Today, Eli Lilly and Company (Lilly) announced that the National Institute for Health and Care Excellence (NICE) has published final draft guidance recommending pirtobrutinib for use on the NHS in England and Wales as an option to treat relapsed or refractory chronic lymphocytic leukaemia (CLL) in adults who have had a Bruton’s tyrosine kinase (BTK) inhibitor, only if:
- retreatment with a covalent BTK inhibitor (including after fixed-duration regimens) is not clinically appropriate
- the company provides it according to the commercial arrangement.i
Pirtobrutinib will now be available to eligible patients in England within 30 days, and within 60 days in Wales.
“This approval represents a critical step forward in expanding treatment options for patients living with CLL,” said Toby Eyre, Consultant Haematologist, Oxford University Hospital NHS Foundation Trust. “As a newly approved treatment option in this patient population, pirtobrutinib builds on the progress of BTK inhibition and provides an additional treatment option for patients in the UK with relapsed or refractory CLL, particularly in the post-covalent BTK inhibitor setting.”
Peter Allen (pictured), Chair of Trustees, CLL Support Association, said: “For people living with chronic lymphocytic leukaemia (CLL), the availability of additional treatment options can make a difference. Every new option means greater choice for patients and their healthcare teams. We know how important it is for treatments like this to reach eligible patients.”
“This treatment for eligible adults living with relapsed or refractory CLL following progression on a covalent BTK inhibitor in the UK, provides an option for patients with limited treatment alternatives,” said Holly Thomas, Associate Vice-President of Specialty Care, Lilly UK & Ireland.
CLL
This recommendation is based on positive results from the BRUIN CLL-321 clinical trial, the first randomised Phase 3 study in CLL in patients previously treated with a BTK inhibitor. The trial enrolled 238 patients with CLL/SLL. Baseline characteristics were similar between treatment arms. Overall, the median age was 67 years (range: 42 to 90 years), 70% were male and 81% were White. Baseline ECOG performance status was 0 or 1 in 93% of patients and 44% of patients had Rai stage III or IV disease. Among those patients with central testing available, 57% (101 of 176 patients) had 17p deletion and/or TP53 mutation, 86% (164 of 190 patients) had unmutated IGHV, and 65% (97 of 149) had complex karyotype[ii].
The study’s primary endpoint of progression-free survival (PFS) was met at the prespecified time of final analysis (Aug. 29, 2023), based on independent review committee (IRC) assessment, demonstrating pirtobrutinib was superior to investigator’s choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR)iii . At an updated descriptive analysis (Aug. 29, 2024), with a median follow-up of 19.4 months (range 0.03 to 33.3 months) for pirtobrutinib and 17.7 months (range 0.03 to 27.9 months) for the investigator’s choice arm, improved IRC-assessed PFS was observed with pirtobrutinib compared to the investigator’s choice arm, consistent with the primary analysis (median PFS: 14.0 (95% CI: 11.2, 16.6) vs. 8.7 months(95% CI: 8.1, 10.4)). Overall survival was a key secondary endpoint, with a median follow up time of 20.4 months for pirtobrutinib and 19.2 months in investigator’s choice arm. Median OS was 29.7 months (95 % CI: 27.1, NE) in the pirtobrutinib arm and not reached in the investigator’s choice arm. The HR was 1.090 (95% CI: 0.679, 1.749; p = 0.7202). OS analysis may be confounded by the 50 out of 119 patients who crossed over from the investigator’s choice arm to pirtobrutinib.ii
Summary of the safety profile
Of the 1153 patients treated with pirtobrutinib across all trials, the most common adverse reactions of any grade (in ≥20 % of patients) were neutropenia (27.4%) and haemorrhage (20.4%). The most common severe (Grade ≥ 3) adverse reactions (in ≥5 % of patients) were neutropenia (22.8 %), anaemia (9.0 %), pneumonia (8.8%), and thrombocytopenia (7.2%). The frequency of treatment discontinuations due to adverse reactions was 3.3% and the most common adverse reaction leading to treatment discontinuation was pneumonia (0.8 %). The frequency of dose reductions due to adverse reactions was 4.3% and the most common adverse reaction leading to dose reduction was neutropenia (2.4%). Serious adverse reactions associated with pirtobrutinib have occurred in 18.0% of patients and the most common serious adverse reactions (in ≥1% of patients) were pneumonia (8.2%), haemorrhage (2.9%), neutropenia (2.6%), anaemia (2.4%), atrial fibrillation/atrial flutter (1.1%) and urinary tract infection (1.0%). Fatal adverse reactions have been observed in 0.7% of patients for pneumonia, in 0.3% of patients for haemorrhage and in 0.1% of patients for urinary tract infection.ii
About pirtobrutinib
Pirtobrutinib (formerly known as LOXO-305) is a non-covalent (reversible) inhibitor of the enzyme BTK.[iii] BTK is a validated molecular target found across numerous B-cell leukaemias and lymphomas including mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL).[iv],[v] Pirtobrutinib is an oral prescription medicine, 100 mg or 50 mg tablets taken as a once-daily 200 mg dose with or without food until disease progression or unacceptable toxicity.
About Chronic Lymphocytic Leukaemia (CLL)
CLL is a form of slow-growing non-Hodgkin lymphoma that develops from white blood cells known as lymphocytes.CLL is one of the most common types of leukaemia in adults.[vi],[vii] There are roughly 100,000 new cases of CLL globally each year, [viii] and around 4,000 new chronic lymphocytic leukaemia cases in the UK every year.[ix] The overall incidence of CLL in Europe is approximately 4.92 cases per 100,000 persons per year.[x]
▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: website –https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.
References
[i] Project information | Pirtobrutinib for treating relapsed or refractory chronic lymphocytic leukaemia after a BTK inhibitor [ID6269] | Guidance | NICE
[ii] Jaypirca 100 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 101263 Available at https://www.medicines.org.uk/emc/product/101263/smpc
[iii] Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5
[iv] Hanel W, Epperla N. Emerging therapies in mantle cell lymphoma. J Hematol Oncol. 2020;13(1):79. Published 2020 Jun 17. doi:10.1186/s13045-020-00914-1
[v] Gu D, Tang H, Wu J, Li J, Miao Y. Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies. J Hematol Oncol. 2021;14(1):40. Published 2021 Mar 6. doi:10.1186/s13045-021-01049-7
[vi] Mukkamalla SKR, Taneja A, Malipeddi D, et al. Chronic Lymphocytic Leukemia. [Updated 2023 Feb 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470433/
[vii] The Leukemia and Lymphoma Society. NHL Subtypes.
Available from: https://www.lls.org/lymphoma/non-hodgkin-lymphoma/nhl-subtypes
[viii] Ou Y, Long Y, Ji L, et al. Trends in Disease Burden of Chronic Lymphocytic Leukemia at the Global, Regional, and National Levels From 1990 to 2019, and Projections Until 2030: A Population-Based Epidemiologic Study. Front Oncol. 2022;12:840616. Published 2022 Mar 10. doi:10.3389/fonc.2022.840616
[ix] Cancer Research UK. Chronic lymphocytic leukaemia (CLL statistics). Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/leukaemia-cll#Chronic_lymphocytic_leukaemia_stats
[x] Sant M, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010. 116:3724–34. Available from: https://pubmed.ncbi.nlm.nih.gov/20664057/
