A drug for patients who have become resistant to marketed members of a class of therapies commonly used to treat certain blood cancers has shown broad activity in patients, regardless of whether they harbor a mutation believed to promote that resistance.
Indianapolis-based Eli Lilly & Co. unveiled interim, dose-escalation data Sunday on LOXO-305, a BTK inhibitor, in patients with chronic lymphocytic leukemia and non-Hodgkin’s lymphomas. The data, from the Phase I/II BRUIN study, were presented at the American Society of Hematology’s annual meeting in Orlando, Florida. The drug was developed by Loxo Oncology at Lilly, which Lilly acquired for $8 billion in January. Loxo itself acquired the drug in July 2017, when it bought U.K.-based Redx Pharma for $40 million, which had originally created it.
The presentation included 28 patients treated once daily at 25mg, 50mg, 100mg, 150mg or 200mg, including 16 who had CLL and 12 with NHL, specifically mantle cell lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma and Waldenstrom’s macroglobulinemia. A majority of patients – 75% of those with CLL and 88% of those with MCL – had received at least one prior BTK inhibitor; overall, CLL patients received a median of four prior therapies, while MCL patients had received a median of three. Marketed BTK inhibitors include AbbVie and Johnson & Johnson’s Imbruvica (ibrutinib), AstraZeneca’s Calquence (acalabrutinib) and BeiGene’s Brukinsa (zanubrutinib).
So far, no maximum tolerated dose has been reached. In a phone interview, Loxo Chief Medical Officer Jacob Van Naarden said the company will continue to dose escalate and has also not yet identified a recommended dose for further development. “Our goal is not to take too long in declaring what that dose is,” he said.
Among 13 CLL patients evaluable for response, there were eight partial responses and two partial responses with ongoing elevated white blood cell counts that are a sign of the disease. Six MCL patients were evaluable for responses, among whom one patient had a complete response and two had partial responses.
The aforementioned marketed BTK inhibitors are covalent, and while they’re effective, patients eventually develop resistance, rendering them ineffective. LOXO-305 is based on the thinking that a non-covalent BTK inhibitor would be able to overcome resistance, particularly in those patients who have a mutation known as C481, which is a putative mechanism of resistance to the covalent drugs. Nevertheless, the data presented Sunday found that patients responded regardless of C481 status.
Whether the company will end up developing a companion diagnostic for the drug depends on what the data show with respect to responses and C481 status. “If we accrue a larger data set that clusters in mutated patients, we will develop a companion diagnostic,” Van Naarden said. “But if activity remains as broad as it seems so far, then a companion diagnostic may not be necessary.”
Just as patients become resistant to other BTK inhibitors, they likely will develop resistance to LOXO-305 as well, though Van Naarden said that hasn’t been observed yet. For the time being, he said, the data allow the company to think about potential combination strategies, such as with BCL2 inhibitors like AbbVie’s Venclexta (venetoclax) or chemotherapy, as well as disease settings beyond salvage treatment.
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