Pediatric Oncology Advances Could Prompt More FDA-Required Studies

Findings being presented at ASCO next month could signify major increase in targets relevant to pediatric oncology, meaning sponsors should prepare for more US FDA-required studies under the RACE for Children legislation.

Pediatric oncology received a major policy boost from the RACE for Children provisions in the US FDA Reauthorization Act, and new research being presented at the American Society of Clinical Oncology annual meeting highlights how much better focus is being brought to the field of pediatric oncology.

One of the trials highlighted in the 15 May presentation ahead of the abstract release for the conference, being held 31 May-4 June in Chicago, was the NCI-COG Pediatric MATCH trial – a precision medicine protocol sponsored by the National Cancer Institute and the Children’s Oncology Group.

While precision oncology approaches do make it possible to select treatment based on the particular genetic signature of a patient’s tumor, it has not been known how useful this strategy is for pediatric cancer patients, Will Parsons, Baylor College of Medicine, told the 15 May “presscast.” The NCI-COG Pediatric MATCH trial was developed to see how many pediatric patients can be matched to targeted therapies, and how effective those therapies are for the pediatric population.

The trial is a descendent of the NCI-MATCH trial, one of the first large-scale basket trials to introduce a different model of targeted cancer drug development based on screening a large population to guide them into the appropriate cohorts to test targeted therapy matching their genetic signatures. (Also see "Genomics-Driven Trials Built To Be Fast And Flexible" - Pink Sheet, 21 Sep, 2015.)

After the initial screening “basket,” patients are randomized into specific protocols that can test particular targeted therapies for registrational purposes.

Drugs Included In NCI-COG Pediatric MATCH

Larotrectinib (targeting NTRK)

Erdafitinib (targeting FGFR)

Tazemetostat (targeting EZH2 and other SWI/SNF complex genes)

LY3023414 (targeting the PI3K/MTOR pathway)

Selumetinib (targeting the MAPK pathway)

Ensartinib (targeting ALK or ROS1)

Vemurafenib (targeting BRAF)

Olaparib (targeting defects in DNA damage repair)

Palbociclib (targeting cell cycle genes)

Ulixertinib (targeting the MAPK pathway)

 

The NCI-COG Pediatric MATCH trial is enrolling 1,000 children with treatment-refractory cancer and has already enrolled faster than expected.

Ten drugs have been included so far, though more will be added over time; four additional drug protocols are being developed already. (See box for drugs included in the study.) The breakdown of the population includes some common and some ultra-rare tumor types, with more than 60 cancers represented.

A 10% match rate was predicted, based on experience with disease-specific pediatric and adult trials, although most of these were in newly diagnosed pediatric trials. However, “an interim analysis of more than 400 patients screened has revealed the match rate appears to be significantly higher, with 24% of participants eligible to receive treatment with at least one drug being tested in the trial,” ASCO reported.

As of the interim look, 41% of matched patients have enrolled in a treatment protocol.

Only a small number of targeted therapies have been approved for pediatric cancers, while “by comparison, there are more than 150 U.S. approvals for targeted therapies in adult cancers,” ASCO noted.

“These results bring us one step closer to bringing the precision medicine era to pediatric cancer care. Now that we know that targetable genetic alterations are fairly common in pediatric cancers, we have an exciting opportunity to boost success rates,” ASCO president Monica Bertagnolli said during the presscast.

Evidence Of Entrectinib Benefit

Pairing the potential for a better model for pediatric oncology development with early evidence of a targeted drug showing benefit in a pediatric cancer, ASCO also highlighted a small Phase I/Ib study of Roche’s entrectinib in central nervous system tumors and recurrent solid tumors with alterations in the TrkA/B/C, ROS1 and ALK kinase pathways.

Roche has been developing the drug for a tumor-agnostic indication, it is undergoing priority review at the US FDA for a histology-agnostic indication for NTRK gene fusion tumors and a lung cancer-specific indication for ROS1-positive metastatic disease, with an 18 August user fee deadline.

But Roche’s attempt for accelerated assessment in Europe was stymied by trying for both claims at once, as the process only works for one claim at a time (Also see "Roche’s EU Accelerated Assessment Bid For Tumor Agnostic Entrectinib Backfires" - Scrip, 4 Mar, 2019.)

