 months, median L-PFS (new lesions 1 cm or less from the tumor cavity border) was 16 months, and median D-PFS (new lesions more than 1 cm from the tumor cavity border) was 30 months.

The estimated Kaplan-Meier 1-, 2-, and 3-year OS rates were 79.5%, 38.7%, and 25.6%, respectively. The estimated median PFS over the same time points was 46.2%, 29.4%, and 5.9. The 1-, 2-, and 3-year estimated L-PFS was 60.9%, 37.9%, and 12.6%, and D-FPS rates were 76.7%, 65.0%, and 39.0% respectively.

In slightly more than one-third of the cases (35.3%), the first progression occurred locally. Grade 1 radionecrosis occurred in 7.8% of patients, and 17.6% had grade 3 radionecrosis. There were no grade 4 toxicities reported, and no treatment-related deaths.

The investigators noted that IORT added to standard of care is being tested against standard care alone in a multinational phase 3 randomized trial (NCT02685605).

The authors did not receive outside funding for the study. Dr. Sarria reported Grants from Carl Zeiss Meditec outside the submitted work.

SOURCE: Sarria G et al. J Rad Oncol. 2019 Oct 16. doi: 10.1016/j.radonc.2019.09.023.

Although only a small percentage of non–small cell lung cancers are positive for HER2 mutations, HER2-mutant lung cancers are associated with a high incidence of brain metastases, investigators have found.

Among 98 consecutive patients with HER2-mutant non–small cell lung cancer (NSCLC), the incidence of brain metastases at initial diagnosis was comparable with or slightly lower than that seen with other, more common mutations, but the incidence during treatment was significantly higher than in patients with KRAS-mutant NSCLC, and trended higher than the incidence rate of brain metastases in patients with epidermal growth factor receptor (EGFR)–mutated NSCLC, reported Michael Offin, MD, and colleagues from Memorial Sloan Kettering Cancer in New York.

“This finding provides a framework for CNS surveillance and treatment strategies, including radiotherapy, for patients with HER2-mutant lung cancers and underlines the urgent need for the development of novel HER2-targeted agents with activity in the CNS,” they wrote in Cancer.

NSCLC with oncogenic driver mutations in HER2 account for 2% of adenocarcinomas of the lung, but relatively little is known about the risk for brain metastases in patients HER2-mutant lung cancer, the authors wrote.

“Because HER2-amplified breast cancers are more likely to develop brain metastases through constitutive HER2 signaling, we hypothesize that HER2-mutant lung cancers are also more apt to develop brain metastases in comparison with lung cancers driven by other oncogenes,” they wrote.

To explore this hypothesis, they conducted a retrospective record review of 98 patients treated at their center with metastatic HER2-mutant NSCLC, and compared them with 200 patients with metastatic KRAS-mutant NSCLC, and 200 with metastatic, sensitizing EGFR-mutant NSCLC.

They found that at the initial diagnosis of metastatic disease, the percentage of patients with brain metastases was similar between patients with HER2 mutations and those with KRAS mutations (19% vs. 24%; odds ratio for HER2 vs. KRAS, 0.7; P = .33). However significantly more patients with EGFR-mutant tumors had brain metastases at diagnosis, compared with patients HER2 mutations (31% vs. 19%; OR, 0.5; P = .03).

Interestingly, significantly more patients with HER2-mutant tumors developed brain metastases on treatment than patients with KRAS-mutant tumors (28% vs. 8%; hazard ratio, 5.2; P less than .001). There was also a trend toward more on-treatment brain metastases among patients with HER2 mutations, compared with patients with EGFR mutation (28% vs .16%; HR, 1.7), but this difference was not statistically significant.

The risk for on-treatment brain metastases was even higher among patients with a HER2 mutation characterized by a 12 base–pair, in-frame insertion in exon 20 (HER2 YVMA). In these patients, the OR for brain metastases developing during treatment versus patients with KRAS mutations was 5.9 (P less than .001).

The median overall survival was worse for patients with KRAS-mutant NSCLC (1.1 years) and HER2-mutant cancers (1.6 years) versus 3 years for patients with EFGR-mutant cancers (P less than .001 for KRAS; P = .002 for HER2 vs. EGFR).

The use of HER2-targeted therapies did not have an effect on either the development of brain metastases or survival, and overall survival was slightly but significantly worse for patients with HER2-mutant tumors who had radiotherapy of the brain.

The study was supported by the National Institutes of Health through a National Cancer Institute Cancer Center support grant and by the Eloise Briskin Foundation. Dr. Offin reported honoraria from Bristol-Myers Squibb, Merck, PharmaMar, Novartis, and Targeted Oncology. Multiple coauthors had similar disclosures.

SOURCE: Offin M et al. Cancer. 2019 Aug 30. doi: 10.1002/cncr.32461.

Although only a small percentage of non–small cell lung cancers are positive for HER2 mutations, HER2-mutant lung cancers are associated with a high incidence of brain metastases, investigators have found.

Among 98 consecutive patients with HER2-mutant non–small cell lung cancer (NSCLC), the incidence of brain metastases at initial diagnosis was comparable with or slightly lower than that seen with other, more common mutations, but the incidence during treatment was significantly higher than in patients with KRAS-mutant NSCLC, and trended higher than the incidence rate of brain metastases in patients with epidermal growth factor receptor (EGFR)–mutated NSCLC, reported Michael Offin, MD, and colleagues from Memorial Sloan Kettering Cancer in New York.

“This finding provides a framework for CNS surveillance and treatment strategies, including radiotherapy, for patients with HER2-mutant lung cancers and underlines the urgent need for the development of novel HER2-targeted agents with activity in the CNS,” they wrote in Cancer.

NSCLC with oncogenic driver mutations in HER2 account for 2% of adenocarcinomas of the lung, but relatively little is known about the risk for brain metastases in patients HER2-mutant lung cancer, the authors wrote.

