Eli Lilly has launched four randomized phase 3 studies for its noncovalent BTK inhibitor pirtobrutinib in chronic lymphocytic leukemia alone.
A new BTK inhibitor could be in town soon. With a different construct compared with the three incumbents, the Eli Lilly candidate is angling for a unique treatment setting.
Eli Lilly offered updated analyses of BTK inhibitor pirtobrutinib in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL), as well as the first sizable cohorts of Waldenström macroglobulinemia and Richter transformation, at the American Society of Hematology (ASH) 2022 annual meeting. The drug’s proposed use in MCL is expecting FDA decision in January.
Existing BTK inhibitors, namely AbbVie and Johnson & Johnson’s Imbruvica, AstraZeneca’s Calquence and BeiGene’s Brukinsa, are all vying for market share in newly diagnosed patients, mainly in CLL/SLL. But Lilly sees “a real opportunity” for pirtobrutinib to treat those who’ve failed one of those current BTK drugs, Jake Van Naarden, CEO of Lilly’s oncology unit Loxo, said in an interview with Fierce Biotech.
Lilly is testing pirtobrutinib in front-line settings. “Over time, physicians may want to use the drug in the first line. That’s great,” Van Naarden said. “That’s not the core value proposition of the drug.”
The three currently marketed products are covalent BTK inhibitors. How these drugs block BTK in an irreversible manner means they can’t really be used sequentially in patients who’ve failed one another. But as a nonvalent, reversible BTK inhibitor, pirtobrutinib can reintroduce long-lasting responses in those BTK-experienced patients, Van Naarden said.
And Van Naarden has clinical data to back his statement. Pirtobrutinib shrank tumors in 82.2% of a group of 247 previously treated CLL/SLL patients in the phase 1/2 BRUIN trial, according to data presented Monday at ASH 2022. The patients had previously all received a BTK inhibitor and had tried a median three prior lines of therapy.
Among 100 patients who had tried both a BTK inhibitor and a BCL2 inhibitor like AbbVie and Roche’s Venclexta, pirtobrutinib’s response rate came in at 79% after a median follow-up of 18.2 months. This subgroup of patients had a median five prior lines of therapy.
Pirtobrutinib kept patients alive without disease progression for a median 19.6 months in the larger group and for a median 16.8 months in the BTK/BCL2-experienced subgroup.
As for the MCL patients in the BRUIN trial, pirtobrutinib showed an overall response rate of 57.8% in patients who had received a prior BTK inhibitor and of 85.7% in BTK inhibitor-naïve individuals, according to data presented at ASH 2022.
Compared with covalent BTK inhibitors, nonvalent reversible BTK drugs are potentially safer. In all dosed patients in the phase 1/2 BRUIN study, including those with MCL and others, treatment-related hypertension happened in 3.4% of patients, including 0.6% at grade 3 or above, and treatment-related atrial fibrillation and flutter were recorded in 0.8% of patients, including 0.1% grade 3 or above cases. Overall, 20 patients (2.6%) discontinued because of treatment-related side effects.
By comparison, BeiGene’s Brukinsa, which touts a safety edge over Imbruvica in a head-to-head CLL/SLL trial dubbed ALPINE, posted a treatment-related discontinuation rate of 16.2% in second-line patients. And Brukinsa had a 5.2% rate of atrial fibrillation and flutter.
While three BTKs jostle against each other in front-line CLL, Lilly could have patients who relapsed on a BTK all to itself at least for a while. But the question is, just how many patients would live long enough to reach pirtobrutinib? Van Naarden’s answer was almost all of the front-line patients.
“There’s this idea out there that patients [who] start a BTK inhibitor in first line will die of something other than their CLL because it’s an elderly population. That’s not really true,” Van Naarden said. The Loxo chief noted that the phenomenon was perhaps true when BTK drugs were first introduced into a relatively late-line setting. But now, patients in the first line are around late 60s or early 70s and could be on first-line treatment for about five years.
“Those patients aren’t dying of other things. They just need new therapy,” Van Naarden said. “Eventually we think the vast majority—if not all—of these patients will eventually need something new.”
RELATED: ASH: AbbVie, J&J's Imbruvica under serious threat as BeiGene's Brukinsa delivers head-to-head trial win
Besides the phase 1/2 BRUIN study, Lilly has launched four randomized phase 3 studies in CLL alone. The one closest to a readout is BRUIN-CLL-321, which compares pirtobrutinib monotherapy against investigator’s choice of therapy in post-BTK inhibitor patients, which reflects, as Van Naarden put it, “the core proposition” of the drug.
BRUIN-CLL-322 is adding pirtobrutinib on top of a regimen of Venclexta and Rituxan also in pretreated patients to reflect clinical practice in certain patients, Van Naarden explained. The patients may or may not have received a BTK inhibitor.
In a similar study as Brukinsa’s SEQUOIA trial, BRUIN-CLL-313 is pitting the Lilly drug alone against bendamustine and Rituxan in treatment-naïve CLL/SLL. And a fourth study is a head-to-head study between pirtobrutinib and Imbruvica.
