Datopotamab deruxtecan development UPDATES_MAY 2024
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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
Trial |
P1/2 ARTEMIDE (Cohort A + B) |
P1b TROPION-Lung02 (1L Cohort) |
P1b TROPION-Lung04 (1L Cohort) |
P3 TROPION-Lung01 (Nsq only) |
Patient Segment |
2L+ (750mg, N=54) |
1L all comer (Doublet, N=61, Triplet N=71) |
1L all comer (Doublet, N=14, Triplet N=13) |
2L+ Nsq (N=234 vs 234) |
Regimen |
Rilvegostomig monotherapy |
Dato-DXd + pembro ± chemo |
Dato-DXd + durva ± chemo |
Dato-DXd mono vs docetaxel |
OS |
- |
- |
- |
13.4mo vs 11.4mo (HR=0.79) |
PFS |
3.8mo |
- |
- |
5.5mo vs 3.6mo (HR=0.63) |
ORR |
6% |
Doublet: 50% Triplet 57% |
Doublet: 50% Triplet 77% |
31% vs 13% |
Source |
ESMO 2023 |
ASCO 2023 |
WCLC 2023 |
ELCC 2023 |
- 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