“Because HER2-amplified breast cancers are more likely to develop brain metastases through constitutive HER2 signaling, we hypothesize that HER2-mutant lung cancers are also more apt to develop brain metastases in comparison with lung cancers driven by other oncogenes,” they wrote.

To explore this hypothesis, they conducted a retrospective record review of 98 patients treated at their center with metastatic HER2-mutant NSCLC, and compared them with 200 patients with metastatic KRAS-mutant NSCLC, and 200 with metastatic, sensitizing EGFR-mutant NSCLC.

They found that at the initial diagnosis of metastatic disease, the percentage of patients with brain metastases was similar between patients with HER2 mutations and those with KRAS mutations (19% vs. 24%; odds ratio for HER2 vs. KRAS, 0.7; P = .33). However significantly more patients with EGFR-mutant tumors had brain metastases at diagnosis, compared with patients HER2 mutations (31% vs. 19%; OR, 0.5; P = .03).

Interestingly, significantly more patients with HER2-mutant tumors developed brain metastases on treatment than patients with KRAS-mutant tumors (28% vs. 8%; hazard ratio, 5.2; P less than .001). There was also a trend toward more on-treatment brain metastases among patients with HER2 mutations, compared with patients with EGFR mutation (28% vs .16%; HR, 1.7), but this difference was not statistically significant.

The risk for on-treatment brain metastases was even higher among patients with a HER2 mutation characterized by a 12 base–pair, in-frame insertion in exon 20 (HER2 YVMA). In these patients, the OR for brain metastases developing during treatment versus patients with KRAS mutations was 5.9 (P less than .001).

The median overall survival was worse for patients with KRAS-mutant NSCLC (1.1 years) and HER2-mutant cancers (1.6 years) versus 3 years for patients with EFGR-mutant cancers (P less than .001 for KRAS; P = .002 for HER2 vs. EGFR).

The use of HER2-targeted therapies did not have an effect on either the development of brain metastases or survival, and overall survival was slightly but significantly worse for patients with HER2-mutant tumors who had radiotherapy of the brain.

The study was supported by the National Institutes of Health through a National Cancer Institute Cancer Center support grant and by the Eloise Briskin Foundation. Dr. Offin reported honoraria from Bristol-Myers Squibb, Merck, PharmaMar, Novartis, and Targeted Oncology. Multiple coauthors had similar disclosures.

SOURCE: Offin M et al. Cancer. 2019 Aug 30. doi: 10.1002/cncr.32461.

Although only a small percentage of non–small cell lung cancers are positive for HER2 mutations, HER2-mutant lung cancers are associated with a high incidence of brain metastases, investigators have found.

Among 98 consecutive patients with HER2-mutant non–small cell lung cancer (NSCLC), the incidence of brain metastases at initial diagnosis was comparable with or slightly lower than that seen with other, more common mutations, but the incidence during treatment was significantly higher than in patients with KRAS-mutant NSCLC, and trended higher than the incidence rate of brain metastases in patients with epidermal growth factor receptor (EGFR)–mutated NSCLC, reported Michael Offin, MD, and colleagues from Memorial Sloan Kettering Cancer in New York.

“This finding provides a framework for CNS surveillance and treatment strategies, including radiotherapy, for patients with HER2-mutant lung cancers and underlines the urgent need for the development of novel HER2-targeted agents with activity in the CNS,” they wrote in Cancer.

NSCLC with oncogenic driver mutations in HER2 account for 2% of adenocarcinomas of the lung, but relatively little is known about the risk for brain metastases in patients HER2-mutant lung cancer, the authors wrote.

“Because HER2-amplified breast cancers are more likely to develop brain metastases through constitutive HER2 signaling, we hypothesize that HER2-mutant lung cancers are also more apt to develop brain metastases in comparison with lung cancers driven by other oncogenes,” they wrote.

To explore this hypothesis, they conducted a retrospective record review of 98 patients treated at their center with metastatic HER2-mutant NSCLC, and compared them with 200 patients with metastatic KRAS-mutant NSCLC, and 200 with metastatic, sensitizing EGFR-mutant NSCLC.

They found that at the initial diagnosis of metastatic disease, the percentage of patients with brain metastases was similar between patients with HER2 mutations and those with KRAS mutations (19% vs. 24%; odds ratio for HER2 vs. KRAS, 0.7; P = .33). However significantly more patients with EGFR-mutant tumors had brain metastases at diagnosis, compared with patients HER2 mutations (31% vs. 19%; OR, 0.5; P = .03).

Interestingly, significantly more patients with HER2-mutant tumors developed brain metastases on treatment than patients with KRAS-mutant tumors (28% vs. 8%; hazard ratio, 5.2; P less than .001). There was also a trend toward more on-treatment brain metastases among patients with HER2 mutations, compared with patients with EGFR mutation (28% vs .16%; HR, 1.7), but this difference was not statistically significant.

The risk for on-treatment brain metastases was even higher among patients with a HER2 mutation characterized by a 12 base–pair, in-frame insertion in exon 20 (HER2 YVMA). In these patients, the OR for brain metastases developing during treatment versus patients with KRAS mutations was 5.9 (P less than .001).

The median overall survival was worse for patients with KRAS-mutant NSCLC (1.1 years) and HER2-mutant cancers (1.6 years) versus 3 years for patients with EFGR-mutant cancers (P less than .001 for KRAS; P = .002 for HER2 vs. EGFR).

The use of HER2-targeted therapies did not have an effect on either the development of brain metastases or survival, and overall survival was slightly but significantly worse for patients with HER2-mutant tumors who had radiotherapy of the brain.

The study was supported by the National Institutes of Health through a National Cancer Institute Cancer Center support grant and by the Eloise Briskin Foundation. Dr. Offin reported honoraria from Bristol-Myers Squibb, Merck, PharmaMar, Novartis, and Targeted Oncology. Multiple coauthors had similar disclosures.

SOURCE: Offin M et al. Cancer. 2019 Aug 30. doi: 10.1002/cncr.32461.

For patients with recurrent, high-grade glioblastoma, localized, drug-inducible gene therapy could unlock the anticancer potential of interleukin-12, based on a phase 1 trial.