Entrectinib was shown to shrink tumors in 57.4% of patients with NTRK fusion-positive solid tumors in an integrated analysis of 54 patients from the pivotal Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, presented at the European Society for Medical Oncology annual meeting last October. There was a 10.4 month median duration of response across 10 tumor types, including patients with CNS-metastases. (Also see "Plenty Of Potential For Roche's Entrectinib Despite Lack Of ESMO Enthusiasm" - Scrip, 24 Oct, 2018.)

The CNS effect was also seen in the ROS1-positive lung cancer trials. (Also see "Roche’s Entrectinib Differentiates Itself From NSCLC Competitors With CNS Data" - Scrip, 24 Sep, 2018.)

However, the data do not appear as good as those for Bayer AG’s Vitrakvi (larotrectinib), which it gained when Eli Lilly & Co. acquired partner Loxo Oncology Inc. early this year. (Also see "Bayer Bags Full Vitrakvi Rights As Lilly Signs Off Loxo Buy" - Scrip, 18 Feb, 2019.)

Larotrectinib was the first drug developed specifically for tissue-agnostic use, and was cleared last November for use in adults and children with a solid tumor with an NTRK-fusion. (Also see "FDA Nod For Loxo/Bayer Tissue Agnostic Drug Marks Paradigm Shift In Cancer " - Scrip, 27 Nov, 2018.)

The target mutations and fusions (NRTK1/2/3, ROS1 and ALK) are common in a variety of pediatric cancers, including infantile fibrosarcoma, high grade gliomas, neuroblastoma and inflammatory myofibroblastic tumors. “While rare, this list is growing as alterations are recognized more and more with next-generation sequencing,” Robinson told the presscast.

The Phase I/Ib STARTRK-NG data being presented for entrectinib at ASCO are from 29 patients from 4.9 months to 20 years of age (median age 7 years), who had CNS tumors, neuroblastoma or other solid tumors. Twelve of the 29 patients had tumors with NRTK1/2/3, ROS1 or ALK gene fusions or mutations.

Twelve patients had objective responses with their tumors shrinking or disappearing, with median treatment duration of 281 days at 400mg/m2 or higher. “No responses were seen in tumors lacking aberrations in target kinases,” the abstract reports.

“The medicine was well tolerated and there appears to be no time frame yet studied in which the medicine stops working or toxicities become limiting,” Robinson reported.

The side effects included fatigue, elevated creatinine levels, dysgeusia resulting in loss of taste, and one incident of pulmonary edema at a higher dose. Weight gain was also seen, which is unusual for cancer drugs but is considered an on-target effect for entrectinib.

Roche will soon begin recruitment for Phase II, to establish entrectinib’s effectiveness and determine long-term side effects as well as duration of response on and off therapy.

The RACE To More Pediatric Cancer Trials

The RACE For Children Act provisions of the FDA Reauthorization Act mandate that beginning in August 2020, novel drugs and biologics intended for treatment of an adult cancer and directed at a molecular target that FDA determines to be “substantially relevant” to a pediatric cancer must include reports on a “molecularly targeted pediatric cancer investigation.”

While the bill essentially extends the reach of the Pediatric Research Equity Act to cancer, it will mean a significant increase in pediatric cancer trials. FDA officials already report that discussions with sponsors about pediatric studies are “accelerating a lot.” (Also see "Oncology Sponsors Getting A Jump On Pediatric Study Requirements, US FDA Says" - Pink Sheet, 25 Mar, 2019.)

The findings being presented at ASCO could signify a major increase in the range of targets that are considered relevant to pediatric oncology. The higher-than-predicted matching in the NCI-COG Pediatric MATCH trial suggest that many more targets than thought are implicated in pediatric cancers. And the entrectinib data underscore that rapid and durable responses are possible when a targeted therapy is matched to a patient’s tumor genetics.

Sponsors should prepare to run more trials than originally thought. (Also see "Pediatric Cancer Studies: US FDA Promises Flexible Approach On Requirements" - Pink Sheet, 22 Feb, 2018.)