An investigational RET inhibitor demonstrated clinical activity in a subgroup of patients with RET fusion-positive non–small cell lung cancer (NSCLC), according to data from a phase Ib trial reported at the ESMO Annual Congress in Madrid.<br />
Lyudmila Bazhenova, MD
An investigational RET inhibitor demonstrated clinical activity in a subgroup of patients with RET fusion-positive nonsmall cell lung cancer (NSCLC), according to data from a phase Ib trial reported at the ESMO Annual Congress in Madrid.
Six of the 8 patients on the trial with RET fusions other than KIF5B achieved partial responses with RXDX-105, a VEGFR-sparing RET inhibitor. In contrast, of the 14 patients on the trial with KIF5B-RET fusion-positive tumors, 3 patients achieved stable disease.
One patient with metastatic colorectal cancer (mCRC) and a non-KIF5B RET fusion achieved a complete response.
“RXDX-105 has demonstrated a manageable safety profile in patients with advanced or metastatic solid tumors,” said Lyudmila Bazhenova, MD, a medical oncologist and professor of medicine at the University of California, San Diego Moores Cancer Center. “The disparity in response between tumors with the KIF5B and non-KIF5B fusion partners is consistent with previous pooled efficacy evidence with other RET-active agents, suggesting that KIF5B fusion may be less susceptible to targeted inhibition.”
Chromosomal rearrangement of the RET proto-oncogene during transfection leads to oncogenic signaling. Fusion proteins resulting from chromosomal rearrangement of RET induce “partnering” with other genes to create gene fusions, which occur predominantly in NSCLC and papillary thyroid cancer. Activating mutations in the RET have been identified in association with medullary thyroid cancer.
Activating RET gene fusions occur in 1-2% of NSCLC. RET partners with several genes to create gene fusions in NSCLC, most often KIF5B (more than 50% of the time), but also CCDC6, NCO44, and EML, said Bazhenova.
In vitro, RXDX-105 exhibits high potency against RET fusions and activating mutations, but is VEGFR sparing. It has about 500 times greater potency against RET than VEGFR. In studies involving preclinical models harboring known activating RET fusions, RXDX-105 demonstrated strong antitumor activity, effecting tumor regression at clinically achievable drug levels.
Clinical exposures at the recommended phase II dose of 275 mg once daily in the fed state resulted in target drug thresholds sufficient to inhibit RET, but remained well below the threshold for VEGFR2 inhibition.
During phase I and Ib clinical evaluations, a total of 152 patients were treated with RXDX-105, consisting of 74 patients who received the recommended phase II dose and 78 who received other evaluated doses. The patients had a median age of 60-65 and had an even distribution between the sexes. The entire study population had a median treatment history of 3 prior regimens.
Of 33 patients remaining on treatment, 27 received the 275 mg fed-state dose. Among the 119 patients who discontinued, 76 did so because of disease progression. By comparison, 15 of 47 patients in 275 mg subgroup discontinued treatment. Adverse events led to discontinuation of 19 patients overall, but only patients who received the recommended phase II dose.
In the subgroup of patients who received the recommended phase II dose, the most common grade 1/2 adverse events were rash (22%), diarrhea (16%), fatigue (16%), and decreased appetite (11%). Rash was the most common grade ≥3 adverse event, occurring in 12% of treated patients.
Across all tested doses, 13 patients developed 19 treatment-related serious adverse events, all but 1 of which resolved with dose modification or treatment discontinuation, said Bazhenova. Adverse events commonly associated with VEGFR inhibition, such as hypertension, hypothyroidism, proteinuria, and nephrotoxicity, rarely occurred.
The study population included 40 patients with RET fusion-positive NSCLC, 9 of whom had prior exposure to RET inhibitor therapy. Gene fusion status included 27 patients with KIF5B-RET fusions and 11 with non-KIF5B fusions: 6 with CCDC6-RET, 2 with EML4-RET, and 1 each with PARD3-RET, NCOA4-RET, and CLIP1-RET. Two additional patients tested positive for RET unknown by fluorescence in-situ hybridization. All but 9 patients had no prior exposure to a RET inhibitor.
Seven other patients had different types of tumors with RET-positive histology: 1 with mCRC, 5 with medullary thyroid cancer, and 1 with sarcoma. Five of the 7 had prior exposure to a RET inhibitor.
Of 14 evaluable patients with KIF5B -RET-positive NSCLC, none had objective responses to treatment with RXDX-105, but 3 had stable disease lasting 6 months or longer. Among 8 evaluable patients with non-KIF5B RET-positive NSCLC, 6 had partial responses. The only complete response occurred in a patient with mCRC harboring a CCDC6-RET fusion and no prior exposure to a RET inhibitor.
The median duration of response had yet to be reached. Thus far, the longest duration of response has been 10.2 months.
A Drilon, Lin S V, Doebele R, et al. A Phase IB Study of RXDX-105, a VEGFR-Sparing Potent RET Inhibitor, in RET Inhibitor Naïve Patients With RET Fusion-Positive NSCLC. Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA19.