In 31 patients who had their tumors excised, intraoperative site injection with an IL-12 vector followed by postoperative administration of veledimex, an oral activator of the transgene, increased IL-12 levels in the brain and appeared to improve overall survival, reported E. Antonio Chiocca, MD, PhD, Harvey W. Cushing Professor of Neurosurgery at Harvard Medical School, Boston, and colleagues. Although some serious adverse events were encountered, the investigators noted that these were less common with lower doses of veledimex and were reversible upon discontinuation. These findings mark a turning point in IL-12 cancer research, which previously encountered prohibitive safety obstacles.

“There was interest in the use of recombinant IL-12 in humans with cancer, and clinical trials of systemic IL-12 were undertaken but had to be stopped because the cytokine, administered as a recombinant soluble protein, was poorly tolerated,” the investigators wrote in Science Translational Medicine.

To overcome this issue, a novel treatment approach was developed. “With the objective of minimizing systemic toxicity, a ligand-inducible expression switch [RheoSwitch Therapeutic System] was developed to locally control production of IL-12 in the tumor microenvironment. In this system, transcription of the IL-12 transgene occurs only in the presence of the activator ligand, veledimex,” they noted.

The primary aim of the study was to evaluate safety and determine the optimal dose of veledimex; four dose levels were tested: 10, 20, 30, and 40 mg. Survival outcomes also were reported.

The protocol-defined maximum tolerated dose was not reached; however, the 20-mg dose was chosen, based on observed tolerability. At this dose level, the most common grade 3 or higher adverse events were lymphopenia (20.3%), thrombocytopenia (13.3%), and hyponatremia (13.3%). Specifically for grade 3 or higher neurologic adverse events, headache was most common, occurring in 13.3% of patients. Grade 2 cytokine release syndrome occurred in about one-fourth of patients (26.7%), whereas grade 3 cytokine release syndrome occurred about half as frequently (13.3%). All adverse events, including cytokine release syndrome, were reversible upon discontinuation of veledimex.

After a mean follow-up of 13.1 months, the median overall survival among patients receiving the 20-mg dose was 12.7 months. The investigators pointed out that this compared favorably with historical controls, who had a weighted median overall survival of 8.1 months. Those who received 30- or 40-mg doses had the poorest survival, which the investigators attributed to intolerability and other subgroup factors.

Data analysis also revealed a negative correlation between dexamethasone use and survival. Among patients in the 20-mg veledimex group who received 20 mg or less of dexamethasone during active veledimex dosing, median overall survival was extended to 17.8 months. The investigators speculated that this was because of reduced immune suppression, although dexamethasone could have induced cytochrome P450 3A4, which may have increased elimination of veledimex.

“In summary, this phase 1 trial reports the use of a transcriptional switch to safely control dosing of [IL-12], highlighting that this can be accomplished across the [blood-brain barrier] to remodel the tumor microenvironment with an influx of activated immune cells,” the investigators wrote.

They noted that this strategy could potentially be applied to other types of cancer, particularly those that are immunologically cold. “These data contribute to our understanding of IL-12 as a ‘master regulator’ of the immune system and highlight that even the transient production of this cytokine may function as a match to turn tumors from cold to hot.”

The study was funded by Ziopharm Oncology and the National Institutes of Health. The investigators reported additional relationships with Advantagene, Stemgen, Sigilon Therapeutics, and others.

SOURCE: Chiocca EA et al. Sci Transl Med. 2019 Aug 14. doi: 10.1126/scitranslmed.aaw5680.

For patients with recurrent, high-grade glioblastoma, localized, drug-inducible gene therapy could unlock the anticancer potential of interleukin-12, based on a phase 1 trial.

In 31 patients who had their tumors excised, intraoperative site injection with an IL-12 vector followed by postoperative administration of veledimex, an oral activator of the transgene, increased IL-12 levels in the brain and appeared to improve overall survival, reported E. Antonio Chiocca, MD, PhD, Harvey W. Cushing Professor of Neurosurgery at Harvard Medical School, Boston, and colleagues. Although some serious adverse events were encountered, the investigators noted that these were less common with lower doses of veledimex and were reversible upon discontinuation. These findings mark a turning point in IL-12 cancer research, which previously encountered prohibitive safety obstacles.

“There was interest in the use of recombinant IL-12 in humans with cancer, and clinical trials of systemic IL-12 were undertaken but had to be stopped because the cytokine, administered as a recombinant soluble protein, was poorly tolerated,” the investigators wrote in Science Translational Medicine.

To overcome this issue, a novel treatment approach was developed. “With the objective of minimizing systemic toxicity, a ligand-inducible expression switch [RheoSwitch Therapeutic System] was developed to locally control production of IL-12 in the tumor microenvironment. In this system, transcription of the IL-12 transgene occurs only in the presence of the activator ligand, veledimex,” they noted.

The primary aim of the study was to evaluate safety and determine the optimal dose of veledimex; four dose levels were tested: 10, 20, 30, and 40 mg. Survival outcomes also were reported.

The protocol-defined maximum tolerated dose was not reached; however, the 20-mg dose was chosen, based on observed tolerability. At this dose level, the most common grade 3 or higher adverse events were lymphopenia (20.3%), thrombocytopenia (13.3%), and hyponatremia (13.3%). Specifically for grade 3 or higher neurologic adverse events, headache was most common, occurring in 13.3% of patients. Grade 2 cytokine release syndrome occurred in about one-fourth of patients (26.7%), whereas grade 3 cytokine release syndrome occurred about half as frequently (13.3%). All adverse events, including cytokine release syndrome, were reversible upon discontinuation of veledimex.

After a mean follow-up of 13.1 months, the median overall survival among patients receiving the 20-mg dose was 12.7 months. The investigators pointed out that this compared favorably with historical controls, who had a weighted median overall survival of 8.1 months. Those who received 30- or 40-mg doses had the poorest survival, which the investigators attributed to intolerability and other subgroup factors.

