Bristol-Myers advances new LAG-3 drug relatlimab to fight PD-1 resistance

The wave of immuno-oncology treatments that hit the market in 2015 have transformed the standard of care—for some patients. Many don’t respond. And even those who respond can develop resistance along the way. The drugs simply stop working.

What’s the solution? Combination therapies—and that’s why scientists are digging deeply into the tumor microenvironment for targets that could lead to add-on meds. And that’s the idea behind Bristol-Myers Squibb’s BMS-986016, now moving into late-stage development.

Now dubbed relatlimab, the drug targets LAG-3, a protein that not only helps boost T-cell activity against tumors but put the brakes on other T-cells that can suppress it. Bristol-Myers is testing it in combination with its PD-1 therapy Opdivo.

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“For LAG-3 positive tumors cells, the response rate triples,” said Fouad Namouni, Bristol-Myers’ head of oncology, in a Friday interview. 

A phase 1/2a study in melanoma patients who hadn’t responded or became resistant to immunotherapies—many of them on their third round of treatment—showed that 18% of LAG-3 positive patients responded to the dual therapy, compared with 5% of those whose LAG-3 expression amounted to less than 1%. The data, rolled out at the European Society for Clinical Oncology Congress in Madrid over the weekend, are an update to numbers presented in May at the American Society of Clinical Oncology meeting.

Further confirming that LAG-3 is a valid target was an important outcome of the latest analysis, of course, but safety with combination approaches is always a worry. In this case, the side effects of the pairing were in line with Opdivo’s when used alone, with 10% of patients dropping out as a result of severe side effects, lead author Paolo Ascierto, a researcher at the National Tumor Institute in Italy.

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LAG-3 is just one of the new targets drugmakers are studying. More biomarkers in several categories are in early research at BMS, and the company is putting its pocketbook behind the work. “Biomarkers is a major investment field for us,” Namouni said. “This is really the tip of the iceberg.” 

Ascierto, like many scientists hoping to help generate precision cancer treatment, said testing drugs and evaluating tumors after treatment is essential for learning more about “the biology of the tumor and mechanisms of resistance.”

“We are learning the full picture of tumors with different markers,” Ascierto said during a panel talk convened by BMS Friday, rattling off a list of acronyms under study: TMB, IDO, PD-1, LAG-3. Ultimately the idea is to use multiple biomarkers to choose the right combination for patients. “This is the way of personalizing treatment.”

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Take Incyte’s IDO1 med epecadostat, which grabbed a lot of attention at ESMO (though not all of it good) with its Keytruda combo data. Merck has a collaboration with Incyte on combo testing, and Bristol-Myers forged its own deal with the company to test Opdivo with epecadostat in three different cancers earlier this year.

Bristol-Myers has its own IDO in the pipeline, too, acquired along with Flexus in 2015. Researchers presenting data on that med at the American Association for Cancer Research meeting in April were enthusiastic: Lillian Siu, lead investigator, called it a potential best-in-class IDO1.

Incyte might dispute that assertion. But in any case, that company’s Echo-202 presentation, on a melanoma cohort, gave further substance to IDO1 as a target, Leerink analyst Michael Schmidt said in a Monday note.

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The presenter “highlighted the strong mechanistic rationale to combine IOD1 inhibitors with PD-1 inhibitors which explains why the combination of these agents work best in similar patient subsets (anti-PD1-responsive cancers, PDL1+ patients),” Schmidt wrote after the data unveiling.

Meanwhile, on the LAG-3 side, relatlimab will be moving into later-stage trials. Bristol-Myers doesn’t have the timing nailed down yet, but the first indication will be in melanoma, Vicki Goodman, head of new asset development, said.

“There’s clearly evidence of activity,” Goodman said, “where we see patients clearly had disease progression after PD-1 therapy, and add in LAG-3 in patients with that expression on the tumor.”