TNO155 Plus Spartalizumab or Ribociclib Elicits Disease Control, Is Safe in Advanced Solid Tumors

Omar Saavedra, MD

Treatment with TNO155 in combination with spartalizumab (PDR001) or ribociclib (Kisqali) led to disease control and was well tolerated in heavily pretreated patients with advanced solid tumors, according to data from the phase 1b CTNO155B12101 trial (NCT04000529) presented at the 2024 ESMO Targeted Anticancer Therapies Congress.

Findings showed that patients treated with TNO155 plus spartalizumab across all doses (n = 57) experienced a disease control rate (DCR) of 26.3%, including a partial response (PR) rate of 1.8%, a stable disease (SD) rate of 24.6%, and a progressive disease (PD) rate of 50.9%. Response was unknown in 22.8% of patients. Notably, the recommended dose of 60 mg of TNO155 once per day for 2 weeks on and 1 week off, plus 300 mg of spartalizumab once every 3 weeks (n = 19), elicited a DCR of 31.6% with PR and SD rates of 5.3% and 26.3%, respectively. Response was unknown in 21.1% of patients in this subset.

Additionally, TNO155 plus ribociclib did not generate any responses across all dose levels (n = 46); however, the combination demonstrated a DCR of 13.0%. The PD rate was 67.4%, and response was unknown for 19.6% of patients.

Notably, patients treated with the recommended dose of TNO155 at 40 mg plus 200 mg of ribociclib once per day on a 2-weeks-on, 1-week-off schedule (n = 9) experienced a DCR of 44.4% and a PD rate of 55.6%.

Regarding safety, no fatal treatment-related adverse effects (TRAEs) occurred in patients treated with either combination. Three fatal AEs were reported in the TNO155/spartalizumab cohort, including ischemic stroke (n = 1), esophageal perforation and sepsis (n = 1), and pneumonia (n = 1); however, no fatal AEs occurred in patients treated at the recommended dose of TNO155/spartalizumab.

For all patients treated with TNO155/spartalizumab, the rates of any-grade AEs leading to dose reduction and treatment discontinuation were 14.0% and 8.8%, respectively. For those treated at the recommended dose, those rates were both 15.8%. In the overall TNO155/ribociclib cohort, the rates of any-grade AEs leading to dose reduction and treatment discontinuation were 15.2% and 10.9%, respectively. At the recommended dose of TNO155/ribociclib, any-grade AEs led to dose reductions in 22.2% of patients, and no patients discontinued treatment due to AEs.

“The safety profiles of the combinations were consistent with those observed with each single agent, and no new safety signals were identified,” lead study author Omar Saavedra, MD, of the Early Drug Development Unit (phase 1 Unit) at Vall d'Hebron Institute of Oncology in Barcelona, Spain, said in a presentation of the data.

TNO155 is a selective, orally bioavailable allosteric SHP2 phosphatase inhibitor intended to block tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven tumors. Based on preclinical studies that demonstrated antitumor activity for TNO155 in combination with a murine anti–PD-1 antibody, as well as with ribociclib, the phase 1 trial was designed to assess the safety and tolerability of the 2 combinations in patients with advanced solid tumors.

CTNO155B12101 was a dose-escalation study that enrolled patients at least 18 years of age who had advanced solid tumors with evaluable disease per RECIST v1.1 criteria. An ECOG performance status of 0 or 1 was also required.

Enrolled patients with advanced head and neck squamous cell carcinoma (HNSCC), esophageal squamous cell carcinoma (ESCC), colorectal cancer (CRC), or EGFR/ALK wild-type non–small cell lung cancer (NSCLC) were assigned to receive TNO155 in combination spartalizumab. The PD-1 inhibitor was given at 300 mg once every 3 weeks across all cohorts, and TNO155 was administered on a 2-weeks-on, 1-week-off schedule at doses of 5 mg twice per day (n = 6), 10 mg twice per day (n = 5), 20 mg once per day (n = 5), 20 mg twice per day (n = 5), 30 mg twice per day (n = 6), 40 mg twice per day (n = 7), 50 mg twice per day (n = 3), 60 mg once per day (n = 19), and 60 mg twice per day (n = 1).

The TNO155/ribociclib cohort included patients with any advanced solid tumor. Treatment regimens consisted of TNO155 at 20 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day (n = 3); TNO155 at 20 mg twice per day plus ribociclib at 150 mg once per day for 3 weeks on and 1 week off (n = 5); TNO155 at 30 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off (n = 9); TNO155 at 40 mg once per day plus ribociclib at 200 mg once per day for 2 weeks on and 1 week off (n = 9); TNO155 at 40 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day (n = 5); TNO155 at 40 mg once per day plus ribociclib at 150 mg once per day for 3 weeks on and 1 week off (n = 4); TNO155 at 40 mg once per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off (n = 5); TNO155 at 40 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off (n = 1); and TNO155 at 60 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day (n = 5).

