AACR 2021 preview – the early themes emerge

The most important of this year’s two virtual AACRs features immunotherapy combos, new Kras players and first clinical data for several assets.

Conferences

The first big oncology meeting of the year, AACR, starts next month, and could shed more light on combining checkpoint blockade with modulation of cytokine activity. Investors will also note the unveiling of several competitors in the Kras space, where Mirati and Amgen are the most advanced competitors.

Other key presentations, whose titles have all now been made public, include the first clinical results of Iteos’s anti-Tigit MAb and of Alpine’s ALPN-202. Clinical datasets also feature Iovance’s TILs, due to be filed this year, and an intriguing trial of PD-1 plus Parp inhibition.

2021’s AACR has been split into two virtual meetings, the first of which will likely feature all clinical results, and takes place on April 10-15. Though most abstract titles are out, full texts of clinical trial and late-breaking presentations will remain under wraps until April 9.

New Kras players

In Kras AACR reveals Lilly as a new player with LY3537982, an apparently in-house G12C inhibitor. Still, this is a preclinical abstract, as is that for Boehringer Ingelheim’s low-key G12C challenger BI 1823911.

Clinical Kras watchers will focus on a late-breaker for what promises to be human data on Revolution Medicines’ RMC-4630, an SHP2 inhibitor partnered with Sanofi. The battle to be first to market with a Kras inhibitor remains between Amgen, which has filed sotorasib in the US, and Mirati’s adagrasib.

Meanwhile, some investors will take interest in PD-1/cytokine combos given the recent blow-up of Merck KGaA/Glaxosmithkline’s bintrafusp alfa, an anti-PD-L1/TGF-β trap bispecific. The very same mechanism, albeit with two separately titratable molecules, will be on show at AACR in a clinical presentation from Abbvie’s ABBV-151 with or without budigalimab.

Other cytokine approaches include a first look at clinical data for Kadmon’s KD033, an anti-PD-L1/IL-15 fusion protein. And a Keytruda combo of Sanofi’s SAR444245, a not-alpha IL-2, features in a late-breaker that could inform trials of an in-house Libtayo combination; SAR444245 is in the spotlight after Sanofi bought its originator, Synthorx, for $2.5bn.

Keytruda has an AACR presence in its own right, and two clinical presentations look intriguing. One comprises the first data from the Keylynk-007 basket study, where the Merck & Co drug is being combined with Lynparza; this trial is one of several in the Keylynk programme testing combined blockade of PD-1 and Parp.

Perhaps prostate cancer patients in Keylynk-007 will be of most interest, given standalone activity in this cancer in the Profound and Keynote-199 studies. And separate data on subcutaneous Keytruda, from Keynote-555, will be of interest given Pfizer’s recent push to improve PD-(L)1s’ convenience via sasanlimab.

Selected AACR 2021 abstracts
Project Company Clinical trial Detail Abstract
Keytruda SC Merck & Co Keynote-555 SC delivery of anti-PD-1 CT143
Keytruda + Lynparza Merck/Astra Keylynk-007 PD-1/Parp inhibitor combo CT178
KD033 Kadmon NCT04242147 Anti-PD-L1/IL-15 fusion protein; first human data CT227
AMG 256 Amgen NCT04362748 PD-1/IL-21 mutein fusion protein; first human data CT205
ABBV-151 +/- budigalimab Abbvie/Argenx NCT03821935 TGFβ trap +/- PD-1 blockade CT207
THOR-707 (SAR444245) Sanofi (ex Synthorx) Hammer Not-alpha IL-2, Keytruda combo LB041
ALPN-202 Alpine NCT04186637 CD28 co-stimulator/anti-PD-1/anti-CTLA-4; first human data CT213
EOS884448 Iteos NCT04335253 Anti-Tigit MAb; first human data CT118
SEA-TGT Seagen Anti-Tigit MAb; preclinical 1583
RMC-4630 Revolution Medicines/Sanofi NCT03634982 SHP2 inhibitor; single-agent study in Ras-driven cancers LB001
LY3537982 Lilly Kras G12C inhibitor; first preclinical data 1259
KRAS G12V (ON) inhibitors Revolution Medicines Kras G12V inhibitor; preclinical discovery data 1260
BI 1823911 Boehringer Ingelheim Kras G12C inhibitor; preclinical data 1271
Lifileucel Iovance C-144-01 Pivotal cohort 2 in melanoma, to support delayed 2021 filing CT008
Oleclumab Astrazeneca NCT03381274 Anti-CD73 MAb combo with Tagrisso CT163
INCA00186 Incyte Anti-CD73 MAb; preclinical LB174
Adavosertib Astrazeneca ADVL1312 Wee-1 inhibitor; ph2 paediatric trial CT029
ZN-c3 Zentalis NCT04158336 Wee-1 inhibitor; first human data CT016
AB521 Arcus HIF-2α inhibitor; first preclinical data 1206
CMP-001 Checkmate Pharma NCT02680184 TLR9 agonist (NB Idera failure with tilsotolimod) CT032
ICT01 Imcheck Therapeutics Eviction Anti-BTN3A MAb; first-in-human trial CT034
OP-1250 Olema SERD; preclinical data LB122
BLU-263 Blueprint Unclear Next-gen Kit inhibitor; first human data CT122
Source: AACR, company communication & clinicaltrials.gov.

Those keenly tracking first clinical data will also look out for Iteos’s anti-Tigit MAb EOS884448, a cornerstone of the recently Nasdaq-listed Belgian biotech.

Tigit inhibition is becoming competitive, with Roche’s tiragolumab and Merck & Co’s vibostolimab in large pivotal programmes. The former has shown efficacy in NSCLC, albeit in combination with Tecentriq and ironically in PD-L1-high subjects; any efficacy in EOS884448’s monotherapy trial, where patients have no further treatment options, would be positive.

These data are being watched by Arcus, whose own anti-Tigit MAb, domvanalimab, is subject to a possible opt-in by Gilead, but which does not feature at AACR. Another Tigit newcomer, Seagen’s SEA-TGT, has a preclinical AACR poster, while Arcus presents preclinical data on the HIF-2α inhibitor AB521; Merck & Co’s similarly acting, Peleton-derived, belzutifan was recently filed with the FDA.

And investors in Alpine Immune Sciences will look for first clinical data from the Neon-1 trial of ALPN-202, a protein that combines dual checkpoint blockade (PD-L1/CTLA-4) with CD28 co-stimulation. The full impact of this and other clinical presentations will become clearer on April 9.

This year’s AACR conference takes place virtually on April 10-15 and May 17-21. All clinical and late-breaking abstracts appear to have been scheduled for presentation during the first dates.

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