ASCO: Replacing chemotherapy with ADCs? AbbVie rebuilds next-gen assets after Rova-T flop

A new trend has emerged at this year’s American Society of Clinical Oncology conference: the possibility of replacing decades-old chemotherapy with novel approaches.

“We want to be part of that wave,” AbbVie Pedro Valencia, Ph.D., AbbVie’s vice president of solid tumor pipeline strategy and execution, told Fierce Biotech onsite in Chicago. “This is the ASCO where we show the most antibody-drug conjugate (ADC) data in history for AbbVie.”

“You look back five years ago, ADCs were primarily in the hematology space. Now you're seeing ADCs playing a significant role in solid tumors,” Daejin Abidoye, M.D., head of solid tumors, oncology development, said in a joint interview with Valencia. “If there is, for me, one takeaway, it’s that we expect that over time there will be therapies available for patients that do not include chemotherapy.”

The Illinois-based company shared primary results from a phase 2 study, dubbed Luminosity, evaluating next-gen ADC telisotuzumab vedotin (Teliso-V) in non-small cell lung cancer (NSCLC). The c-Met directed asset is made up of the monoclonal antibody (mAb) telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E.

Among 161 patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC, the overall response rate (ORR) was 28.6%.

“We're pretty encouraged by what we've seen thus far in terms of there was not only a response rate, but the durability of those responses, as well as the overall safety profile,” Abidoye said.

The 28.6% compares to chemotherapy docetaxel, which historically has an ORR of about 15% to 20%, or a slightly higher 20-22% when adding mAb ramucirumab, according to Valencia.

Patients with high c-Met expression had a higher ORR of 34.6% in the phase 2 ADC trial, compared to a 22.9% ORR for patients with intermediate c-met expression.

The data is down from what AbbVie previously shared of the study. A 2022 update, which helped secure a breakthrough designation for Teliso-V, linked the ADC to response rates of 53.8% and 25% in c-Met high and c-Met intermediate patients, respectively.   

The new data reveals two treatment-related patient deaths, one from interstitial lung disease (ILD) and one from respiratory failure.

“ILD has obviously been a concern for a lot of these ADCs, particularly the ones that are being evaluated in non-small cell lung cancer,” Abidoye said. “We do have a ILD adjudication team that's really looking at these cases to better understand which cases are actually treatment related.”

The current general consensus is that the nature of the damage to the lungs coming into the trial might put a person at greater risk of the adverse event.

“For the most part, we see that the safety profile is manageable,” Abidoye added.

Abbvie will look to an ongoing phase 3 trial to better understand the ADC’s safety profile, he explained. The confirmatory study compares Teliso-V to docetaxel in 700 patients with c-Met overexpressing, previously treated NSCLC. A primary readout is slated for mid-2025.

Last November, the pharma said it planned on seeking accelerated FDA approval for the ADC. That’s still the plan, according to Abidoye, who said the company couldn’t provide further comment at this time.

In addition to Teliso-V, AbbVie shared early data from a monotherapy dose escalation portion of a phase 1 trial assessing ABBV-706, a SEZ6 directed ADC, among patients with advanced solid tumors. The pharma also presented early data from a phase 1 dose-escalation and colorectal cancer dose-expansion cohort of ABBV-400, an investigational c-Met directed ADC.

The ADC push follows the failure of AbbVie’s Rova-T, an ADC the pharma picked up in a $5.8 billion buyout of Stemcentrx eight years ago. The pharma let go of its hopes for the asset after several lung cancer trials failed to deliver significant efficacy results.   

AbbVie learned quite a bit from Rova-T, Valencia said, emphasizing that the Stemcentrx platform had a different payload and set of antibodies.

“Since then, we've spent a lot of time trying to find a combination of target linkers, of payloads, that maximizes the therapeutic interface, as opposed to just being very narrow. You have to hit in the right dose before it gets too toxic,” Valencia said.

AbbVie’s next generation of ADCs are carefully engineered to be purified, have very stable linkers, and optimize drug antibody ratios to maximize efficiency, the solid tumor executive said.