SHP2 Inhibition With TNO155 for Advanced Solid Tumors Shows Initial Safety, Favorable Pharmacokinetic Data

Reliable SHP2 inhibition and an encouraging safety and tolerability profile were noted with use of TNO155 in adults with advanced solid tumors who were treated in the ongoing dose-escalation and -expansion trial CTNO1552101 (NCT03114319).

“TNO155 has the potential to enhance antitumor activity when used in combination with multiple mechanisms,” Irene Brana, MD, PhD, a clinical investigator at the Vall d’Hebron Institute of Oncology in Barcelona, Spain, said during her presentation of the data at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting. Data from the dose-escalation portion were being presented at the conference.

Patients initially received a starting regimen of 1.5 mg of TNO155 followed by a dose escalation upwards to 70 mg once a day on a 2-weeks on, 1 week off schedule.1 Twice a day dosing was explored to determine if this might improve tolerability. Other schedules were explored to support flexibility with other agents.

The patient population initially eligible for the study were patients whose tumors were expected to have dependency on receptor tyrosine kinases such as RAS/BRAF wild type or KRAS G12C colorectal cancer; EGFR-mutant non-small cell lung cancer, gastrointestinal stromal tumors (GISTs), and others, said Brana.

Emerging data showed that some KRAS G12-mutant tumors, especially KRAS G12C-mutant NSCLC, were sensitive to SHP2 inhibition. Based on these data, the protocol was amended to include patients with KRAS G12-mutant NSCLC and BRAF/NRAS wild-type melanoma.

The median age among patients was 59 years (range, 18-80) and the majority (58.5%) were male. Most (54.4%) patients had ECOG performance status of 1; 44.8% had ECOG performance status of 0. Over half (52.8%) of patients enrolled had colorectal cancer, followed by GIST (16.8%), and NSCLC (12.0%). The median number of prior systemic therapies for the treatment group was 4 (range, 1-10).

As of the data cutoff of February 8, 2021, 94% of patients had discontinued treatment because of disease progression (82%), adverse effects (6%), patient/physician decision (5%) and death (2%). Brana said the median duration of exposure was 7.4 weeks (range, 0.1-147.0). Regarding dose-limiting toxicities (DLTs), 11 patients experienced DLTs in the first cycle of study treatment, Brana explained. Six patients experienced reversible left ventricle ejection fraction (LVEF).

Brana noted that treatment-related AEs were consistent with anticipated effects of SHP2 inhibition, with most AEs grade 1 or 2 in severity, and no suspected treatment-related grade 5 AEs were reported.

Ten percent of patients experienced ejection fraction decreases/left ventricular dysfunction of any grade, and 4% of patients had LVEF decreases of 10% or greater from baseline to a value below 50%, with 1 patient with LVEF below 40%. The decrease was resolved in 4 patients within 7 to 9 days; the remaining patient had their LVEF resolve in 23 days. Branda said that most ejection fraction decreases were mild and were identified as a result of frequent monitoring.

Pharmacokinetic analysis revealed that TNO155 was rapidly absorbed, with median maximum concentration occurring approximately 1.1 hours post dose. Drug exposure increased nearly proportionally with dose level and moderate interpatient pharmacokinetic variability was observed. Brana also noted best percentage change in target lesions was observed in patients with NSCLC, GIST, and colorectal cancer.

“I would like to highlight this patient with BRAF/NRAS melanoma, who experienced a tumor shrinkage of 25% in the first evaluation,” Brana said. “This patient is still on treatment.” In general, 22% of patients reported stable disease and the median duration of patients observed having stable disease was 5.6 months (range, 1.6-32.9 months).

Regarding pharmacodynamic biomarkers, the investigators measured DUSP6 suppression, a marker of the MAP kinase pathway activity downstream of SHP2 and found consistent suppression regardless of the dosing schedule. Furthermore, the investigators reported downregulation of several genes involved in the MAP kinase pathway.

Clinical trials evaluating TNO155 in combination with other agents are ongoing, including with adagrasib (NCT04330664), JDQ443 (NCT04699188), nazartinib (NCT03114319), and loratinib (Lorbrena; NCT04292119).

“In conclusion, the recommended dosing schedule for TNO155 has not yet been declared,” Brana said. “TNO155 has the potential to enhance antitumor activity when used in combination with KRAS G12C inhibitors, blockade of MAP kinase pathway feedback reactivation, and reduction of immunosuppressive signaling in the tumor microenvironment.”

References

Brana I, Shapiro G, Johnson M, et al. Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors. J Clin Oncol. 2021;39(suppl 15):3005. doi: 10.1200/JCO.2021.39.15_suppl.3005