MEK inhibition combined with an anti-IGFR1 agent shrank tumors in pediatric PAX fusion–negative rhabdomyosarcoma.
MEK inhibition combined with an anti-IGFR1 agent shrank tumors in pediatric PAX fusion–negative rhabdomyosarcoma, according to Marielle E. Yohe, MD, PhD, who presented the preclinical findings during week 2 of the 2021 AACR Annual Meeting.
The combination approach is part of the wave of ongoing trials focused on combating the disease in this pediatric population.
Mutations in RAS oncogenes are common in both adult and pediatric tumors. Whereas KRAS mutations are most common in adult tumors, mutations in NRAS (17%) are the most common in pediatric rhabdomyosarcoma, followed by NF1 (15%), HRAS (8%) KRAS (8%), and PTPN11 (1%).
Until recently, it was not possible to directly inhibit the mutant RAS isoform, said Yohe, head of the molecular signaling section in the pediatric oncology branch at the National Cancer Institute (NCI). Investigators instead focused on inhibiting the kinase pathways activated by oncogenic RAS, including the PI3-AKT pathway and the RAF-MEK-ERK pathway.
“We were therefore not at all surprised to find in an unbiased draft screen that inhibitors of the MAP kinase pathway would be selectively potent in our rescue team cell lines,” she said. “These included MEK inhibitors and pan-RAF inhibitors.”
Since MEK inhibition alone was not enough to stop rhabdomyosarcoma tumor growth in animal subjects, Yohe and colleagues experimented with the combination of BMS-754807, an IGF1R inhibitor, in combination with the MEK inhibitor trametinib (Mekinist).
The FDA first approved oral trametinib in 2013 as a single agent for patients with unresectable or metastatic melanoma who harbor BRAF V600E or V600K mutations. The agency later approved the drug in combination with dabrafenib (Tafinlar) for the treatment of patients with BRAF V600E–mutant metastatic non–small cell lung cancer (NSCLC), BRAF V600–mutant melanoma, and BRAF V600E–mutant anaplastic thyroid cancer.
“We are able to see synergy across a wide variety of concentrations of [both] drugs that was not observed with trametinib by itself,” Yohe said. “We were really excited about this combination because this synergy had been observed previously in adult tumors, such as lung cancer, even leading to a phase 1 clinical trial.”
Yohe and her colleagues hypothesized that this combination would perform better in this setting because pediatric tumors, including rhabdomyosarcoma, have a dependency on IGF1R that adult tumors do not.
Investigators next compared the combination versus both trametinib and BMS-754807 alone in in vivo cell line xenograft models. One model, SMS-CTR, was relatively resistant to trametinib monotherapy while the other, RD, was relatively sensitive. Test animals were treated for 45 days, then investigators stopped treatment and watched for tumor formation.
“In the resistant model, we can see that the tumors grew through treatment with trametinib by itself or BMS-754807 by itself but were suppressed by the combination. In the sensitive model, we saw tumor growth suppression in each of the treatment arms,” Yohe said. “However, when we stopped treatment, we immediately saw tumor regrowth in the single-agent arms in the SMS-CTR [model]. However, we saw continued tumor growth depression in the combination arm.”
“For the less sensitive RD model, we saw that the tumors regrew immediately upon stopping the combination treatment.”
Yohe said investigators were “encouraged” by the results but noticed treatment-related toxicity. Subjects on the combination arm experienced body weight loss from day 14 to approximately day 24.
Investigators suspected the toxicity was related to off-target effects from BMS-754807. They then used a more specific agent, the human monoclonal anti-IGF1R antibody ganitumab (AMG 479). Ganitumab was granted an orphan drug designation by the FDA in 2017 for the treatment of patients with Ewing sarcoma.
Investigators found that trametinib/ganitumab had synergy similar to trametinib/BMS-754807. They then tested 5 treatments—vehicle, the 2 monotherapies, the trametinib/ganitumab combination, and vincristine as the standard of care—in the SMS-CTR model and stopped treatment after 28 days.
Investigators found tumor regrowth in the monotherapy arms but found that the trametinib/ganitumab combination inhibited tumor growth for approximately 40 days. Yohe said the tumors responded to a second course of trametinib/ganitumab, but tumors regrew in a shorter time.
The trametinib/ganitumab combination did appear to be more tolerable than the BMS-754807 combination. No weight loss was observed from day 14 to 25. Further, the trametinib/ganitumab combination had no effect on serum insulin, absolute neutrophil count, or platelet count.
Yohe said limited drug availability has hampered her ability to clinically translate these findings, but other groups, including several arms of the NCI-Children’s Oncology Group Pediatric MATCH study are also conducting research targeting the RAS/MAP kinase pathway. She is co-principal investigator on an arm of MATCH studying tipifarnib in patients with HRAS-mutated solid tumors.
“We hope to have an update on the use of combinations of targeted agents in RAS/MAP kinase-altered pediatric solid tumors very shortly,” she said.
Yohe M. Targeting RAS signaling in pediatric solid tumors. Presented at: 2021 AACR Annual Meeting; May 17-21, 2021; virtual.