Data analysis also revealed a negative correlation between dexamethasone use and survival. Among patients in the 20-mg veledimex group who received 20 mg or less of dexamethasone during active veledimex dosing, median overall survival was extended to 17.8 months. The investigators speculated that this was because of reduced immune suppression, although dexamethasone could have induced cytochrome P450 3A4, which may have increased elimination of veledimex.

“In summary, this phase 1 trial reports the use of a transcriptional switch to safely control dosing of [IL-12], highlighting that this can be accomplished across the [blood-brain barrier] to remodel the tumor microenvironment with an influx of activated immune cells,” the investigators wrote.

They noted that this strategy could potentially be applied to other types of cancer, particularly those that are immunologically cold. “These data contribute to our understanding of IL-12 as a ‘master regulator’ of the immune system and highlight that even the transient production of this cytokine may function as a match to turn tumors from cold to hot.”

The study was funded by Ziopharm Oncology and the National Institutes of Health. The investigators reported additional relationships with Advantagene, Stemgen, Sigilon Therapeutics, and others.

SOURCE: Chiocca EA et al. Sci Transl Med. 2019 Aug 14. doi: 10.1126/scitranslmed.aaw5680.

For patients with recurrent, high-grade glioblastoma, localized, drug-inducible gene therapy could unlock the anticancer potential of interleukin-12, based on a phase 1 trial.

In 31 patients who had their tumors excised, intraoperative site injection with an IL-12 vector followed by postoperative administration of veledimex, an oral activator of the transgene, increased IL-12 levels in the brain and appeared to improve overall survival, reported E. Antonio Chiocca, MD, PhD, Harvey W. Cushing Professor of Neurosurgery at Harvard Medical School, Boston, and colleagues. Although some serious adverse events were encountered, the investigators noted that these were less common with lower doses of veledimex and were reversible upon discontinuation. These findings mark a turning point in IL-12 cancer research, which previously encountered prohibitive safety obstacles.

“There was interest in the use of recombinant IL-12 in humans with cancer, and clinical trials of systemic IL-12 were undertaken but had to be stopped because the cytokine, administered as a recombinant soluble protein, was poorly tolerated,” the investigators wrote in Science Translational Medicine.

To overcome this issue, a novel treatment approach was developed. “With the objective of minimizing systemic toxicity, a ligand-inducible expression switch [RheoSwitch Therapeutic System] was developed to locally control production of IL-12 in the tumor microenvironment. In this system, transcription of the IL-12 transgene occurs only in the presence of the activator ligand, veledimex,” they noted.

The primary aim of the study was to evaluate safety and determine the optimal dose of veledimex; four dose levels were tested: 10, 20, 30, and 40 mg. Survival outcomes also were reported.

The protocol-defined maximum tolerated dose was not reached; however, the 20-mg dose was chosen, based on observed tolerability. At this dose level, the most common grade 3 or higher adverse events were lymphopenia (20.3%), thrombocytopenia (13.3%), and hyponatremia (13.3%). Specifically for grade 3 or higher neurologic adverse events, headache was most common, occurring in 13.3% of patients. Grade 2 cytokine release syndrome occurred in about one-fourth of patients (26.7%), whereas grade 3 cytokine release syndrome occurred about half as frequently (13.3%). All adverse events, including cytokine release syndrome, were reversible upon discontinuation of veledimex.

After a mean follow-up of 13.1 months, the median overall survival among patients receiving the 20-mg dose was 12.7 months. The investigators pointed out that this compared favorably with historical controls, who had a weighted median overall survival of 8.1 months. Those who received 30- or 40-mg doses had the poorest survival, which the investigators attributed to intolerability and other subgroup factors.

Data analysis also revealed a negative correlation between dexamethasone use and survival. Among patients in the 20-mg veledimex group who received 20 mg or less of dexamethasone during active veledimex dosing, median overall survival was extended to 17.8 months. The investigators speculated that this was because of reduced immune suppression, although dexamethasone could have induced cytochrome P450 3A4, which may have increased elimination of veledimex.

“In summary, this phase 1 trial reports the use of a transcriptional switch to safely control dosing of [IL-12], highlighting that this can be accomplished across the [blood-brain barrier] to remodel the tumor microenvironment with an influx of activated immune cells,” the investigators wrote.

They noted that this strategy could potentially be applied to other types of cancer, particularly those that are immunologically cold. “These data contribute to our understanding of IL-12 as a ‘master regulator’ of the immune system and highlight that even the transient production of this cytokine may function as a match to turn tumors from cold to hot.”

The study was funded by Ziopharm Oncology and the National Institutes of Health. The investigators reported additional relationships with Advantagene, Stemgen, Sigilon Therapeutics, and others.

SOURCE: Chiocca EA et al. Sci Transl Med. 2019 Aug 14. doi: 10.1126/scitranslmed.aaw5680.

Researchers say they have identified potential prognostic markers and targets for treatment in patients with non–small cell lung cancer (NSCLC) and brain metastases (BM).

There was “substantial” concordance in driver mutations, such as EGFR and KRAS, between BM and primary tumor samples but greater genomic instability in BM samples, reported Hong-Sheng Wang, PhD, of Sun Yat-Sen University in Guangzhou, China, and colleagues.

PI3K signaling was significantly associated with an increased risk of BM, and CDKs and PIK3CA were “potential druggable mutations,” they reported in Cancer.

The researchers conducted a retrospective study of 61 Chinese patients with NSCLC and BM. The patients had adenocarcinoma (n = 50), squamous cell carcinoma (n = 3), and mixed subtypes (n = 8). Less than half of patients (n = 28) had stage IV disease at diagnosis, 36 had metachronous disease, and 25 had synchronous disease. All patients had undergone surgery, 33 had received chemoradiation, 26 had received no systemic treatment, and 5 had been treated with tyrosine kinase inhibitors.

The researchers performed next-generation sequencing on primary tumors and matched BM samples from the 61 patients, targeting 416 cancer-relevant genes.

