Postmarketing Colitis Cases Associated With Alpelisib Use Reported to the US Food and Drug Administration

Abstract

This case series investigates reports of 20 patients with colitis temporally associated with alpelisib use.

Alpelisib is a phosphatidylinositol 3-kinase (PI3K) inhibitor approved by the US Food and Drug Administration (FDA) in combination with fulvestrant for the treatment of postmenopausal women and men with hormone receptor–positive, ERBB2 (formerly HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer that was detected by an FDA-approved test following progression on or after an endocrine-based regimen.¹ Although diarrhea is a common adverse event associated with use of alpelisib, during postmarketing surveillance, we identified colitis as a new safety signal and herein report the findings.

Methods

In this case series, we reviewed postmarketing reports of noninfectious colitis and alpelisib use submitted to the FDA Adverse Event Reporting System or available in the published literature through February 28, 2021. The work was performed under specific federal statutory authority to support public health surveillance and is exempt from institutional review board approval or informed consent under 45 §CFR 46.101(b)(5). The study followed the reporting guideline for case series. We considered cases with diagnostic confirmation of colitis (ie, histologic findings, radiologic imaging) or requiring immunosuppressive therapy to control diarrhea as category I (highest level of evidence) and cases with limited diagnostic or treatment information as category II. After excluding duplicate reports, we applied the World Health Organization–Uppsala Monitoring Centre causality assessment system to determine drug-event causal association. This system categorizes the causal assessments as unassessable, unlikely, possible, probable, or certain.²

Results

A total of 20 patients with colitis temporally associated with alpelisib use were identified. All patients were female with a mean (range) age of 54 (36-74) years. All patients had at least 1 serious outcome, including hospitalization (n = 19), intestinal perforation (n = 4), or death (n = 2). Fifteen patients (75%) met the category I case definition criteria (Table). Causality was assessed and found to be probable in 4 patients and possible in 16. Among the 18 case reports that included time-to-onset information, colitis occurred within 6 months of alpelisib initiation in 72% (n = 13). Twelve case reports (60%) described a positive rechallenge (n = 3) or dechallenge (n = 9) with alpelisib use. In all cases, alpelisib was either interrupted (n = 9) or discontinued (n = 11).

Table. Characteristics of Postmarketing Patients With Noninfectious Colitis Reported With Alpelisib Use (n = 20)^a.

Patient No.	WHO-UMC causality	Case definition categoryb	Grade of toxicity (CTCAE)	Relevant diagnostic criteria	Enteric and/or systemic steroid treatment	Challenge informationc	Drug disposition/clinical outcomes
1	Probable	I	4	CT	No	Positive dechallenge	DC/HO, IP
2	Probable	I	4	CT	No	NR	DC/HO, IP
3	Probable	I	3	CT	Yes	Positive rechallenge	DC/HO
4	Probable	I	3	CT	Yes	Positive dechallenge	DC/HO
5	Possible	I	5	CT	No	NR	DC/HO, IP, DE
6	Possible	I	3	CT	No	Positive dechallenge	Interrupted, dose reduction/HO
7	Possible	I	3	CT	No	NR	Interrupted/HO
8	Possible	I	3	CTd	No	Positive dechallenge	Interrupted/HO
9	Possible	I	3	CT	No	NR	Interrupted/HO
10	Possible	I	3	CT	No	Positive rechallenge	Interrupted/HO
11	Possible	I	3	NR	Yes	Positive dechallenge	DC/HO
12	Possible	I	2	CT	No	Positive dechallenge	DC/HO
13	Possible	I	2	CT	No	Positive dechallenge	DC/HO
14	Possible	I	2	CT	No	NR	Interrupted/HO
15	Possible	I	2	CT, biopsy	Yes	NR	DC/HO, DEe
16	Possible	II	4	NR	No	NR	Interrupted/HO, IP
17	Possible	II	3	NR	No	Positive dechallenge	DC/HO
18	Possible	II	2	NR	No	Positive rechallenge	Interrupted, dose reduction/HO
19	Possible	II	2	NR	No	NR	Interrupted/NR
20	Possible	II	2	NR	No	Positive dechallenge	DC/HO

Abbreviations: CT, computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; DC, discontinued; DE, death; HO, hospitalization; IP, intestinal perforation; NR, not reported; WHO-UMC, World Health Organization–Uppsala Monitoring Centre.

^a Reports of noninfectious colitis were retrieved from the US Food and Drug Administration Adverse Event Reporting System database using the Medical Dictionary for Regulatory Activities preferred terms of colitis, colitis ulcerative, colitis ischaemic, diarrhoea, and enterocolitis. The manual review of reports allowed exclusion of those cases with other causes, such as infections (eg, on the basis of stool culture results, brisk response to antibiotic therapy).

^b Cases with diagnostic confirmation of colitis (ie, histologic findings, radiologic imaging) or requiring immunosuppressive therapy to control diarrhea were considered category I (highest level of evidence), and cases with limited diagnostic or treatment information were considered category II.

^c Positive dechallenge is defined as permanent discontinuation of alpelisib or resumption of alpelisib at a reduced dose after resolution of colitis. Positive rechallenge is defined as recurrence of colitis after reintroduction of alpelisib (at any dose).

^d The report indicated that “the scan showed colitis.”

^e The reported cause of death was Pneumocystis jirovecii pneumonia.

Discussion

In this case series, the findings support alpelisib as a likely cause of colitis on the basis of temporality and positive dechallenge/rechallenge. Affected individuals exhibited serious outcomes that may have been averted with early recognition and intervention. Although colitis was not identified as a serious adverse event during the SOLAR-1 registration trial, 58% of participants who were treated with alpelisib experienced diarrhea vs 16% in the comparator group.¹ Although corticosteroids are not considered first-line treatment for uncomplicated diarrhea, some of these participants who were treated with alpelisib received corticosteroids for diarrhea.^3,4

Inhibition of the PI3K pathway plays a complex role in regulating proinflammatory and anti-inflammatory pathways.⁵ Drugs considered PI3K inhibitors, including alpelisib, may disrupt the anti-inflammatory pathways protecting the gastrointestinal tract.⁵ Notably, the US prescribing information of other orally administered PI3K inhibitors (duvelisib, idelalisib, umbralisib) contains a warning/precaution for colitis.⁶

The postmarketing identification of colitis with alpelisib use was possible because of astute and conscientious clinicians who report suspected drug-related adverse events to the manufacturer or the FDA. Despite limitations inherent to spontaneous reporting systems (ie, underreporting, variable report quality, lack of comparator, population of uncertain size), these data, together with clinical trial information and biological plausibility, support colitis as an alpelisib-induced adverse event. The US prescribing information for alpelisib was recently updated to increase clinicians’ awareness and promote early recognition of colitis and guideline-based treatment (eg, enteric-acting and/or systemic steroids, drug discontinuation or interruption).^1,4