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Verzenios ® (abemaciclib)
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How should ILD/pneumonitis with Verzenios® (abemaciclib) be managed in early breast cancer?
Persistent or recurrent Grade 2 toxicity was managed with dose suspension until toxicity resolved to baseline or Grade 1, while Grade 3 or 4 required discontinuation. Grade 1 or 2 did not require dose adjustment.
Dose modifications and management of interstitial lung disease (ILD)/pneumonitis
Dose modification and management are summarized in Management recommendations for ILD/pneumonitis.
ILD/pneumonitis was reported in patients receiving abemaciclib. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and treat as medically appropriate.1
Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.
Based on the severity of ILD/pneumonitis, abemaciclib may require dose modification. Permanently discontinue abemaciclib in patients with grade 3 or 4 ILD/pneumonitis.1
Grades=NCI CTCAE Grades
Incidence and Characterization of ILD in monarchE at the AFU1 Analysis
Abemaciclib + endocrine therapy (ET) demonstrated a manageable safety profile in patients with high-risk HR+, HER2- EBC. The safety profile of abemaciclib in monarchE was consistent with previous MONARCH studies with no new safety concerns.2-6 The most comprehensive safety analysis was conducted at the additional follow-up 1 analysis (AFU1). Safety data from the AFU1 analysis are considered to be mature as the median duration of treatment was 24 months with 90% of patients off the study treatment period. These data have been published.5
Patients with serious preexisting ILD were excluded from participation in the monarchE study. The incidence of patients reporting ILD in the abemaciclib + ET arm was 3.2% compared with 1.3% of patients in the ET alone arm.5
In patients treated with abemaciclib, half of ILD events were asymptomatic (grade 1), with 0.4% experiencing grade ≥3 events and 1 fatal event.5
Most abemaciclib-treated patients (98%) experiencing an ILD event did not experience a recurrence of an ILD event.5
In both treatment arms, most patients (95%) had prior adjuvant radiotherapy, a known risk factor for ILD.5
In the abemaciclib arm, the incidence of any grade ILD/pneumonitis events was higher in patients from Asia (5.4%), compared to the overall population (3.2%). However, the overall incidence of grade ≥3 or serious adverse events (SAEs) was <1% and similar across regions.5
Symptomatic (grade ≥2) events mostly occurred during the first year of treatment (80%) and were treated with steroids and/or antibiotics. Dose modifications due to ILD were rare; abemaciclib discontinuation due to ILD occurred in 19 (0.7%) patients.5
ILD events are summarized in ILD Events in monarchE at the AFU1 Analysis.
|
Abemaciclib + ET |
ET Alone |
||||||
Event Term, n (%) |
Any Grade |
Grade 1 |
Grade 2 |
Grade ≥3 |
Any Grade |
Grade 1 |
Grade 2 |
Grade ≥3 |
ILDa |
89 (3.2) |
44 (1.6) |
34 (1.2) |
11 (0.4)b |
37 (1.3) |
26 (0.9) |
10 (0.4) |
1 (0.0)b |
Pneumonitis |
49 (1.8) |
21 (0.8) |
21 (0.8) |
7 (0.3) |
10 (0.4) |
7 (0.3) |
3 (0.1) |
0 (0.0) |
Radiation pneumonitis |
25 (0.9) |
13 (0.5) |
10 (0.4) |
2 (0.1) |
15 (0.5) |
9 (0.3) |
5 (0.2) |
1 (0.0) |
Serious ILD eventsc |
14 (0.5) |
NA |
NA |
NA |
1 (<0.1) |
NA |
NA |
NA |
Time to onset of first ILD event (days); median (range) |
211.0 (23.0-736.0) |
176 (29.0-655.0) |
||||||
Leading to dose reduction |
5 (5.6) |
NA |
||||||
Leading to dose hold |
13 (14.6) |
NA |
||||||
Antibiotic and/or corticosteroid treatment |
47 (52.8) |
12 (32.4) |
||||||
Abbreviations: AFU1 = additional follow-up 1; CTCAE = Common Terminology Criteria for Adverse Events; ET = endocrine therapy; ILD = interstitial lung disease; NA = not applicable.
aPatients with serious preexisting ILD were excluded from participation in the monarchE study. ILD was analyzed as a composite term and included: abemaciclib arm (any grade): interstitial lung disease (n=6), lung opacity (n=3), pneumonitis (n=49), pulmonary fibrosis (n=4), radiation fibrosis-lung (n=2), radiation pneumonitis (n=25), sarcoidosis (n=0), organizing pneumonia (n=2), pulmonary granuloma (n=0); and ET alone arm (any grade): pneumonitis (n=10), radiation pneumonitis (n=15), interstitial lung disease (n=1), pulmonary fibrosis (n=3), lung opacity (n=2), radiation fibrosis--lung (n=2), organizing pneumonia (n=3), pulmonary granuloma (n=1), and sarcoidosis (n=1).
bThere was one fatality due to ILD (pneumonitis) in the abemaciclib arm and none in the ET alone arm.
cSerious ILD events were defined as events that first occurred or worsened in severity while on therapy and within 30 days after treatment discontinuation, or serious ILD events which occurred beyond 30 days after treatment discontinuation and were considered related to study treatment by the investigator. These events did not receive standardized CTCAE grading.