Results showed high concordance between the primary and BM samples with regard to major driver mutations – 92% for EGFR, 82% for KRAS, and 83% for TP53 mutations.

For nearly half of patients (48%), all mutations found in primary tumor samples were also found in BM samples. In fact, 18% of patients had the same mutational profiles in lung and brain lesions.

Conversely, 30% of patients had more brain-specific mutations, 13% had more lung-specific mutations, 28% had mixed profiles, and 11% had completely unique mutational profiles in lung and brain lesions.

Compared with primary tumor samples, BM samples had a significantly higher frequency of copy number variations (P = .0002); alterations in CDKN2A/2B, CCND1, CDK4, and RB1 (P = .0019); and alterations in PIK3CA, PTEN, STK11, RICTOR, and NF2 (P = .0037).

Patients with activated PI3K signaling in their primary tumors had significantly shorter BM-free survival. The hazard ratio (adjusted for baseline clinicopathologic parameters) was 8.49 (P = .0005).

There was no significant difference in BM-free survival between EGFR-/KRAS-mutated patients and patients with wild-type EGFR/KRAS (P = .29). However, there was a trend toward shorter BM-free survival in patients with TP53 mutations (P = .15).

There was a trend toward shorter BM-free intervals in patients with an activated WNT pathway via CTNNB1 mutations (P = .22) or APC and AXIN2 mutations (P = .015). However, the researchers said these findings should be treated with caution due to a small sample size.

The National Natural Science Foundation of China and the Natural Science Foundation of Guangdong Province supported the research. The researchers disclosed relationships with Geneseeq Technology Inc. in Toronto and Nanjing Geneseeq Technology Inc.

SOURCE: Wang H et al. Cancer. 2019 Jul 9. doi: 10.1002/cncr.32372.

Researchers say they have identified potential prognostic markers and targets for treatment in patients with non–small cell lung cancer (NSCLC) and brain metastases (BM).

There was “substantial” concordance in driver mutations, such as EGFR and KRAS, between BM and primary tumor samples but greater genomic instability in BM samples, reported Hong-Sheng Wang, PhD, of Sun Yat-Sen University in Guangzhou, China, and colleagues.

PI3K signaling was significantly associated with an increased risk of BM, and CDKs and PIK3CA were “potential druggable mutations,” they reported in Cancer.

The researchers conducted a retrospective study of 61 Chinese patients with NSCLC and BM. The patients had adenocarcinoma (n = 50), squamous cell carcinoma (n = 3), and mixed subtypes (n = 8). Less than half of patients (n = 28) had stage IV disease at diagnosis, 36 had metachronous disease, and 25 had synchronous disease. All patients had undergone surgery, 33 had received chemoradiation, 26 had received no systemic treatment, and 5 had been treated with tyrosine kinase inhibitors.

The researchers performed next-generation sequencing on primary tumors and matched BM samples from the 61 patients, targeting 416 cancer-relevant genes.

Results showed high concordance between the primary and BM samples with regard to major driver mutations – 92% for EGFR, 82% for KRAS, and 83% for TP53 mutations.

For nearly half of patients (48%), all mutations found in primary tumor samples were also found in BM samples. In fact, 18% of patients had the same mutational profiles in lung and brain lesions.

Conversely, 30% of patients had more brain-specific mutations, 13% had more lung-specific mutations, 28% had mixed profiles, and 11% had completely unique mutational profiles in lung and brain lesions.

Compared with primary tumor samples, BM samples had a significantly higher frequency of copy number variations (P = .0002); alterations in CDKN2A/2B, CCND1, CDK4, and RB1 (P = .0019); and alterations in PIK3CA, PTEN, STK11, RICTOR, and NF2 (P = .0037).

Patients with activated PI3K signaling in their primary tumors had significantly shorter BM-free survival. The hazard ratio (adjusted for baseline clinicopathologic parameters) was 8.49 (P = .0005).

There was no significant difference in BM-free survival between EGFR-/KRAS-mutated patients and patients with wild-type EGFR/KRAS (P = .29). However, there was a trend toward shorter BM-free survival in patients with TP53 mutations (P = .15).

There was a trend toward shorter BM-free intervals in patients with an activated WNT pathway via CTNNB1 mutations (P = .22) or APC and AXIN2 mutations (P = .015). However, the researchers said these findings should be treated with caution due to a small sample size.

The National Natural Science Foundation of China and the Natural Science Foundation of Guangdong Province supported the research. The researchers disclosed relationships with Geneseeq Technology Inc. in Toronto and Nanjing Geneseeq Technology Inc.

SOURCE: Wang H et al. Cancer. 2019 Jul 9. doi: 10.1002/cncr.32372.

Researchers say they have identified potential prognostic markers and targets for treatment in patients with non–small cell lung cancer (NSCLC) and brain metastases (BM).

There was “substantial” concordance in driver mutations, such as EGFR and KRAS, between BM and primary tumor samples but greater genomic instability in BM samples, reported Hong-Sheng Wang, PhD, of Sun Yat-Sen University in Guangzhou, China, and colleagues.

PI3K signaling was significantly associated with an increased risk of BM, and CDKs and PIK3CA were “potential druggable mutations,” they reported in Cancer.

The researchers conducted a retrospective study of 61 Chinese patients with NSCLC and BM. The patients had adenocarcinoma (n = 50), squamous cell carcinoma (n = 3), and mixed subtypes (n = 8). Less than half of patients (n = 28) had stage IV disease at diagnosis, 36 had metachronous disease, and 25 had synchronous disease. All patients had undergone surgery, 33 had received chemoradiation, 26 had received no systemic treatment, and 5 had been treated with tyrosine kinase inhibitors.

The researchers performed next-generation sequencing on primary tumors and matched BM samples from the 61 patients, targeting 416 cancer-relevant genes.

Results showed high concordance between the primary and BM samples with regard to major driver mutations – 92% for EGFR, 82% for KRAS, and 83% for TP53 mutations.

