Not so fast for AbbVie in SEZ6

AbbVie raised eyebrows last year when it quickly took its SEZ6-directed ADC turmetabart adizutecan into a pivotal trial in first-line small-cell lung cancer, but now it looks like the focus might be shifting to relapsed/refractory disease.

A second-line phase 3 study has just been listed on clinicaltrials.gov, a few months after the front-line Sezanne trial was downgraded from a phase 2/3 to a phase 2, and its recruitment target slashed. In addition, overall survival is no longer a co-primary endpoint of Sezanne, with the trial now primarily evaluating progression-free survival and adverse events.

In its scaled-back form Sezanne can hardly suffice for a front-line filing. Perhaps regulators put a spanner in AbbVie’s ambitious plans; the decision to move straight from phase 1 to phase 2/3 looked particularly questionable given that the company hadn’t nailed down the optimal dose for turmeta-A, with the study testing two different doses in combination with Tecentriq.

It’s also notable that the changes were made before the trial even began: Sezanne was listed on clinicaltrials.gov in September, overhauled in October, and started in November. It’s set to complete in May 2029, from September 2031 previously.

AbbVie didn't respond to a request for clarification from ApexOnco. On its fourth-quarter call on Wednesday executives only said a phase 2 first-line trial had recently begun, and a phase 3 in the second line was planned. It's possible that moving into a formal first-line pivotal study will depend on phase 2 data from Sezanne.

Relapsed/refractory

Turmeta-A might have a quicker route to market via the new relapsed/refractory trial, which is slated to start in April and is known as M23-384.

That study will enrol patients progressed on checkpoint inhibitors, if eligible, and Amgen’s DLL3-targeting T-cell engager Imdelltra. Patients will be randomised to either turmeta-A or standard of care: topotecan, Zepzelca, or amrubicin. The primary endpoints are overall response rate and overall survival, and the study is set to complete in September 2030.

A phase 1 trial of turmeta-A produced ORRs of 56% and 59%, and median PFS of 6.8 and 5.6 months at 1.8mg/kg and 2.5mg/kg respectively in relapsed/refractory SCLC. On a cross-trial basis, this looks better than the 35% and 4.2 months seen in Dellphi-304, the confirmatory second-line trial of Amgen’s approved DLL3-targeting T-cell engager Imdelltra.

However, it’s notable that AbbVie isn’t pitting turmeta-A against Imdelltra, but instead is focusing on post-Imdelltra patients. Perhaps the company is being pragmatic in a fast-evolving SCLC space. Imdelltra’s recent full FDA approval in second-line disease has caused problems for another DLL3 hopeful, Zai Lab, raising questions about whether the accelerated approval path is still open for that company’s project, zocilurtatug pelitecan.

The pivotal study of zoci-P had been set to include Imdelltra as an option in the control arm, but the current listing only gives topotecan, Zepzelca, or amrubicin as options. ApexOnco understands that Zai has now chosen to enrol both second-line, post-chemo patients, and third-line, post Imdelltra-patients, because of the limited availability of Imdelltra in countries outside the US. 

The Amgen drug could also be heading to the front line, with the Dellphi-305, 306 and 312 studies set to start reading out from next year.

As for competition in SEZ6, turmeta-A is the only clinical-stage asset with this target, according to OncologyPipeline, although various preclinical projects are in preclinical development, including bispecific ADCs from Biocytogen and Shanghai Affinity Biopharmaceutical. 

Mid to late-stage trials of turmetabart adizutecan in SCLC

Notes: CPI=checkpoint inhibitor; ES=extensive stage. Source: OncologyPipeline & clinicaltrials.gov.