Abstract
According to preliminary data from the phase I/Ib STARTRK-NG trial, the investigational multikinase inhibitor entrectinib showed efficacy in children and adolescents with CNS and other tumor types harboring NTRK1/2/3, ROS1, or ALK fusions. Durable responses were seen even in CNS tumors such as high-grade glioma.
Early findings from the phase I/Ib STARTRK-NG trial indicate that children and adolescents whose tumor types harbor NTRK1/2/3, ROS1, or ALK fusions respond well to entrectinib (Genentech), an investigational multikinase inhibitor. The results were presented by Giles Robinson, MD, of St. Jude Children's Research Hospital in Memphis, TN, during a media preview of the 2019 American Society of Clinical Oncology Annual Meeting, to be held in Chicago, IL, May 31–June 4.
Entrectinib is a counterpart of larotrectinib (Vitrakvi; Loxo Oncology and Bayer), albeit with broader activity beyond targeting NTRK fusion–positive tumors. At present, larotrectinib is the sole FDA-approved agent in this class, but entrectinib is under priority review for adult and pediatric indications. Both are considered first-generation TRK inhibitors; Loxo Oncology's pipeline already includes a newer iteration—LOXO-195, developed specifically to combat the acquired resistance that almost always occurs with these drugs.
As of October 31, 2018, STARTRK-NG had enrolled 29 patients, 13 whose cancers—mainly high-grade glioma, infantile fibrosarcoma, and inflammatory myofibroblastic tumor (IMT)—harbored various entrectinib-targeted gene fusions. The rest, all diagnosed with neuroblastoma, had no relevant alterations, other than one whose sequencing results revealed an ALK point mutation, F1174L, rather than a fusion. Interestingly, Robinson noted, this particular patient had a complete response to treatment.
Among 12 evaluable patients with actionable mutations, Robinson reported that all had objective responses to entrectinib, including two complete responses in high-grade glioma (NTRK3 fusion) and IMT (ALK fusion), respectively. None of the patients whose tumors lacked alterations responded to treatment.
“As a pediatric neuro-oncologist, it gives me great pleasure to be able to report responses in a devastating, nearly universally fatal CNS tumor type like high-grade glioma,” Robinson said. “Our results do need to be interpreted with some degree of caution, being preliminary, but the responses have been durable so far, and entrectinib appears to show promising efficacy in this population.”
Overall, these early data are quite similar to that of larotrectinib at the same stage of development, says Wendy Allen-Rhoades, MD, of Texas Children's Hospital in Houston, “with the best results being seen in patients whose tumors have mutations in the targeted kinases.”
Entrectinib was well tolerated, Robinson said, with the main side effects being fatigue, elevated creatinine levels, and loss of taste. Another issue, “which is actually a significant worry for patients,” he remarked, was weight gain among some who had been receiving treatment for a while.
“Body weight regulation is controlled, in part, through TRKB signaling in neurons that express the dopamine-1 receptor; inhibition of this pathway leads to hyperphagia [overeating] and hyperglycemia,” Allen-Rhoades explains. Weight gain has also been observed with larotrectinib, she notes, and “is considered an on-target effect of these drugs.”
Should entrectinib receive the FDA's nod later this year, Allen-Rhoades thinks “it would make sense to start with this drug” in patients with NTRK-fusion positive glioma and other tumor types affecting the brain or spine. There have been reports of metastatic brain lesions responding to larotrectinib, she says, “so it likely does cross into the CNS space, but to my knowledge, specific CNS studies have not been completed in children. As such, until we have more data on larotrectinib and primary CNS tumors, I think most clinicians would choose entrectinib.”
Robinson, meanwhile, noted that even as next-generation sequencing is more widely done and “we're finding NTRK fusions in tumor types we wouldn't have expected before,” the flip side of the coin is that “many childhood tumors have no targetable alterations or any mutations at all, really.” Through efforts like the NCI-COG Pediatric MATCH trial, as well as the RACE for Children Act—which requires companies developing adult cancer drugs to also test their product in pediatric populations, where appropriate—he hopes “we can step up and figure out options for these kids.” –Alissa Poh