For nearly half of patients (48%), all mutations found in primary tumor samples were also found in BM samples. In fact, 18% of patients had the same mutational profiles in lung and brain lesions.

Conversely, 30% of patients had more brain-specific mutations, 13% had more lung-specific mutations, 28% had mixed profiles, and 11% had completely unique mutational profiles in lung and brain lesions.

Compared with primary tumor samples, BM samples had a significantly higher frequency of copy number variations (P = .0002); alterations in CDKN2A/2B, CCND1, CDK4, and RB1 (P = .0019); and alterations in PIK3CA, PTEN, STK11, RICTOR, and NF2 (P = .0037).

Patients with activated PI3K signaling in their primary tumors had significantly shorter BM-free survival. The hazard ratio (adjusted for baseline clinicopathologic parameters) was 8.49 (P = .0005).

There was no significant difference in BM-free survival between EGFR-/KRAS-mutated patients and patients with wild-type EGFR/KRAS (P = .29). However, there was a trend toward shorter BM-free survival in patients with TP53 mutations (P = .15).

There was a trend toward shorter BM-free intervals in patients with an activated WNT pathway via CTNNB1 mutations (P = .22) or APC and AXIN2 mutations (P = .015). However, the researchers said these findings should be treated with caution due to a small sample size.

The National Natural Science Foundation of China and the Natural Science Foundation of Guangdong Province supported the research. The researchers disclosed relationships with Geneseeq Technology Inc. in Toronto and Nanjing Geneseeq Technology Inc.

SOURCE: Wang H et al. Cancer. 2019 Jul 9. doi: 10.1002/cncr.32372.

The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.

Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.

Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.

Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.

The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Specific indications for the biosimilar are as follows:

Metastatic colorectal cancer

Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.

Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.

Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.

First-line nonsquamous non–small cell lung cancer

Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.

Recurrent glioblastoma

Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.

Metastatic renal cell carcinoma

Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.

Persistent, recurrent, or metastatic cervical cancer

Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Complete prescribing information can be found on the FDA website.

The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.

Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.

Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.

Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.

The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Specific indications for the biosimilar are as follows:

Metastatic colorectal cancer

Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.

Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.

Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.

First-line nonsquamous non–small cell lung cancer

Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.

Recurrent glioblastoma

Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.

Metastatic renal cell carcinoma

Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.

Persistent, recurrent, or metastatic cervical cancer

Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Complete prescribing information can be found on the FDA website.

The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.

Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.

Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.

Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.

The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Specific indications for the biosimilar are as follows:

Metastatic colorectal cancer

Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.

Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.

Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.

First-line nonsquamous non–small cell lung cancer

Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.

Recurrent glioblastoma

Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.

Metastatic renal cell carcinoma

Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.

Persistent, recurrent, or metastatic cervical cancer

Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

Complete prescribing information can be found on the FDA website.

Simply adding a default order to the electronic health record that automatically opts patients out of commonly used but unnecessary radiation oncology procedures can dramatically curtail their use, suggests a stepped-wedge, cluster-randomized, controlled trial.

Daily x-ray or CT imaging is often used to better reproducibly position patients during curative radiotherapy, but guidelines consider it unnecessary during palliative radiotherapy because of limited clinical benefit, according to the investigators, led by Sonam Sharma, MD, of the Icahn School of Medicine at Mount Sinai, New York, and the Abramson Cancer Center at the University of Pennsylvania, Philadelphia. “Unnecessary imaging can increase treatment time and expense for patients in distress,” they noted.

The investigators conducted a 2-year trial among 21 radiation oncologists from five practices (one university, four community) in which they added to the EHR a default order that specified no daily imaging during palliative radiation therapy. (Radiation oncologists could select another imaging frequency if they preferred.) The default order was first rolled out in the university practice and subsequently in the community practices.

Study analyses were based on 1,019 adult patients with bone, soft tissue, or brain metastases who received 1,188 courses of palliative three-dimensional conformal radiotherapy during the trial.

Results reported in a JAMA Oncology research letter showed that the proportion of patients receiving daily imaging during their palliative radiotherapy (imaging during 80% or more of treatments) fell from 68.2% during the combined preintervention periods to 32.4% during the combined intervention periods.

After potential confounders were taken into account, implementation of the default order in the EHR was associated with a more than halving of the odds of daily imaging during palliative radiotherapy (adjusted odds ratio, 0.37; P = .003), with an adjusted percentage point reduction of –18.8.

Findings were similar in the university practice alone (aOR, 0.33; P = .01; –22.3 percentage points) and in the community practices alone (aOR, 0.45; P = .02; –27.5 percentage points).

“In a network of five radiation oncology practices, introducing a default order in the EHR reduced unnecessary daily imaging during palliative radiotherapy,” Dr. Sharma and colleagues concluded. “Our findings suggest that simple nudges, such as setting default orders, can meaningfully reduce unnecessary care.”

Dr. Sharma reported that she had no relevant conflicts of interest. The study was funded in part by the National Cancer Institute and the University of Pennsylvania Health System through the Penn Medicine Nudge Unit and the department of radiation oncology.

SOURCE: Sharma S et al. JAMA Oncol. 2019 Jun 27. doi: 10.1001/jamaoncol.2019.1432.

Simply adding a default order to the electronic health record that automatically opts patients out of commonly used but unnecessary radiation oncology procedures can dramatically curtail their use, suggests a stepped-wedge, cluster-randomized, controlled trial.

Daily x-ray or CT imaging is often used to better reproducibly position patients during curative radiotherapy, but guidelines consider it unnecessary during palliative radiotherapy because of limited clinical benefit, according to the investigators, led by Sonam Sharma, MD, of the Icahn School of Medicine at Mount Sinai, New York, and the Abramson Cancer Center at the University of Pennsylvania, Philadelphia. “Unnecessary imaging can increase treatment time and expense for patients in distress,” they noted.

The investigators conducted a 2-year trial among 21 radiation oncologists from five practices (one university, four community) in which they added to the EHR a default order that specified no daily imaging during palliative radiation therapy. (Radiation oncologists could select another imaging frequency if they preferred.) The default order was first rolled out in the university practice and subsequently in the community practices.

