AACR 2024 preview – clinical highlights and lowlights

Clinical trial results selected for oral presentation at the upcoming AACR conference include AstraZeneca’s shot at selective PARP1 inhibition and a new battleground for Merck & Co’s Kelun-derived anti-TROP2 conjugate sacituzumab tirumotecan, abstract titles unveiled yesterday reveal.

The abstract drop also shows that two clinical setbacks will be discussed at a high-profile clinical trials plenary, one on Crispr’s now discontinued anti-CD70 Car-T asset CTX130, and the other on Tecentriq’s Imvoke-010 study, whose failure Roche quietly slipped out last month. And Krazati’s Krystal-1 update will be of note given that drug’s recent US filing for colorectal cancer.

Krystal-1’s KRAS G12C-mutated colorectal cancer cohort last had data at ESMO 2022, with an Erbitux combo yielding ORR of 46%, albeit in just 28 patients. Progress has been slow – Bristol Myers Squibb only recently filed, giving a 21 June PDUFA date – and though Krazati has long looked like a leading asset in colorectal cancer it now faces formidable clinical competition from Roche’s divarasib.

For now it’s unclear how much new data AACR will hear, or indeed whether the US filing comprises just those 28 patients. The only AACR abstracts available in full concern preclinical studies, and sessions with clinical data, including the plenary, minisymposia and posters, remain under wraps until 5 April.

One clinical trial minisymposium will discuss another KRAS approach, namely Nitto’s siRNA asset NBF-006, which targets GSTP (glutathione S-transferase pi) in KRAS-mutant lung cancer.

TROP2 and PARP1

Perhaps more prominent will be phase 2 data at this session on Merck/Kelun’s sacituzumab tirumotecan in gastric/gastroesophageal junction cancer; this asset is vying against Daiichi Sankyo/AstraZeneca’s datopotamab deruxtecan in the anti-TROP2 ADC space, and is in phase 3 in breast, lung and endometrial cancers.

In PARP1 inhibition, a field that saw Gilead acquire Xinthera last year, AstraZeneca has a leading presence with two projects, saruparib and the brain-penetrant AZD9574. AACR will hear more data from the former’s first-in-human Petra study, which at AACR two years ago showed a 28% ORR in solid tumours.

AACR 2024: selected clinical trials plenaries & minisymposia

Source: AACR.

Given the amount of clinical trials selected for discussion at AACR it might seem surprising that three failures have been given prominence.

At its fourth-quarter presentation Roche revealed that the Imvoke-010 study of Tecentriq in adjuvant head and neck cancer had failed – perhaps not a surprising outcome given the relative intractability of this cancer type for PD-(L)1 blockade. Imvoke-010 will be discussed at a 7 April clinical trial plenary.

The same session will hear a post-mortem of the Cobalt-RCC study of Crispr’s CD70-directed Crispr/Cas9-edited allogeneic Car-T asset CTX130 in renal cell cancer. Last December Crispr discontinued CTX130 in favour of a follow-on project, CTX131, which includes additional knockouts of Regnase-1 and TGFBR2. A separate allogeneic anti-CD70 Car, ALLO-316, remains in development by Allogene.

And a third dud, the failed Keylynk-008 study of Keytruda combined with Astra/Merck & Co’s Lynparza and chemo in first-line squamous NSCLC, will be discussed at an AACR clinical minisymposium. Backing for such a combo in NSCLC was always weak, so the fact Keylynk-008 failed was perhaps less surprising than the fact such a phase 3 trial was undertaken to begin with.

The 2024 AACR meeting takes place in San Diego on 5-10 April.