Verzenios ® ▼ (abemaciclib)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information.For current prescribing information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).

How do I Manage ILD/Pneumonitis with Verzenios® ▼ (abemaciclib) 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.

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Interstitial Lung Disease (ILD)/Pneumonitis Monitoring and Dose Modification

Dose modification and management is summarized in Management recommendations for interstitial lung disease (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

Management recommendations for interstitial lung disease (ILD)/pneumonitis1

Toxicitya

Management recommendations

Grade 1 or 2

No dose adjustment required.

Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1

Suspend dose until toxicity resolves to baseline or Grade 1.

Resume at next lower dose.

Grade 3 or 4

Discontinue abemaciclib.

aNCI CTCAE

Incidence of ILD in monarchE

The data and information presented in this document are from the primary outcome (PO) analysis (19.1 months of median follow up in both arms).2 At a later data cut with a median follow-up time of 27 months (Additional Follow-up 1 [AFU1] analysis), there were minimal increases in incidence of most frequently reported treatment-emergent adverse events, including ILD, in the abemaciclib + ET arm.3

At the primary outcome analysis, in patients treated with abemaciclib, most ILD events were Grade 1 and primarily pneumonitis, with 0.4% experiencing Grade 3 events and 1 fatal event. The incidence of serious ILD events was low (0.5%).4

The majority of Grade >3 ILD events (82%) had a serious outcome (e.g. hospitalization). In both treatment arms, most patients (95.4%) had prior adjuvant radiotherapy, a known risk factor for ILD.4

Approximately half of the patients who experienced an ILD/pneumonitis event in the abemaciclib arm received concomitant medications, including steroids and antibiotics, consistent with the treatment required of symptomatic (Grade >2) events per CTCAE definition.4

Most ILD events were single occurrences (>97%) and most patients continued abemaciclib after an ILD event without further recurrence; 23% (n=19) patients discontinued abemaciclib primarily due to Grade ≥2 events.5

ILD events are summarized in ILD Events in monarchE.

ILD Events in monarchE4-6

 

Abemaciclib + ET

N=2791

ET Alone

N=2800

Event Term, n (%)

Any Grade

Grade 1

Grade 2

Grade >3

Any Grade

Grade 1

Grade 2

Grade >3

ILD

82 (2.9)a

39 (1.4)

32 (1.1)

11 (0.4)b

34 (1.2)a

23 (0.8)

10 (0.4)

1 (0.1)

   Pneumonitis

43 (1.5)

17 (0.6)

19 (0.7)

7 (0.3)b

10 (0.4)

7 (0.3)

3 (0.1)

0

   Radiation pneumonitis

25 (0.9)

13 (0.5)

10 (0.4)

2 (0.1)

14 (0.5)

8 (0.3)

5 (0.2)

1 (0.1)

   ILD

5 (0.2)

2 (0.1)

2 (0.1)

1 (0.1)

1 (0.1)

0

1 (0.1)

0

Serious ILD events

14 (0.5)

N/A

N/A

N/A

1 (0.1)

N/A

N/A

N/A

Time to onset of first ILD event (days); median (range)

190 (23-517)

158 (29-539)

Discontinuations due to ILD

19 (0.7)

0

Abbreviations: ET = endocrine therapy; ILD = interstitial lung disease.

aAfter 27 months of median follow-up, the incidence of any grade ILD was 3.2% in the abemaciclib+ET treatment arm and 1.3% in the ET alone treatment arm.

b1 Grade 5 event.

Approximately half of the events occurred early in the treatment, with 47% starting within the first 180 days.5

Overall the majority of clinically significant ILD events occurred within the first 6 months; no cumulative effect or increased risk with longer treatment duration of abemaciclib was observed.5

How was ILD/Pneumonitis Defined 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.4

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.7,8 In clinical practice, the terms ILD and pneumonitis are often used interchangeably.

What is ILD?

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.7

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.9

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.9

Mechanism of Action and Etiology of ILD

The reasons patients develop ILD 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.3Furthermore, ILD is considered a class effect of CDK 4 & 6 inhibitors.10

The monarchE Study

monarchE is an open-label, randomized, phase 3 trial comparing adjuvant abemaciclib 150 mg twice daily plus endocrine therapy (ET) versus ET alone for a two-year duration, in 5,637 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. 11 

References

1Verzenios [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2O'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. Abstract presented at: 43rd Annual San Antonio Breast Cancer Symposium (SABCS Virtual); December 8-11, 2020. Accessed December 9, 2020. https://www.abstractsonline.com/pp8/#!/9223/presentation/664

3Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4Rugo HS, O'Shaughnessy J, Song C, et al. Safety outcomes from monarchE: phase 3 study of abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high risk, early breast cancer. Poster presented at: 17th Annual St. Gallen International Breast Cancer Conference (SGBCC Virtual); March 17-21, 2021.

5Toi M, Harbeck N, Puig JM, et al; monarchE Investigators. Characterization of venous thromboembolic events (VTE), elevated aminotransferase (EAT) and interstitial lung disease (ILD) in monarchE. Abstract presented at: 3rd Annual Meeting of the European Society of Medical Oncology Breast Cancer Congress (ESMOBCC Virtual); May 5-8, 2021. 

6O'Shaughnessy J, Rastogi P, Harbeck N, et al; monarchE Investigators. Adjuvant abemaciclib combined with endocrine therapy: updated results from monarchE. Poster presented at: ESMO Virtual Plenary: October 2021; October 14-15, 2021. 

7Anthimopoulos 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

8Bourke SJ. Interstitial lung disease: progress and problems. Postgrad Med J. 2006;82(970):494-499. http://dx.doi.org/10.1136/pgmj.2006.046417

9Skeoch 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

10Raschi E, Fusaroli M, Ardizzoni A, Poluzzi E, De Ponti F. Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment. Breast Cancer Res Treat. 2021;186(1):219-227. https://doi.org/10.1007/s10549-020-06001-w

11Johnston 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

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: 16 September 2021


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