ASCO: I-Mab's checkpoint inhibitor drug helper uliledlimab sees early promise in Tecentriq cancer combo test

In the first data drop for the drug, I-Mab has some early positives from a phase 1 trial of its CD73 antibody uliledlimab when wedded to Roche’s Tecentriq.

China’s I-Mab made headlines over the past year for a huge $418 million raise followed swiftly by a $2 billion biobucks pact with AbbVie for its other pipeline asset lemzoparlimab, the biotech’s anti-CD47 monoclonal antibody, which AbbVie is also eyeing as a potential combination med with the blood cancer drug Venclexta.

The data out at ASCO next month, with a peek today via its abstract, isn’t for that drug but rather for I-Mab's earlier effort, the CD73 antibody uliledlimab, from a small phase 1 trial that combined the drug with Roche’s PD-1 checkpoint inhibitor Tecentriq.

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Uliledlimab is, according to the Chinese company, a highly differentiated CD73 antibody with a “unique epitope that confers pharmacological advantages,” with the belief that it can break tumor resistance to immunotherapies like Tecentriq through a combo approach. While most CD73 antibodies in the clinic frequently experienced the "hook effect", where the antibody loses its effectiveness at high concentrations, uliledlimab is designed to unhook this affect, which could increase the therapeutic window and potentially improve clinical outcomes.

The early data is a little light on specifics, as you’d expect, and focused predominately on safety and tolerability, which I-Mab said was clean “with no dose-limiting toxicities,” but did also tease out some efficacy data.

Among the 13 efficacy-evaluable patients, three had complete or partial responses (with an objective response rate of 23%), and three had stable disease (hitting a disease control rate of 46%).

Ahead of the data, analysts at Jefferies said: “We consider ≥20% ORR in the uliledlimab + atezolizumab combo cohort as a favorable outcome, which may lift shares by 10-20%. Looking at the other anti-CD73 programs in early stage trials, they generally achieved a suboptimal ~5%-12% ORR and ~10%-67% SD in refractory advanced solid tumors.” So the data look good.

The clinical activity was seen in both PD-(L)1 treatment naïve and refractory cancer patients, including one partial response (PR) patient who previously failed on Bristol Myers Squibb’s Opdivo.

Those who saw complete or partial responses or stable disease included ovarian clear cell carcinoma, non-small cell lung cancer and “a few other cancers.”

“Higher co-expression of tumor CD73 and PD-L1 was found in all responders compared to that in non-responders, indicating potential correlation between higher CD73 expression and clinical activity of uliledlimab and a potential role of CD73 as a predictive biomarker to warrant further investigation,” said I-Mab in its abstract. 

The plan is now to kickstart a phase 2 test in the U.S. to focus on ovarian cancer and other selected tumor types, Jingwu Zang, M.D., Ph. D, I-Mab’s founder and chair, told Fierce Biotech ahead of the data release.

This will be guided by biomarkers to confirm the efficacy signal observed from the phase 1 study.

The biotech said these trials will “hopefully lead” to a registrational study in an accelerated development timeline, even though “we do not have a specific timeline for potential filling for approval yet in China and the U.S.”

Zang added that for these new tests, the biotech will consider ORR/duration of response (DOR) to be the primary endpoints, but will also add progression-free survival (PFS), and overall survival (OS), which are tougher standards, as “key secondary endpoints” for single-arm studies, while this will be flipped for its placebo-controlled studies.

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Zang said he was “very encouraged” by the early data for the uliledlimab combo, especially as the study was limited to evaluate safety and dose finding and toward efficacy.

“Nevertheless, we are encouraged to see this level of ORR in this group of advanced cancer patients who had exhausted all available therapies [there was an average three lines of therapy prior to entry, half of the patients had failed more than four lines of therapies].”

He said that one patient with CR has been in the study for 17 months, while the one with a PR had failed repeated PD-1 therapy.

This level of ORR is, according to Zang, “significant” compared to other combo therapies, adding that in a similar phase 1a dose escalation study of TIGIT antibody in combination with PDL-1 antibody, no CR or PR was observed in 24 cancer patients, though he didn’t name the drug or study.

Looking around at previous trials, however, we can see that Bristol Myers Squibb’s BMS-986179 in combination with Opdivo showed just 11.9% (7/59) PR and 16.9% (10/59) stable disease (SD) in pre-treated advanced solid tumors.

AstraZeneca’s MEDI9447 plus Imfinzi has also shown just 4.8% (1/21) PR and 9.5% (2/21) SD in refractory colorectal cancer and 10% (2/20) PR and 15% (3/20) SD in patients with pancreatic cancer in the phase 1 expansion cohort.