The primary end points included safety and tolerability, as well as establishing the maximum tolerated dose and/or recommended dose. Secondary end points consisted of pharmacokinetics and preliminary antitumor activity. Changes in DUSP6 mRNA expression in tumors was a key exploratory end point.

Among patients treated across all doses of TNO155/spartalizumab, the median age was 57.0 years (range, 30-77), and most patients were male (61.4%) and White (71.9%). Histology included CRC (59.6%), ESCC (3.5%), HNSCC (14.0%), NSCLC (21.1%), and other (1.8%). The median number of prior antineoplastic regimens was 3.0 (range, 1-9). Additionally, the rates of patients with an ECOG performance status of 0 and 1 were both 49.1%, and performance status data were missing for 1 patient (1.8%).

In all patients treated with TNO155/ribociclib, the median age was 57.5 years (range, 29-81), and half of patients were male. The majority of patients were White (67.4%) and had an ECOG performance status of 0 (69.6%). Cancer diagnosis included CRC (58.7%), ESCC (6.5%), HNSCC (2.2%), NSCLC (15.2%), and other (17.4%). Patients in this group received a median of 4.0 (range, 1-9) prior antineoplastic regimens.

As of the November 1, 2023, data cutoff, all patients enrolled in the TNO155/spartalizumab cohort had discontinued treatment. Reasons for discontinuation included PD (77.2%), AEs (8.8%), death (7.0%), patient decision (5.3%), and physician decision (1.8%). In the TNO155/ribociclib cohort, 45 of 46 patients (97.8%) had discontinued treatment due to PD (80.4%), AEs (10.9%), death (2.2%), and patient decision (4.3%).

Additional safety data for the TNO155/spartalizumab combination showed that all patients experienced any-grade AEs, and 68.4% encountered grade 3 or higher AEs. The rates of any-grade and grade 3 or higher TRAEs were 94.7% and 26.3%, respectively.

The most common AEs with TNO155/spartalizumab included increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased creatine phosphokinase (CPK), anemia, thrombocytopenia, increased N-terminal prohormone of brain natriuretic peptide, peripheral edema, and diarrhea.

Furthermore, dose-limiting toxicities (DLTs) reported across various dose levels for TNO155/spartalizumab included grade 3 decreased ejection fraction (n = 1; dose level, TNO155 at 20 mg once per day for 2 weeks on and 1 week off), grade 2 decreased ejection fraction (n = 1; dose level, TNO155 at 20 mg once per day for 2 weeks on and 1 week off), grade 3 autoimmune encephalopathy (n = 1; dose level, TNO155 at 60 mg once per day for 2 weeks on and 1 week off), grade 3 febrile neutropenia (n = 1; dose level, TNO155 at 20 mg twice per day for 2 weeks on and 1 week off), grade 3 rhabdomyolysis (n = 1; dose level, TNO155 at 40 mg twice per day for 2 weeks on and 1 week off), grade 3 localized edema (n = 1; dose level, TNO155 at 50 mg twice per day for 2 weeks on and 1 week off), and grade 2 swelling (n = 1; dose level, TNO155 at 50 mg twice per day for 2 weeks on and 1 week off).

Additional safety data for TNO155/ribociclib showed that the most common any-grade AEs consisted of thrombocytopenia, increased AST, increased CPK, anemia, increased ALT, diarrhea, neutropenia, pyrexia, and peripheral edema.

DLTs reported in patients treated with TNO155/ribociclib included grade 3 dyspnea and grade 3 pneumonitis (n = 1; dose level, TNO155 at 40 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day); grade 3 pulmonary edema (n = 1; dose level, TNO155 at 60 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day); grade 3 diarrhea and grade 3 decreased platelet count (n = 1; dose level, TNO155 at 60 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day); grade 2 decreased ejection fraction (n = 1; dose level, TNO155 at 40 mg once per day plus ribociclib at 150 mg once per day for 3 weeks on and 1 week off); grade 4 thrombocytopenia (n = 1; dose level, TNO155 at 30 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off); grade 3 decreased neutrophil count (n = 1; dose level, TNO155 at 30 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off); grade 3 urate increase and grade 1 increased blood creatinine (n = 1; dose level, TNO155 at 30 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off); grade 3 pneumonitis and grade 4 decreased platelet count (n = 1; dose level, TNO155 at 40 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off); and grade 3 hypertransaminasemia (n = 1; dose level, TNO155 at 40 mg once per day plus ribociclib at 200 mg once per day for 2 weeks on and 1 week off).

Pharmacokinetic data for both combinations demonstrated that drug exposures were consistent for each agent compared with their single-agent use from past studies. Furthermore, more than 50% of patients who received TNO155 at doses of at least 40 mg once per day experienced suppression of DUSP6 mRNA, which is a marker of SHP2 inhibition.

Reference

Saavedra O, Machiels JP, Soo R, et al. A dose-escalation study of TNO155 (TN) in combination with spartalizumab (SPA) or ribociclib (RIB) in adults with advanced solid tumors. Ann Oncol. 2024;9(suppl 1):1-11. doi:10.1016/esmoop/esmoop102271