ASCO 2024 preview – jury still out on AbbVie's cancer push

AbbVie signalled its intent in antibody-drug conjugates when it bought ImmunoGen for $10bn late last year, but it already had various ADC efforts ongoing – and three of these will feature at this year’s ASCO meeting.

Perhaps most notable is the next-generation SEZ6-targeting ADC ABBV-706, which will yield first-in-human data at the conference, not long after AbbVie dumped its similarly acting predecessor. A 40% ORR in second-line or later small cell lung cancer, detailed in a just released ASCO abstract, looks in line with that seen with Amgen’s recently approved anti-DLL3 drug Imdelltra on a cross-trial basis.

Separately, AbbVie is doubling down on cMet, and data on two ADCs against this target, telisotuzumab vedotin and ABBV-400, are set to be presented. The company is keen to take both forward, the company told ApexOnco, but a fly in the ointment could be toxicity: there were two treatment-related deaths in the Luminosity trial of teliso-V, while adverse event rates also look high with ABBV-400. 

AbbVie’s ASCO ADCs

Notes: *data previously reported by AbbVie in Nov 2023; CRC=colorectal cancer; NEN=neuroendocrine neoplasm; NSCLC=non-small cell lung cancer; SCLC=small-cell lung cancer. Source: ASCO abstracts & OncologyPipeline.

AbbVie Sez

Last August AbbVie abandoned its previous effort at targeting SEZ6, with the Stemcentrx-originated ABBV-011. But it still clearly believes in this target, despite a search of OncologyPipeline showing no other SEZ6-directed projects in development.

In an email interview ahead of the ASCO abstract drop, AbbVie's vice-president of solid tumour pipeline strategy and execution, Pedro Valencia, noted a couple of reasons why ABBV-706 might be more efficacious than ABBV-011, which yielded a 25% ORR in a phase 1 trial in relapsed/refractory SCLC. For one, ABBV-706 delivers a topoisomerase 1 inhibitor, a currently popular payload, while ABBV-011 used a calicheamicin. Secondly, ABBV-706 is said to employ a more stable linker.

The latest clinical data, although in a small number of SEZ6-unselected patients in the dose-escalation portion of a phase 1 trial, suggest that ABBV-706 is indeed an improvement. The confirmed ORR of 40% in SCLC jumped to 73% when unconfirmed responses were also included. With updated results to be presented at ASCO, “we anticipate that some of these unconfirmed responses will become confirmed”, Valencia said.

Any improvement would see ABBV-706 exceed the bar set in relapsed SCLC by Amgen’s tarlatamab, now branded Imdelltra, which was granted accelerated approval last week based on a 40% ORR in the Dellphi-301 trial.

As well as the novel target, reasons to be cautious about ABBV-706 include two cytopenia-related dose-limiting toxicities, seen at 3.0mg/kg and 3.5mg/kg. AbbVie deemed such events “manageable”, especially as it moves into the dose-expansion portion of the trial, but didn’t disclose which dose(s) it will be testing here.

The study will also evaluate ABBV-706 alongside AbbVie's PD-1 inhibitor budigalimab, carboplatin or cisplatin.

Teliso-V deaths

In cMet targeting things look less rosy. Last year AbbVie toplined data from the Luminosity trial of its lead project here, teliso-V, showing a waning response rate in second-line cMet-overexpressing, EGFR wild-type non-squamous NSCLC – with the best results seen in cMet-high patients.

The ASCO abstract reaffirms these numbers, but also notes two patient deaths, from interstitial lung disease and respiratory failure. In its November press release AbbVie had only said that the safety profile of teliso-V “was consistent with previous findings, and no new safety concerns were identified”. 

At ASCO 2022, a previous analysis of Luminosity in 136 patients reported two patient deaths, but these occurred in the squamous cohort, and were attributed to sudden death and pneumonitis. 

AbbVie notes that it hasn't "seen any change to that low rate in the updated dataset".

The company has previously said it hopes to file teliso-V for accelerated approval later this year, but Valencia would not be drawn on timelines, only saying that discussions with regulators are ongoing. A phase 3 NSCLC study, Telimet NSCLC-01, is under way, and could act as the confirmatory trial.

AbbVie estimates that around a quarter of advanced EGFR wild-type NSCLC patients overexpress cMet. However, its ADC rival Mythic reckons teliso-V can only hit the 10% of these patients with the highest expression levels; that group is developing a project that, it hopes, will be effective in cMet-intermediate and perhaps even low expressers. 

Two cMet strands

While the focus for teliso-V is lung cancer, AbbVie is aiming for a different use with its next-gen cMet project, ABBV-400: colorectal cancer.

The company says it “has confidence in both” assets, noting their differences, most notably in their payloads. Teliso-V employs the tubulin inhibitor monomethyl auristatin E, while ABBV-400 delivers a topoisomerase 1 inhibitor. 

However, it’s unclear whether this has given ABBV-400 an edge over teliso-V. The latest data come from 113 colorectal cancer patients in the dose-escalation and expansion portions of a phase 1 solid tumour study. The patients had received a median of four prior therapies, and don't appear to have been selected for cMet expression.

Across three doses, 1.6mg/kg, 2.4mg/kg and 3.0mg/kg, the ORR was just 12%. However, focusing on the two higher doses gave an ORR of 17% – and patients with high cMet expression receiving these had an ORR of over 30%, the abstract notes.

Again, however, there is toxicity, with 64% of patients experiencing grade 3 or higher treatment-emergent adverse events, most frequently anaemia and neutropenia. AbbVie might choose to focus on the apparently more tolerable 2.4mg/kg dose, but could take a hit in terms of efficacy.

The group says it will give more details on a planned phase 3 trial in third-line colorectal cancer “in the near future”. 

The ASCO annual meeting takes place in Chicago on 31 May to 4 June.