Datopotamab deruxtecan development UPDATES_MAY 2024

Phase 3 TROPION-Lung10 (NCT06357533) investigates datopotamab deruxtecan (Dato-DXd; TROP2 ADC) + rilvegostomig (TIGIT / PD-1 bispecific) vs rilvegostomig monotherapy vs pembrolizumab (PD-1) monotherapy as first-line therapy in patients with PD-L1>50% non-squamous (Nsq) mNSCLC without AGAs.

Implications:

• This is the first pivotal trial combining a TROP2 ADC with a TIGIT molecule and will directly compete with Phase 3 EVOKE-03 (TDV) and Phase 3 STAR-121 (ZIM+DOM) in the 1L PD-L1>50% Nsq mNSCLC setting. 
• Phase 3 TROPION-Lung10’s primary endpoints are in TROP2 positive patients, signaling continued commitment to pushing a TROP2 biomarker strategy in 1L mNSCLC
  • Phase 3 AVANZAR: Dato-DXd + durva (PD-L1) + chemo in 1L mNSCLC is also ongoing and includes primary endpoints in TROP2 positive patients
  • In comparison to P3 AVANZAR (N=1280), P3 TROPION-Lung10’s sample size (N=675) may be low for a three-arm study with TROP2 stratification
• Despite this combo targeting three different major MOAs, Rilvegostomig has previously demonstrated a generally well-tolerated safety profile in monotherapy data and should add minimal additional toxicity to Dato-DXd’s safety profile
  • likely need to combine Dato-DXd and rilvegostomig with chemo to be relevant in other PD-L1 expressions, and it remains to be seen whether a triplet with chemo would be tolerable
  • Rilvegostomig monotherapy in 1L mNSCLC is currently under investigation in P1-2 ARTEMIDE-01: expansion (Part C) and dose optimization (Part D) (data expected H2’24)
  • P1b TROPION-Lung04 Cohorts 5-8: Dato-DXd + rilvegostomig +/- chemo in 1L mNSCLC
  • P2 TROPION-PanTumor03 Substudy 6B: Dato-DXd + rilvegostomig in mUC

Study Details for P3 TROPION-Lung10 (NCT06357533):

• Target population: 1L non-squamous PD-L1>50% Stage IIIB-IV mNSCLC w/o AGAs
• 1EP: PFS and OS in TROP2 positive patients
• 2EP: PFS and OS in ITT population, ORR, DoR
• Estimated enrolment: 675
• Study design:
  • Experimental Arm: Dato-DXd + rilvegostomig via IV infusion Q3W
  • Experimental Arm: Rilvegostomig monotherapy via IV infusion Q3W
  • Active Comparator: Pembro monotherapy via IV infusion Q3W
• Study start date: April 26, 2024
• PCD: May 24, 2030
• Study location: Australia, Europe, Japan, Korea, Taiwan, UK

Background

Table 1. Previously presented data for Dato-DXd and rilvegostomig in NSCLC

• Other ongoing Phase 3 TROP2 ADC or TIGIT trials that overlap with 1L PD-L1>50% mNSCLC
  • Roche’s P3 SKYSCRAPER-01 (NCT04294810): Tiragolumab (TIGIT) + atezolizumab (PD-L1) in 1L PD-L1≥50% nsq/sq adv/mNSCLC w/o AGAs
  • Roche’s P2/3 SKYSCRAPER-06 (NCT04619797): atezo + tira (TIGIT) + chemo in 1L Nsq PD-L1-all-comer mNSCLC
  • Beigene’s P3 AdvanTIG-302 (NCT04746924): Tislelizumab (PD-1) + ociperlimab (TIGIT) in 1L PD-L1≥50% nsq/sq adv/mNSCLC w/o AGAs
  • Merck’s P3 KEYVIBE-003 (NCT04738487): Pembrolizumab/vibostolimab (PD-1/TIGIT coform) in 1L PD-L1≥1% nsq/sq adv/mNSCLC w/o AGAs
  • Merck’s P3 KEYVIBE-007 (NCT05226598): pembro + vibo (TIGIT) + chemo in 1L Nsq/Sq PD-L1-all-comer mNSCLC
  • Merck’s P3 MK-2870-007 (NCT06170788): MK-2870 (TROP2 ADC) + pembrolizumab (PD-1) vs pembro alone in 1L PD-L1 TPS≥50% nsq/sq mNSCLC
  • AstraZeneca’s P3 AVANZAR (NCT05687266): Dato-DXd (TROP2 ADC) + durvalumab (PD-L1) + chemo vs pembro + chemo in 1L Nsq PD-L1-all-comer mNSCLC (primary endpoints in TROP2-positive pts)
  • AZ/Daiichi’s P3 TROPION-Lung08 (NCT05215340): Dato-DXd + pembro vs pembro in 1L Nsq PD-L1 ≥50% mNSCLC w/o AGAs