One of the most financially successful cancer treatments of the past few years is Imbruvica, a targeted drug approved in the U.S. to treat a common type of leukemia as well as several forms of lymphoma.
Yet, Eli Lilly thinks an experimental drug it acquired in last year's buyout of Loxo Oncology could be safer and, potentially, more effective. In a unusual move, the Indianapolis drugmaker is putting that belief directly to the test, announcing Saturday and on Monday plans to next year start two late-stage clinical trials pitting its treatment against Imbruvica.
The trials, in chronic lymphocytic leukemia and in mantle cell lymphoma, are likely to be expensive and will take time to deliver answers. Should they prove Lilly's drug superior to Imbruvica, the pharmaceutical company's hopes to become a top oncology company would get a major boost. Negative, or even equivocal results would set them back.
"You don't often see major pharmaceutical companies opening these very long expensive trials that they're not guaranteed to win," said David Hyman, chief medical officer at Lilly's Loxo unit, which was kept as its own division after the acquisition.
Lilly's confidence is fueled by results from an early test of the drug, called LOXO-305. Data presented Saturday and Monday at a virtual meeting of the American Society of Hematology showed treatment led to responses in, respectively, 52% of study participants with mantle cell lymphoma and 63% of trial volunteers with chronic lymphocytic leukemia.
The response rates are encouraging, particularly as patients in the trial were sick, having been unsuccessfully treated with other drugs previously. In both the MCL and CLL groups, participants had received a median of three prior treatments. And between two-thirds and three-quarters of patients in each group had their cancers progress after receiving Imbruvica, or another drug that works similarly.
Hyman and the Loxo team think response rates could improve further in CLL as patients are tracked for longer. Median follow-up for the 139 patients evaluated for efficacy was six months. Among 25 who had been followed for 10 months or more, the response rate was 84%.
In MCL, which is a rare and aggressive sub-type of non-Hodgkin lymphoma, the response rate is likely to remain more "bi-modal," said Hyman, with half responding and the other half not.
Even so, LOXO-305 could still be a good option, according to Catherine Diefenbach, a hematologist-oncologist at NYU Langone Health.
"This is exciting because there are not a lot of options for patients who fail [Imbruvica or similar drugs]," said Diefenbach, who was not part of Lilly's study but reviewed the lymphoma data at BioPharma Dive's request.
Notably, there were few signs in Lilly's trial of treatment-related heart effects or hemorrhages, "two of the most feared side effects" with Imbruvica, according to Diefenbach.
Atrial fibrillation was observed in two of the 323 total patients treated with LOXO-305, but in each case was judged unrelated to the drug. One patient had a hemorrhage that, according to a presentation of the data, was sustained during a bicycle accident and ruled unrelated to LOXO-305.
Imbruvica's label cautions doctors to monitor for both hemorrhages and heart arrhythmias, both of which occurred in small percentages of patients studied during clinical testing. A recent viewpoint article in JAMA Oncology, however, raised more serious concerns about the drug's side effects, citing a 2018 study and a review of a World Health Organization safety database.
Twenty percent of participants in Lilly's study experienced fatigue, 17% diarrhea and 13% bruising, the company said.
LOXO-305 "looks pretty well-tolerated," said Diefenbach.
Both Imbruvica and LOXO-305 block a signaling protein called Bruton's tyrosine kinase that is thought to play a key role in the proliferation of cancerous B cells in CLL and MCL.
First approved in 2013, Imbruvica is widely used to treat both cancers and in 2019 earned AbbVie, which sells the drug in the U.S., nearly $4 billion there. Two other BTK inhibitors — Calquence from AstraZeneca and Brukinsa from BeiGene — are now approved in the U.S. as well.
LOXO-305, which binds to BTK in a different way than the other three, is meant to be more selective — a characteristic that Lilly and Loxo think will result in better efficacy and safety. Tightly targeted cancer drugs are Loxo's calling card, an approach proven with the biotech's first drug, approved as Vitrakvi, and its second, cleared this year as Retevmo.
The ASH data show LOXO-305 works well in patients whose cancers developed a certain mutation that lessens the effectiveness of existing BTK inhibitors and, somewhat more unexpectedly, in those without it, too.
"I think most people in the field felt BTK was being maximally inhibited by BTK inhibitors," said Hyman. "Our data show that even in those patients without those resistance mutations, a lot of tumor is still dependent on BTK."
"This is an example of a drug teaching us about a continued cancer dependence that we didn't know before," Hyman added.
In CLL, Lilly will first start two Phase 3 studies in previously treated patients, testing LOXO-305 against common treatment regimens involving the Roche drug Rituxan and either chemotherapy, Gilead's Zydelig or Roche's Venclexta.
A third trial, comparing LOXO-305 head-to-head against Imbruvica in patients not previously treated, will start sometime later next year.
In MCL, Lilly will launch a Phase 3 trial testing LOXO-305 against doctors' choice of Imbruvica, Calquence or Brukinsa in patients who have never received a BTK inhibitor.
Such a large late-stage program would probably have been out of reach for Loxo, had it remained independent. In buying Loxo, Lilly had hoped to pair the biotech's fast-moving research engine with the financial resources it's now channeling into cancer drug development. The aggressive trial strategy with LOXO-305 appears to be one result.
"We're on the precipice of launching a very large and ambitious suite of randomized Phase 3 studies that require operational heft and a lot of capital," said Jacob van Naarden, chief operating officer at Lilly's Loxo unit.
Lilly isn't the only big drugmaker chasing a better BTK inhibitor. Merck, one of the top oncology companies in the industry, last year spent nearly $3 billion to buy ArQule and an experimental BTK inhibitor in mid-stage testing. The pharma is not presenting data on ArQule's drug at ASH.