ILD was managed per standard clinical practice. Most patients experiencing ILD could continue abemaciclib treatment without further recurrences.7
Updated Results at OS IA2 Analysis
A subsequent analysis (prespecified overall survival interim analysis [OS IA2]) was recently conducted on the monarchE study data. The data cutoff date was July 1, 2022. The median follow-up time for the overall population was 42 months, and all patients were off abemaciclib treatment at the time of the analysis. Safety data continue to be consistent with the known safety profile of abemaciclib and with previous analyses. Since the majority of abemaciclib toxicities occurred during the first few months of treatment, at OS IA2 there were minimal changes in the incidence of AEs and no additional discontinuations due to AEs. Thus, the safety findings presented above for AFU1 remain valid.6
When compared to the AFU1 analysis, patients who received abemaciclib at the OS IA2 analysis experienced no additional incidence of
- grade ≥3 pneumonitis or radiation pneumonitis, and
- SAEs due to ILD.6
Safety monitoring in the long-term follow-up period is ongoing.6
ILD in Safety Population vs Asia Population of monarchE at the PO Analysis
The Asian subgroup population in monarchE included patients located in mainland China, Hong Kong, Japan, Korea, Singapore, and Taiwan.7
While there was a higher incidence of ILD in the Asia population, most ILD events in the Asia population were asymptomatic/grade 1 (4.9%) as summarized in ILD Events in the Safety and Asia Population of monarchE. Furthermore, clinically significant AEs (grade ≥2), SAEs, and discontinuations were similar in both populations.7
In the safety population, characteristics of patients with serious ILD events included
- prior adjuvant radiotherapy (all patients)
- time to onset of 45 to 394 days
- steroid treatment for 86% of patients, and
- discontinuation of abemaciclib in all abemaciclib-treated patients.7
Additionally, in the safety population, the patients with serious ILD events included 9 Caucasian patients, 4 Asian (1 Indian) patients, and 1 classified as other race. The fatal event in the abemaciclib arm was reported for an Asian patient.7
|
Safety Population |
Asia Population |
||||||||||
|
Abemaciclib + ET (N=2791) |
ET (N=2800) |
Abemaciclib + ET (N=572) |
ET (N=572) |
||||||||
|
Grade 1 |
Grade 2 |
Grade ≥3 |
Grade 1 |
Grade 2 |
Grade ≥3 |
Grade 1 |
Grade 2 |
Grade ≥3 |
Grade 1 |
Grade 2 |
Grade ≥3 |
Patients with ≥1 TEAE, n (%) |
39 (1.4) |
32 (1.1) |
11 (0.4)a |
23 (0.8) |
10 (0.4) |
1 (0.1) |
28 (4.9) |
8 (1.4) |
2 (0.3)a |
12 (2.1) |
4 (0.7) |
1 (0.2) |
Pneumonitis |
17 (0.6) |
19 (0.7) |
7 (0.3)a |
7 (0.3) |
3 (0.1) |
0 |
15 (2.6) |
5 (0.9) |
1 (0.2)a |
4 (0.7) |
2 (0.3) |
0 |
Radiation pneumonitis |
13 (0.5) |
10 (0.4) |
2 (0.1) |
8 (0.3) |
5 (0.2) |
1 (0.1) |
10 (1.7) |
3 (0.5) |
1 (0.2) |
6 (1.0) |
2 (0.3) |
1 (0.2) |
SAEs |
14 (0.5)b |
1 (0.1) |
3 (0.5) |
0 |
||||||||
Subjects discontinued due to AEs |
19 (0.7) |
0 |
5 (0.9) |
0 |
||||||||
Abbreviations: AE = adverse event; ET = endocrine therapy; ILD = interstitial lung disease; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
aOne Grade 5 event.
bOne patient was deemed to have pneumonia and not included in the SAE ILD description.
What is ILD/pneumonitis and how did we define it in monarchE?
