Meeting NewsPerspective

Pediatric tumor-sequencing trial finds higher rate of targetable alterations than expected

Will Parsons, MD, PhD
Will Parsons

Genetic sequencing of tumors among children with refractory cancer led to about a quarter of those tested being matched with therapies targeting their specific genetic alteration, according to results of a study scheduled for presentation at ASCO Annual Meeting.

Investigators in the Pediatric MATCH study from the NCI and Children’s Oncology Group had projected only a 10% match rate.

“These data provide some preliminary insight for clinicians into the diagnostic yield of tumor molecular testing for children with refractory cancers in terms of probability of identifying a targeted therapy (either FDA-approved or investigational) that might be relevant to the patient,” Will Parsons, MD, PhD, associate professor of pediatrics-oncology at Baylor College of Medicine and the study’s lead investigator, told HemOnc Today.

“[The results] can be useful to inform clinicians, patients and parents as they make clinical decisions about molecular testing and/or clinical trial enrollment,” he added.

The study enrolled 422 patients (median age, 13 years; range, 1-21) at 93 Children’s Oncology Group sites between July 24, 2017, and Dec. 31, 2018. Seventy-one percent of patients (n = 300) had solid tumors, 24% (n = 101) had central nervous system tumors and 5% (n = 21) had lymphomas or histiocytosis.

Researchers submitted tumor samples from 390 patients for sequencing of more than 160 genes. Of these, 370 (95%) underwent sequencing and 357 (92%) had confirmable results.

Researchers evaluated patients for actionable mutations in the initial phase of the study and, when appropriate, matched patients to one of 10 treatment groups targeting their specific genetic alteration for possible inclusion in a phase 2 clinical trial.

An actionable mutation matching at least one of the treatment groups was identified in 112 patients (29%; 95% CI, 24-33). Actionable MAPK pathway mutations (n = 41) included HRAS/KRAS/NRAS (n = 16), BRAF mutations or fusions (n = 14), or NF1 mutations (n = 11).

Overall, 95 patients (24%; 95% CI, 20-29) were assigned to one of the 10 treatment groups. Thirty-nine patients (10%; 95% CI ,7-13) have been enrolled thus far into a phase 2 trial targeting their specific genetic alterations.

“Matches are prioritized based on our understanding of current clinical and preclinical data,” Parsons told HemOnc Today.

He noted there are two scenarios in which a decision about referral to a specific treatment group must be made: the first being a tumor that has more than one actionable mutation (ie, matching multiple study groups) and second, a single mutation being actionable (ie, a match) to more than one study group.

Parsons said the first scenario, in which a patient has more than one actionable mutation, has been rare so far, occurring in only 2% of tumors screened. It is far more common for a patient’s tumor to have a mutation that matches multiple study groups.

Parsons told HemOnc Today that his group’s study has multiple drugs that target the MAPK signaling pathway.

In all cases, we use predefined levels of evidence for each alteration — relative to each study arm — to prioritize which drug or study arm a patient should be matched to, with clinical evidence outweighing preclinical evidence,” he said. “For example, if the tumor has alterations that match them to two arms of the study, but clinical responses in adult patients have been reported for tumors with that particular mutation treated with one of the drugs — but not the other — then that would be prioritized.” – by Drew Amorosi

Reference:

Parsons DW, et al. Abstract 10011. Scheduled for presentation at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Parsons reports patents, royalties and other intellectual property related to cancer genes discovered through sequencing of several adult cancers. Please see the study for all other authors’ relevant financial disclosures.

Will Parsons, MD, PhD
Will Parsons

Genetic sequencing of tumors among children with refractory cancer led to about a quarter of those tested being matched with therapies targeting their specific genetic alteration, according to results of a study scheduled for presentation at ASCO Annual Meeting.

Investigators in the Pediatric MATCH study from the NCI and Children’s Oncology Group had projected only a 10% match rate.

“These data provide some preliminary insight for clinicians into the diagnostic yield of tumor molecular testing for children with refractory cancers in terms of probability of identifying a targeted therapy (either FDA-approved or investigational) that might be relevant to the patient,” Will Parsons, MD, PhD, associate professor of pediatrics-oncology at Baylor College of Medicine and the study’s lead investigator, told HemOnc Today.

“[The results] can be useful to inform clinicians, patients and parents as they make clinical decisions about molecular testing and/or clinical trial enrollment,” he added.

The study enrolled 422 patients (median age, 13 years; range, 1-21) at 93 Children’s Oncology Group sites between July 24, 2017, and Dec. 31, 2018. Seventy-one percent of patients (n = 300) had solid tumors, 24% (n = 101) had central nervous system tumors and 5% (n = 21) had lymphomas or histiocytosis.

Researchers submitted tumor samples from 390 patients for sequencing of more than 160 genes. Of these, 370 (95%) underwent sequencing and 357 (92%) had confirmable results.

Researchers evaluated patients for actionable mutations in the initial phase of the study and, when appropriate, matched patients to one of 10 treatment groups targeting their specific genetic alteration for possible inclusion in a phase 2 clinical trial.

An actionable mutation matching at least one of the treatment groups was identified in 112 patients (29%; 95% CI, 24-33). Actionable MAPK pathway mutations (n = 41) included HRAS/KRAS/NRAS (n = 16), BRAF mutations or fusions (n = 14), or NF1 mutations (n = 11).

Overall, 95 patients (24%; 95% CI, 20-29) were assigned to one of the 10 treatment groups. Thirty-nine patients (10%; 95% CI ,7-13) have been enrolled thus far into a phase 2 trial targeting their specific genetic alterations.

“Matches are prioritized based on our understanding of current clinical and preclinical data,” Parsons told HemOnc Today.

He noted there are two scenarios in which a decision about referral to a specific treatment group must be made: the first being a tumor that has more than one actionable mutation (ie, matching multiple study groups) and second, a single mutation being actionable (ie, a match) to more than one study group.

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Parsons said the first scenario, in which a patient has more than one actionable mutation, has been rare so far, occurring in only 2% of tumors screened. It is far more common for a patient’s tumor to have a mutation that matches multiple study groups.

Parsons told HemOnc Today that his group’s study has multiple drugs that target the MAPK signaling pathway.

In all cases, we use predefined levels of evidence for each alteration — relative to each study arm — to prioritize which drug or study arm a patient should be matched to, with clinical evidence outweighing preclinical evidence,” he said. “For example, if the tumor has alterations that match them to two arms of the study, but clinical responses in adult patients have been reported for tumors with that particular mutation treated with one of the drugs — but not the other — then that would be prioritized.” – by Drew Amorosi

Reference:

Parsons DW, et al. Abstract 10011. Scheduled for presentation at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Parsons reports patents, royalties and other intellectual property related to cancer genes discovered through sequencing of several adult cancers. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Darrell Yamashiro

    Darrell Yamashiro

    This study from the NCI and Children’s Oncology Group demonstrated that there was a markedly higher rate of assignment to a targeted therapy for children with refractory cancer. It has significant implications for the treatment of children with refractory cancer and supports increased access to novel targeted agents for children.

    • Darrell Yamashiro, MD, PhD
    • NewYork-Presbyterian and Columbia University Medical Center

    Disclosures: Yamashiro reports no relevant financial disclosures.

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