Study analyses were based on 1,019 adult patients with bone, soft tissue, or brain metastases who received 1,188 courses of palliative three-dimensional conformal radiotherapy during the trial.

Results reported in a JAMA Oncology research letter showed that the proportion of patients receiving daily imaging during their palliative radiotherapy (imaging during 80% or more of treatments) fell from 68.2% during the combined preintervention periods to 32.4% during the combined intervention periods.

After potential confounders were taken into account, implementation of the default order in the EHR was associated with a more than halving of the odds of daily imaging during palliative radiotherapy (adjusted odds ratio, 0.37; P = .003), with an adjusted percentage point reduction of –18.8.

Findings were similar in the university practice alone (aOR, 0.33; P = .01; –22.3 percentage points) and in the community practices alone (aOR, 0.45; P = .02; –27.5 percentage points).

“In a network of five radiation oncology practices, introducing a default order in the EHR reduced unnecessary daily imaging during palliative radiotherapy,” Dr. Sharma and colleagues concluded. “Our findings suggest that simple nudges, such as setting default orders, can meaningfully reduce unnecessary care.”

Dr. Sharma reported that she had no relevant conflicts of interest. The study was funded in part by the National Cancer Institute and the University of Pennsylvania Health System through the Penn Medicine Nudge Unit and the department of radiation oncology.

SOURCE: Sharma S et al. JAMA Oncol. 2019 Jun 27. doi: 10.1001/jamaoncol.2019.1432.

Simply adding a default order to the electronic health record that automatically opts patients out of commonly used but unnecessary radiation oncology procedures can dramatically curtail their use, suggests a stepped-wedge, cluster-randomized, controlled trial.

Daily x-ray or CT imaging is often used to better reproducibly position patients during curative radiotherapy, but guidelines consider it unnecessary during palliative radiotherapy because of limited clinical benefit, according to the investigators, led by Sonam Sharma, MD, of the Icahn School of Medicine at Mount Sinai, New York, and the Abramson Cancer Center at the University of Pennsylvania, Philadelphia. “Unnecessary imaging can increase treatment time and expense for patients in distress,” they noted.

The investigators conducted a 2-year trial among 21 radiation oncologists from five practices (one university, four community) in which they added to the EHR a default order that specified no daily imaging during palliative radiation therapy. (Radiation oncologists could select another imaging frequency if they preferred.) The default order was first rolled out in the university practice and subsequently in the community practices.

Study analyses were based on 1,019 adult patients with bone, soft tissue, or brain metastases who received 1,188 courses of palliative three-dimensional conformal radiotherapy during the trial.

Results reported in a JAMA Oncology research letter showed that the proportion of patients receiving daily imaging during their palliative radiotherapy (imaging during 80% or more of treatments) fell from 68.2% during the combined preintervention periods to 32.4% during the combined intervention periods.

After potential confounders were taken into account, implementation of the default order in the EHR was associated with a more than halving of the odds of daily imaging during palliative radiotherapy (adjusted odds ratio, 0.37; P = .003), with an adjusted percentage point reduction of –18.8.

Findings were similar in the university practice alone (aOR, 0.33; P = .01; –22.3 percentage points) and in the community practices alone (aOR, 0.45; P = .02; –27.5 percentage points).

“In a network of five radiation oncology practices, introducing a default order in the EHR reduced unnecessary daily imaging during palliative radiotherapy,” Dr. Sharma and colleagues concluded. “Our findings suggest that simple nudges, such as setting default orders, can meaningfully reduce unnecessary care.”

Dr. Sharma reported that she had no relevant conflicts of interest. The study was funded in part by the National Cancer Institute and the University of Pennsylvania Health System through the Penn Medicine Nudge Unit and the department of radiation oncology.

SOURCE: Sharma S et al. JAMA Oncol. 2019 Jun 27. doi: 10.1001/jamaoncol.2019.1432.

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.

GENEVA – Liquid biopsy appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression, according to investigators.

Will Pass/MDedge News

Plasma circulating tumor DNA (ctDNA) analysis detected molecular abnormalities in almost all patients with systemic disease progression, compared with just two out of five patients with isolated brain lesions, reported lead author Mihaela Aldea, MD, who presented findings at the European Lung Cancer Conference.

Dr. Aldea, of Gustave Roussy Institute in Villejuif, France, said that “central nervous system progression is an example of hard-to-biopsy disease and is common in oncogene addicted non–small cell lung cancer, making it a potential setting to employ ctDNA analysis.” However, Dr. Aldea noted that the blood-brain barrier limits passage of molecules such as ctDNA into systemic circulation, leading to hypothetical skepticism within the medical community, despite “very limited” data.

“Currently, the actual performance of ctDNA in patients with lung cancer and isolated CNS progression remains largely unknown,” Dr. Aldea said, “so this is the question that we put in our study.”

Dr. Aldea and her colleagues screened 959 patients with NSCLC who were involved in prospective trials at Gustave Roussy between 2016 and 2018. Study inclusion required that patients have a molecular alteration detected via tissue sample and at least 1 ctDNA sample available from the time of CNS progression. Molecular alterations included ALK, EGFR, KRAS, ROS1, HER2, BRAF, TP53, and MET. Through these criteria, the study population was narrowed to 58 patients and 66 ctDNA samples, of which 21 were from patients with isolated CNS (I-CNS) progression and 45 were from patients with systemic disease progression (S-CNS). CtDNA was conducted with next generation sequencing and compared with imaging, molecular, and clinical patient data.

Most patients in the I-CNS group were female (94%), compared with about half of the S-CNS group (59%). Rates of adenocarcinoma and smoking history were relatively similar between I-CNS and S-CNS patients; in contrast, S-CNS patients had a median of two metastatic sites, compared with one in the I-CNS group. Rates of ALK, KRAS, and EGFR aberrations were slightly higher in the I-CNS group, whereas HER2, TP53, MET, and BRAF abnormalities were found only in the S-CNS group. Relating to the central hypothesis, 98% of S-CNS patients tested positive for at least one actionable driver via ctDNA analysis, compared with just 38% of I-CNS patients (P less than .0001). Resistance mutations were detected more commonly in the S-CNS group, although not significantly, which Dr. Aldea attributed to small population size.

