Regeneron and Xencor add to the growing evidence backing bispecifics in certain lymphomas, a space that looks set to become fiercely competitive.
Regeneron is behind Roche with its anti-CD3-CD20 bispecific, but early data suggests that might not matter. The Ash medical meeting saw highly encouraging response rates across various subtypes of lymphoma with REGN1979, though as suspected tolerability will be the main concern with this project.
Cytokine release was seen in 59% of patients, a substantially higher proportion than was reported for Roche’s mosunetuzumab over the weekend, including more incidences of serious events; investigators also disclosed one death due to tumour lysis syndrome. Differences in trial design and patient populations make valid comparisons hard at this stage, but it seems that what REGN1979 loses in toxicity it gains in efficacy.
| SAFETY COMPARISON | |||
|---|---|---|---|
| REGN1979 (Regeneron) | Mosunetuzumab (Roche) | Xmab13676 (Xencor) | |
| N | 110 | 270 | 53 |
| CRS | 59% | 29% | 53% |
| CRS grade 3-4 | 6.4% | 1.1% | 5.7% |
| CRS=cytokine release syndrome. Source: Ash 2019. | |||
Physicians are much more comfortable dealing with this safety issue now, but in a crowded space the risk of cytokine release could mark REGN1979 out as a more troublesome option. The project already has something of a reputation, after two patients died in a trial that combined REGN1979 with Regeneron’s PD-1 inhibitor, Libtayo.
Xencor also presented encouraging signals with its contender, Xmab13676; a manageable safety profile is emerging with the project and effectiveness that looks more in line with mosunetuzumab. The results showed an ORR of 38.90% with a CR of 27.80% in the 18 DLBCL patients treated, although these readouts are very early.
As of early November safety data was available on 45 NHL and 8 CLL patients. Investigators reported a 53% rate of cytokine release, most of which were grade 1 or 2, while no grade 3 events occurred once step up dosing was implemented. This dosing strategy looks likely become widely established with these therapies.
Dosing is ongoing with Xmab13676, and these data remain far from the end of the story. The table below provides a brief summary of the results seen with CD3-CD20 bispecifics at Ash this weekend. Roche gained a prominent plenary presentation of mosunetuzumab over the weekend, and has dosed the most patients so far.
The Swiss pharma giant also detailed combination data on its second CD3-CD20 project, RG6026, which some biopharma watchers expect to emerge as a more efficacious agent. This is different to mosunetuzumab in that is contains two CD20 binding domains; it is not yet clear whether Roche will bring both projects to market.
It is clear that bispecifics will play a role in the treatment of haematological cancers in the not too distant future. Where they will fit remains to be answered – while it seems likely that autologous Car-T therapies will increasingly be consigned to salvage settings, off-the-shelf cell therapies have yet to show what they can do.
For the meantime, however, big companies like Roche and Regeneron look well set to ride this wave. Deep pockets count for a lot in a very crowded market.
| COMPARING ANTI-CD3-CD20 BISPECIFICS | ||||||||
|---|---|---|---|---|---|---|---|---|
| Regeneron | Roche | |||||||
| B-NHL diagnosis | N | ORR | CR | B-NHL diagnosis | N | ORR | CR | |
| FL Gr 1–3a | 22 | 95% | 77% | Indolent NHL | 67 | 62.7% | 43.3% | |
| DLBCL without CAR T | 7 | 71% | 71% | All 3L+ FL | 61 | 63.9% | 44.3% | |
| DLBCL with CAR T | 12 | 50% | 25% | Aggressive NHL | 124 | 37.1% | 19.4% | |
| MCL | 6 | 67% | 33% | All 3L+ DLBCL/trFL (n=98) | 98 | 37.8% | 20.4% | |
| MZL | 6 | 67% | 33% | DLBCL prior Car-T | 9 | 22.2% | 22.2% | |
| Source: Ash presentations | ||||||||
