Asco-GI 2022 – Seagen keeps the faith in souped-up CD40 agonism

 Do not write off CD40. Stimulating this target for oncology use has proved difficult, but companies are not giving up, though many have accepted that something more than a simple agonist approach might be needed. Seagen’s SEA-CD40 is a nonfucosylated CD40 agonist MAb, and phase 1 data just unveiled at the Asco-GI meeting show 44% overall response across two doses in 61 evaluable patients in a first-line pancreatic ductal adenocarcinoma cohort; median PFS and OS are 7.4 and 15.0 months respectively. It is difficult to parse SEA-CD40’s contribution, as the project was combined with Keytruda, Abraxane and gemcitabine, but Abraxane’s label cites ORR, mPFS and mOS of 23%, 5.5 months and 8.5 months, respectively, in combination with gemcitabine. SEA-CD40 recently moved into phase 2, as did Celldex’s fully human agonist CDX-1140, while new clinical entrants since Evaluate Vantage last analysed the CD40 field include Abbvie’s ABBV-927, Biontech/Genmab's GEN1042, Lyvgen’s LVGN7409 and Shattuck’s SL-172154. Discontinuations include ABBV-428 and Astrazeneca’s MEDI5083, while Roche recently canned selicrelumab in favour of RG6189, a bispecific that induces CD40 stimulation solely in the presence of FAPα and is now in a phase 1 Tecentriq combo trial.

Selected clinical assets targeting CD40 in cancer
Project	Company	Mechanism	Clinical trial
Phase 2
APX005M/ sotigalimab	Apexigen	CD40 agonist MAb	Melanoma and oesophageal/GEJ
CDX-1140	Celldex Therapeutics	Fully human CD40 agonist MAb	Pancreatic cancer
SEA-CD40	Seagen	Nonfucosylated CD40 agonist MAb	Combo trial
ABBV-927	Abbvie	CD40 agonist MAb	Pancreatic cancer
YH003	Eucure (Biocytogen)	Humanised CD40 agonist MAb	Toripalimab combo
Phase 1/2
Mitazalimab/ ADC-1013	Alligator Bioscience	CD40 agonist MAb; J&J terminated deal Jul 2019	Pancreatic cancer
GEN1042	Biontech/Genmab	CD40 & 4-1BB Duobody	Solid tumours
Phase 1
FAP-CD40/ RO7300490	Roche	FAPα-dependent CD40 agonist bispecific	Tecentriq combo
LVGN7409	Lyvgen Biopharma	CD40 agonist MAb	MonoRx & combo
SL-172154	Shattuck Labs	CD40L-SIRPα fusion protein	Ovarian and head & neck cancers
Source: Evaluate Pharma. Note: excludes non-oncology applications and CD40-blocking approaches for autoimmune diseases. https://www.evaluate.com/vantage/articles/events/conferences-snippets/asco-gi-2022-seagen-keeps-faith-souped-cd40-agonism