“Plasma liquid biopsy is not a reliable marker for analyzing the molecular landscape of CNS progression,” Dr. Aldea concluded, adding that patients with isolated brain lesions may need to be treated with “more potent drugs” even when resistance mutations are not detected.

The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.

SOURCE: Aldea et al. ELCC 2019. Abstract 110O.

GENEVA – Liquid biopsy appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression, according to investigators.

Will Pass/MDedge News

Plasma circulating tumor DNA (ctDNA) analysis detected molecular abnormalities in almost all patients with systemic disease progression, compared with just two out of five patients with isolated brain lesions, reported lead author Mihaela Aldea, MD, who presented findings at the European Lung Cancer Conference.

Dr. Aldea, of Gustave Roussy Institute in Villejuif, France, said that “central nervous system progression is an example of hard-to-biopsy disease and is common in oncogene addicted non–small cell lung cancer, making it a potential setting to employ ctDNA analysis.” However, Dr. Aldea noted that the blood-brain barrier limits passage of molecules such as ctDNA into systemic circulation, leading to hypothetical skepticism within the medical community, despite “very limited” data.

“Currently, the actual performance of ctDNA in patients with lung cancer and isolated CNS progression remains largely unknown,” Dr. Aldea said, “so this is the question that we put in our study.”

Dr. Aldea and her colleagues screened 959 patients with NSCLC who were involved in prospective trials at Gustave Roussy between 2016 and 2018. Study inclusion required that patients have a molecular alteration detected via tissue sample and at least 1 ctDNA sample available from the time of CNS progression. Molecular alterations included ALK, EGFR, KRAS, ROS1, HER2, BRAF, TP53, and MET. Through these criteria, the study population was narrowed to 58 patients and 66 ctDNA samples, of which 21 were from patients with isolated CNS (I-CNS) progression and 45 were from patients with systemic disease progression (S-CNS). CtDNA was conducted with next generation sequencing and compared with imaging, molecular, and clinical patient data.

Most patients in the I-CNS group were female (94%), compared with about half of the S-CNS group (59%). Rates of adenocarcinoma and smoking history were relatively similar between I-CNS and S-CNS patients; in contrast, S-CNS patients had a median of two metastatic sites, compared with one in the I-CNS group. Rates of ALK, KRAS, and EGFR aberrations were slightly higher in the I-CNS group, whereas HER2, TP53, MET, and BRAF abnormalities were found only in the S-CNS group. Relating to the central hypothesis, 98% of S-CNS patients tested positive for at least one actionable driver via ctDNA analysis, compared with just 38% of I-CNS patients (P less than .0001). Resistance mutations were detected more commonly in the S-CNS group, although not significantly, which Dr. Aldea attributed to small population size.

“Plasma liquid biopsy is not a reliable marker for analyzing the molecular landscape of CNS progression,” Dr. Aldea concluded, adding that patients with isolated brain lesions may need to be treated with “more potent drugs” even when resistance mutations are not detected.

The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.

SOURCE: Aldea et al. ELCC 2019. Abstract 110O.

GENEVA – Liquid biopsy appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression, according to investigators.

Will Pass/MDedge News

Plasma circulating tumor DNA (ctDNA) analysis detected molecular abnormalities in almost all patients with systemic disease progression, compared with just two out of five patients with isolated brain lesions, reported lead author Mihaela Aldea, MD, who presented findings at the European Lung Cancer Conference.

Dr. Aldea, of Gustave Roussy Institute in Villejuif, France, said that “central nervous system progression is an example of hard-to-biopsy disease and is common in oncogene addicted non–small cell lung cancer, making it a potential setting to employ ctDNA analysis.” However, Dr. Aldea noted that the blood-brain barrier limits passage of molecules such as ctDNA into systemic circulation, leading to hypothetical skepticism within the medical community, despite “very limited” data.

“Currently, the actual performance of ctDNA in patients with lung cancer and isolated CNS progression remains largely unknown,” Dr. Aldea said, “so this is the question that we put in our study.”

Dr. Aldea and her colleagues screened 959 patients with NSCLC who were involved in prospective trials at Gustave Roussy between 2016 and 2018. Study inclusion required that patients have a molecular alteration detected via tissue sample and at least 1 ctDNA sample available from the time of CNS progression. Molecular alterations included ALK, EGFR, KRAS, ROS1, HER2, BRAF, TP53, and MET. Through these criteria, the study population was narrowed to 58 patients and 66 ctDNA samples, of which 21 were from patients with isolated CNS (I-CNS) progression and 45 were from patients with systemic disease progression (S-CNS). CtDNA was conducted with next generation sequencing and compared with imaging, molecular, and clinical patient data.

Most patients in the I-CNS group were female (94%), compared with about half of the S-CNS group (59%). Rates of adenocarcinoma and smoking history were relatively similar between I-CNS and S-CNS patients; in contrast, S-CNS patients had a median of two metastatic sites, compared with one in the I-CNS group. Rates of ALK, KRAS, and EGFR aberrations were slightly higher in the I-CNS group, whereas HER2, TP53, MET, and BRAF abnormalities were found only in the S-CNS group. Relating to the central hypothesis, 98% of S-CNS patients tested positive for at least one actionable driver via ctDNA analysis, compared with just 38% of I-CNS patients (P less than .0001). Resistance mutations were detected more commonly in the S-CNS group, although not significantly, which Dr. Aldea attributed to small population size.

“Plasma liquid biopsy is not a reliable marker for analyzing the molecular landscape of CNS progression,” Dr. Aldea concluded, adding that patients with isolated brain lesions may need to be treated with “more potent drugs” even when resistance mutations are not detected.

The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.

SOURCE: Aldea et al. ELCC 2019. Abstract 110O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.