Two dose-limiting toxicities had been noticed, and the utmost tolerated dose was not reached in a research evaluating FS-1502 security, tolerability, and efficacy.
FS-1502, an anti-HER2 antibody drug conjugate (ADC) was properly tolerated and demonstrated promising antitumor exercise in sufferers with HER2-positive superior breast most cancers, in response to a part 1a/1b, open-label, single-arm research (NCT03944499) revealed in Nature Communications1.
Topline information exhibits {that a} single occasion of dose-limiting toxicities (DLTs) occurred at 3.0 and three.5 mg/kg dose ranges, respectively. Moreover, the utmost tolerated dose (MTD) was not reached. Nevertheless, a beneficial part 2 dose (RP2D) was discovered, at 2.3 mg/kg as soon as each 3 weeks.
The perfect general response charge (ORR) in part 1b was 53.7% (95% CI, vary, 41.1%-66.0%). Moreover, the confirmed ORR was 37.5% (95% CI, 25.8%-50.0%).
On the information cutoff, 34.3% of sufferers skilled steady illness, and the illness management charge was 88.1% (95% CI, 77.8%-94.7%). The median time to response was 2.7 months (95% CI, 1.2-not reached [NR]) and the median progression-free survival (PFS) was 15.5 months (95% CI, 4.6-NR). Of observe, the median general survival (OS) was not mature on the cutoff.
Performed throughout 9 websites in China, sufferers enrolled within the part 1a/1b trial (n = 150) from November 11, 2019, to December 13, 2022, had been adults expressing HER2-positive superior malignant tumors who didn’t reply to, couldn’t obtain, or lacked obtainable customary remedy. Each a dose-escalation and dose-expansion part was performed.
Sufferers within the dose-escalation part had been enrolled in a 3 + 3 design, the place 1 DLT of three sufferers in a dose group required the addition of three sufferers with no DLTs. If a mixed group of 6 had 2 or extra DLTs, dose group enrollment can be ceased, and dose escalation prevented. Prespecified dose ranges included 0.1, 0.2, 0.4, 0.6, and 0.8 mg/kg at each 4 weeks and 1.0 and 1.3 mg/kg at each 4 weeks and each 3 weeks.
MTD was decided as the utmost dose with 33% or much less DLT noticed in sufferers with evaluable occasions. RP2D or the remedy dose was decided by antitumor exercise, security, and pharmacokinetic information if MTD couldn’t be noticed.
Main finish factors within the dose escalation part had been DLTs, MTD, and RP2D. Secondary finish factors embody security excluding DLTs, investigator-assessed ORR, PFS, and OS, amongst different finish factors.
The first finish level of dose growth was IRC-assessed ORR. Secondary finish factors included security, PFS, OS, 1-year OS charge, and DOR, amongst different finish factors.
Dose ranges of 1.0 mg/kg each 4 weeks had been related to tumor goal response, with goal response reported as finest response in 48.4% of sufferers throughout dose ranges. Of sufferers handled on the RP2D of two.3 mg/kg, 2 had full responses and 34 had partial responses. Steady illness was skilled by 23 sufferers as of the info cutoff, leading to a illness management charge of 88.1% (95% CI, 77.8%-94.7%).
Inside the 1a growth part (n = 85), 1 affected person skilled a grade 2 lower in creatinine clearance at 3.0 mg/kg (n = 9), and one other skilled grade 3 thrombocytopenia with subcutaneous hemorrhage at 3.5 mg/kg (n = 1). Compared with 3.0 mg/kg each 3 weeks, the two.3 mg/kg each 3-week dose routine appeared to have a greater benefit-risk efficiency and a decrease incidence of adversarial results (AEs).
Remedy-emergent adversarial results (TEAEs) had been noticed in 97.3% (n = 147/150) of sufferers. The commonest had been elevated aspartate aminotransferase (66.7%), hypokalemia (51.3%), and elevated alanine amino transferase (44.0%).
Remedy-related AEs of grade 3 or greater had been noticed in 34.0% of sufferers, commonest of which had been hypokalemia (15.3%) and decreased platelet rely (8.0%). Drug-related severe AEs had been reported in 9.3% of sufferers, the most typical of which was decreased platelet rely (2.7%).
TEAEs led to remedy interruptions or reductions in 30.7% and 24.7% of sufferers, respectively. The commonest drug discount or interruption-related TEAEs had been hypokalemia (9.3%), proteinuria (8.7%), and physique weight reduction (8.7%). 4 (2.7%) TEAEs led to loss of life, together with hemoptysis (0.7%), bacterial pneumonia (0.7%), and pneumonitis (1.3%).
Reference
Li Q, Cheng Y, Tong Z, et al. HER2-targeting antibody drug conjugate FS-1502 in HER2-expressing metastatic breast most cancers: a part 1a/1b trial. Nat Commun. 2024;15:5158 doi: 10.1038/s41467-024-48798-w
