Merck’s conjugates dominate pivotal trial initiations
Raludotatug deruxtecan, ABBV-383 and zongertinib advance into phase 3, while other pivotal programmes are expanded.
Raludotatug deruxtecan, ABBV-383 and zongertinib advance into phase 3, while other pivotal programmes are expanded.
Two high-profile antibody-drug conjugates to which Merck & Co has licensed rights feature among a number of phase 3 trials that have recently been disclosed on the clinicaltrials.gov registry.
These are the Daiichi Sankyo-derived raludotatug deruxtecan – starting its first pivotal study – and sacituzumab tirumotecan, an ADC Merck licensed from Kelun that has already moved into pivotal development in five cancer settings. Also newly into phase 3 are a T-cell engaging MAb AbbVie acquired with TeneoOne, and a small molecule Boehringer Ingelheim is developing in a setting where Spectrum stumbled.
Swift development
Merck was already proceeding swiftly with sacituzumab tirumotecan, earlier starting pivotal development in endometrial cancer, two breast and two lung cancer settings, and the latest phase 3 trial merely confirms these efforts. Understandably NSCLC represents a big push, with two phase 3 studies under way in second-line or later settings.
The new trial takes a Keytruda combo into first-line NSCLC, interestingly being limited to patients expressing PD-L1 at 50% or higher, where Keytruda’s Keynote-024 study yielded median PFS of 10.3 months and median OS of 30.0 months. These numbers will act as a benchmark of sorts, though the Keynote-024 data are now rather old.
Meanwhile, raludotatug deruxtecan impressed at ESMO in an early trial in ovarian cancer, suggesting one reason behind the monster deal Merck had struck with the ADC’s originator, Daiichi Sankyo, on the eve of that conference. Now the companies have moved the asset swiftly into a phase 2/3 study in the same cancer.
Daiichi today separately announced the start of phase 3 trials combining its AstraZeneca-partnered anti-TROP2 ADC, datopotamab deruxtecan, with Astra’s Imfinzi in two breast cancer settings. Of course, OncologyPipeline subscribers and ApexOnco readers already had a heads up about these back in October.
The same goes for Merck’s Moderna-partnered cancer neoantigen immunotherapy mRNA-4157/V940, which was last week press released as entering a Keytruda-combo phase 3 trial Interpath-002, in adjuvant NSCLC. That study had already been flagged in OncologyPipeline, and joined the companies’ first pivotal effort, in the Interpath-001 trial in adjuvant melanoma.
In other news for Merck, the FDA last week expanded the first-line urothelial bladder cancer approval of Keytruda and Pfizer's Padcev to include cisplatin-eligible patients, based on the EV-302 trial, presented at ESMO. The nod came five months ahead of the combo's PDUFA date.
Notable recent phase 3 trial initiations
| Project | Mechanism | Company | Trial detail & key endpoints |
|---|---|---|---|
| Newly into phase 3 | |||
| Raludotatug deruxtecan | Anti-CDH6 ADC | Daiichi Sankyo/ Merck & Co | 2nd-line ovarian cancer (ph2/3 study), vs chemo, ORR & PFS co-primaries, OS secondary |
| ABBV-383 | Anti-BCMA T-cell engager | AbbVie (ex TeneoOne) | 3rd-line multiple myeloma, vs standard available therapy, VGPR rate & PFS co-primaries, OS secondary |
| Zongertinib | HER-2 exon 20 inhibitor | Boehringer Ingelheim | Beamion Lung-2, HER2 mutated NSCLC, vs Keytruda + chemo, PFS primary, OS secondary |
| Additional phase 3 trials initiated | |||
| Odronextamab | Anti-CD20 T-cell engager | Regeneron | Olympia-5, Revlimid combo vs Rituxan + Revlimid in 3rd-line follicular/marginal zone lymphoma, PFS co-primary, OS secondary |
| Elrexfio | Anti-BCMA T-cell engager | Pfizer | Magnetismm-32, 2nd to 5th-line multiple myeloma, vs investigator’s choice, PFS primary, OS secondary |
| Sacituzumab tirumotecan | Anti-TROP2 ADC | Merck & Co (ex Kelun) | 1st-line NSCLC, Keytruda combo vs Keytruda in ≥50% PD-L1 expressers, OS primary |
Source: clinicaltrials.gov & OncologyPipeline.
Raludotatug deruxtecan is one of three projects revealed to be newly entering phase 3.
The other two are Boehringer Ingelheim’s zongertinib and AbbVie’s ABBV-383. The latter has a high profile, having come through the buyout of TeneoOne, and AbbVie recently doubled down on it, declining to opt into development of a rival BCMA-targeting multiple myeloma T-cell engager from Harpoon Therapeutics.
In August Pfizer’s rival anti-BCMA T-cell engager Elrexfio received accelerated US approval in fifth-line multiple myeloma, and the phase 3 Magnetismm-32 trial, testing the drug as early as the second-line setting, is starting imminently, according to a new clinicaltrials.gov entry. This is a hugely competitive field, including Johnson & Johnson’s marketed Tecvayli in addition to several Car-T therapies.
Meanwhile, Boehringer’s zongertinib is trying to play into a tiny niche, NSCLC that is driven by exon 20 insertions in HER2. It was here that Spectrum’s rival poziotinib was hit with a 2022 FDA complete response letter that led to that asset being discontinued, and its originator being taken over.
The final notable phase 3 initiation is the Olympia-5 trial of Regeneron’s odronextamab, a CD20-directed asset awaiting US approval in lymphoma based on phase 1 and 2 data; the Olympia studies comprise its confirmatory programme. This too is a competitive space, featuring marketed T-cell engagers from Roche (Columvi and Lunsumio) and AbbVie/Genmab (Epkinly).
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