For the purposes of adverse event reporting in monarchE, all reported terms included in the broad clinical category of ILD were summarized under the composite term interstitial lung disease (ILD), with the most frequently reported individual terms being pneumonitis and radiation pneumonitis.5
Pneumonitis is a general term that refers to inflammation of the lungs. The term ILD is an imprecise clinical term that refers to a group of more than 200 chronic lung disorders characterized by inflammation of the lung tissue, which often leads to scarring.8,9 In clinical practice, the terms ILD and pneumonitis are often used interchangeably.
ILD can be caused by autoimmune diseases, genetic abnormalities (eg, Hermansky–Pudlak syndrome) and long-term exposures to hazardous materials (eg, medications such as bleomycin, occupational exposures such as asbestos, tobacco smoke, or agents in the environment that cause an immune reaction called hypersensitivity pneumonitis).
However, the cause of ILD is mostly unknown and the lung manifestations are described as idiopathic interstitial pneumonia.8
Drug-induced interstitial lung disease (DIILD) occurs when exposure to a drug causes inflammation and eventually fibrosis of the lung interstitium. DIILD has been associated with chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. Cancer drugs account for approximately 23% to 51% of DIILD cases.10
It becomes challenging to identify potentially causative agents in oncology when drugs are combined with other agents, or given in association with radiotherapy; the risk of developing DIILD may be increased when causative agents are combined.10
Mechanism of action and etiology of ILD
The reasons patients develop ILD/pneumonitis when they are taking anticancer medications are not fully understood. There can also be multiple confounding factors, especially in cancer treatment, where multiple drugs are often administered at the same time. Based on the mechanism of action of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor and the etiology of ILD, there is no known mechanistic explanation for an association of abemaciclib and ILD.11
The monarchE study
monarchE is an open-label, randomized, phase 3 trial comparing adjuvant abemaciclib 150 mg twice daily plus endocrine therapy (ET) vs ET alone for a 2-year duration in 5637 patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, early breast cancer (EBC) at high risk of recurrence.
At the end of the study treatment, patients entered physician-directed ET follow-up for a total of 5-10 years, as clinically indicated. At the preplanned interim analysis in June 2020, this event-driven trial met its primary objective of superior invasive disease-free survival (IDFS) when abemaciclib was combined with ET compared to ET alone.3 The trial is active but not recruiting.12
References
1Verzenios [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib in high risk early breast cancer. Ann Oncol. 2020;31(suppl 4):S1143-S1144. European Society of Medical Oncology abstract LBA5_PR. https://doi.org/10.1016/j.annonc.2020.08.2238
3Johnston SRD, Harbeck N, Hegg R, et al; monarchE Committee Members and Investigators. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. https://doi.org/10.1200/JCO.20.02514
4O'Shaughnessy JA, Johnston S, Harbeck N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Cancer Res. 2021;81(4 suppl):GS1-01. American Association for Cancer Research abstract GS1-01. https://doi.org/10.1158/1538-7445.SABCS20-GS1-01
5Rugo HS, O’Shaughnessy J, Boyle F, et al; monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study. Ann Oncol. 2022;33(6):616-627. https://doi.org/10.1016/j.annonc.2022.03.006
6Johnston SRD, Toi M, O'Shaughnessy J, et al; monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90. https://doi.org/10.1016/S1470-2045(22)00694-5
7Toi M, Harbeck N, Puig JM, et al. Characterization of venous thromboembolic events (VTE), elevated aminotransferase (EAT) and interstitial lung disease (ILD) in monarchE. Ann Oncol. 2021;32(suppl 2):S39-S40. European Society of Medical Oncology abstract 44O. https://doi.org/10.1016/j.annonc.2021.03.058
8Anthimopoulos M, Christodoulidis S, Ebner L, et al. Lung pattern classification for interstitial lung diseases using a deep convolutional neural network. IEEE Trans Med Imaging. 2016;35(5):1207-1216. http://dx.doi.org/10.1109/tmi.2016.2535865
9Bourke SJ. Interstitial lung disease: progress and problems. Postgrad Med J. 2006;82(970):494-499. http://dx.doi.org/10.1136/pgmj.2006.046417
10Skeoch S, Weatherley N, Swift AJ, et al. Drug-induced interstitial lung disease: a systematic review. J Clin Med. 2018;7(10). http://dx.doi.org/10.3390/jcm7100356
11Data on file, Eli Lilly and Company and/or one of its subsidiaries.
12Endocrine therapy with or without abemaciclib (LY2835219) following surgery in participants with breast cancer (monarchE). ClinicalTrials.gov identifier: NCT03155997. Updated July 14, 2023. Accessed September 5, 2023. https://clinicaltrials.gov/study/NCT03155997
Date of Last Review: 22 February 2023