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FDA Approves Pirtobrutinib for First-Line CLL/SLL Treatment
Confirmed
In Short: The FDA has approved pirtobrutinib (Jaypirca) for adults with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without 17p deletion.
The FDA has approved pirtobrutinib (Jaypirca; Eli Lilly) for adults with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with no known 17p deletion, according to an announcement from the agency and a news release from Eli Lilly and Company.
This expanded indication comes 10 months after the FDA granted traditional approval to pirtobrutinib for adults with relapsed or refractory CLL/SLL previously treated with a covalent BTK inhibitor, converting a December 2023 accelerated approval.
The approval is based on the phase 3 BRUIN CLL-313 trial, a randomized, open-label, active-controlled study of 282 adults with previously untreated CLL/SLL without 17p deletion.
Patients were randomized 1:1 to pirtobrutinib 200 mg orally once daily until disease progression or unacceptable toxicity (n = 141) or to 6 cycles of bendamustine plus rituximab (BR; n = 141).
With an estimated median follow-up of 28 months, the primary end point of progression-free survival (PFS) assessed by an independent review committee significantly improved with pirtobrutinib vs BR (HR, 0.20; 95% CI, 0.11-0.37; P <.0001).
The overall response rate was 94% with pirtobrutinib and 81% with BR, although complete responses were more frequent in the BR arm (21% vs 13%).
At a median follow-up of about 28 months, pirtobrutinib reduced the risk of progression or death by 80% versus bendamustine/rituximab (HR 0.20; p<0.0001), with median progression-free survival not reached compared with 33.5 months in the control arm.
Serious adverse reactions occurred in 28% of patients receiving pirtobrutinib, while 4.3% discontinued treatment because of adverse reactions.
Pirtobrutinib is a reversible, non-covalent BTK inhibitor that binds independently of the C481 residue, allowing it to retain activity against C481-mutated BTK associated with resistance to covalent BTK inhibitors.
The most common adverse events in the pirtobrutinib arm were upper respiratory tract infections (27%), rash (22%), and COVID (21%).
Jennifer A. Woyach, MD, director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center, said, “Doctors can now consider pirtobrutinib for appropriate patients when initial therapy is needed, not just later in a patient's treatment journey.”
The expanded indication establishes pirtobrutinib as an initial targeted option prior to disease progression or exposure to standard covalent BTK inhibitors.
What this adds
The approval allows pirtobrutinib to be used earlier in the treatment course, providing a non-covalent BTK option earlier in the treatment pathway.
Blood test abnormalities that worsened from the start of treatment included decreased neutrophils, increased bilirubin, increased ALT, decreased hemoglobin, and increased sodium.
What's confirmed
- The FDA has approved pirtobrutinib (Jaypirca; Eli Lilly) for adults with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with no known 17p deletion, according to an announcement from the agency and a news release from Eli Lilly and Company. 1,2 The decision makes the noncovalent Bruton tyrosine kinase (BTK) inhibitor available as a first-line treatment option for appropriate patients.
- The expanded indication comes 10 months after the FDA granted traditional approval to pirtobrutinib for adults with relapsed or refractory CLL/SLL previously treated with a covalent BTK inhibitor, converting a December 2023 accelerated approval. 3 “This approval is grounded in data from BRUIN CLL-313, which showed a significant delay in disease progression for pirtobrutinib compared to chemoimmunotherapy, along with safety and tolerability consistent with its established profile,” Jennifer A.
- Woyach, MD, director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center, said in the Eli Lilly and Company news release. 2 The approval is based on the phase 3 BRUIN CLL-313 trial ( NCT05023980 ), a randomized, open-label, active-controlled study of 282 adults with previously untreated CLL/SLL without 17p deletion. 1 Patients were randomized 1:1 to pirtobrutinib 200 mg orally once daily until disease progression or unacceptable toxicity (n = 141) or to 6 cycles of bendamustine plus rituximab (BR; n = 141).
- Results were published in the Journal of Clinical Oncology. 4 With an estimated median follow-up of 28 months, the primary end point of progression-free survival (PFS) assessed by an independent review committee significantly improved with pirtobrutinib vs BR (HR, 0.20; 95% CI, 0.11-0.37; P <.0001).
- "Doctors can now consider pirtobrutinib for appropriate patients when initial therapy is needed, not just later in a patient's treatment journey,” Woyach said. 2 “Given the efficacy and tolerability of modern targeted therapies—coupled with factors like age or comorbidity—many people diagnosed with CLL or SLL today may only receive 1 or 2 lines of therapy, making initial treatment choices critically important." 1.
- 1 The overall response rate was 94% with pirtobrutinib and 81% with BR, although complete responses were more frequent in the BR arm (21% vs 13%).
- At a median follow-up of about 28 months, pirtobrutinib reduced the risk of progression or death by 80% versus bendamustine/rituximab (HR 0.20; p<0.0001), with median progression-free survival not reached compared with 33.5 months in the control arm.
- Median overall survival was not reached in either group, with three deaths in the pirtobrutinib arm and 10 with BR.
- Pirtobrutinib is a highly selective non-covalent BTK inhibitor that binds both wild-type and C481-mutated BTK.
- After a median follow-up of 28 months, topline data showed that the median progression-free survival (PFS) was not estimable (NE; 95% CI, NE-NE) with pirtobrutinib vs 33.5 months (95% CI, 32.7-NE) with bendamustine/rituximab.
What's still developing
- With the new indication, pirtobrutinib joins the covalent BTK inhibitors acalabrutinib, zanubrutinib, and ibrutinib, as first-line CLL/SLL options.
- Unlike pirtobrutinib, their indications do not exclude patients with chromosome 17p deletions.
- Still, Lilly says pirtobrutinib has an advantage over its covalent BTK rivals: As a noncovalent inhibitor, its reversible binding allows it to retain activity against BTK mutations that can drive resistance to acalabrutinib, zanubrutinib, and ibrutinib.
- A separate phase III trial, BRUIN CLL-314, is comparing pirtobrutinib directly with ibrutinib in a BTK inhibitor-naive population that includes both treatment-naive and previously treated patients.
- Approved on October 2, 2026, this decision authorizes pirtobrutinib as a first-line monotherapy option for eligible treatment-naïve patients.
- A 17p deletion occurs when part of chromosome 17 is missing.
- “The FDA’s approval of pirtobrutinib for frontline chronic lymphocytic leukemia/small lymphocytic lymphoma is an important advancement for people facing this disease,” said Meghan Gutierrez, Chief Executive Officer of the Lymphoma Research Foundation.
- Crossover from the control arm to pirtobrutinib monotherapy was allowed upon confirmed disease progression. 2 In total, 18 patients in the control arm crossed over to receive pirtobrutinib monotherapy.
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