Alectinib and gastrointestinal perforation in ALK-rearranged non-small cell lung cancer: A case series

Abstract

Background:

Alectinib, a second-generation ALK inhibitor, is used in first-line and adjuvant treatment for ALK-rearranged NSCLC, and has proven to be both effective and well tolerated. Gastrointestinal (GI) perforation is an extremely rare but potentially life-threatening complication, with only sporadic cases reported in the literature.

Methods:

We describe, to the best of our knowledge, the largest case series to date of GI perforations that occurred during alectinib treatment in patients with ALK-rearranged NSCLC. Clinical features, management strategies, and outcomes were analyzed and integrated with available literature.

Results:

Three female patients developed GI perforation after variable durations of alectinib treatment, ranging from one month to over three years. Two cases were associated with pre-existing diverticulosis, while one occurred in the absence of any known GI comorbidities. Management included conservative treatment with intravenous antibiotics in two cases and surgical intervention in one. Alectinib was permanently discontinued in all patients. Subsequent therapeutic strategies included lorlatinib or brigatinib, with heterogeneous tolerability and outcomes. Literature review identified other reports of GI perforation or severe toxicity under alectinib.

Conclusions:

Although rare, GI perforation, represents a clinically relevant adverse event associated with alectinib, particularly in patients with diverticulosis or other predisposing conditions. It is essential to optimize safety and long-term disease control by raising awareness of early warning symptoms, conducting a baseline GI evaluation in high-risk patients and carefully sequencing therapy after discontinuation.

Clinical practice points

• – Gastrointestinal (GI) perforation is a rare but potentially life-threatening toxicity during alectinib for ALK-rearranged NSCLC.

• – In patients who develop persistent abdominal pain or new altered bowel habits during treatment with alectinib, prompt abdominal imaging should be performed. In selected high-risk patients with gastrointestinal comorbidities, a baseline endoscopic evaluation may be considered before treatment initiation.

• – Although uncommon, GI perforation is clinically relevant and warrants prompt recognition, as it may require permanent discontinuation of alectinib, an ALK inhibitor with proven durable efficacy and a generally favorable tolerability profile in ALK-rearranged NSCLC.

Introduction

Alectinib is a second-generation ALK inhibitor with proven efficacy and good tolerability. It is approved for the treatment of ALK-rearranged NSCLC both in the advanced and in the adjuvant setting.^1,2 In clinical trials and real-world studies, gastrointestinal (GI) adverse events have generally been reported as uncommon and predominantly low grade, with severe events occurring in a small minority of patients (<5% grade ⩾3). ³ In contrast, GI perforation remains an exceptionally rare but potentially life-threatening complication, currently documented only in isolated case reports or small case series. ⁴ Here we report what, to our knowledge is the largest case series of patients experiencing GI perforation during alectinib treatment.

Case presentation

Case 1

A 75-year-old never-smoker female was diagnosed in November 2023 with metastatic ALK-rearranged NSCLC, presenting both brain and leptomeningeal involvement (cT1b cN0 cM1c, Stage IVB) (Figure 1a).

Figure 1.

(a) Timeline of Case 1 including treatment and adverse event course. (b) Timeline of Case 2 including treatment and adverse event course. (c) Timeline of Case 3 including treatment and adverse event course.

Next-Generation Sequencing (Oncomine Comprehensive Assay Plus DNA/RNA, Thermo Fisher Scientific) revealed an EML4 (exon 6)- ALK (exon 20) fusion, with a Tumor Mutational Burden (TMB) of 0.95 mutations/Mb and no additional co-mutations. Comorbidities included colonic diverticulosis, arterial hypertension, and impaired glucose tolerance. Concomitant medications included pregabalin, rosuvastatin, nebivolol/hydrochlorothiazide, metformin, pantoprazole, and candesartan/amlodipine. The patient at the diagnosis was in good clinical condition, with Eastern Cooperative Oncology Group Performance Status, (ECOG PS) 0, initiated first-line alectinib 600 mg BID in November 2023, achieving a partial systemic and intracranial response (according to RECIST v1.1), without relevant toxicity. In November 2024, after 12 months of therapy, she developed severe abdominal pain and fever and was admitted to the emergency department (ECOG PS 2). A CT scan showed an acute diverticulitis, complicated by G2 intestinal perforation (according to CTCAE v5.0) (Figure 2a). Alectinib was discontinued, since the adverse event was considered potentially treatment related. The patient was treated with intravenous piperacillin–tazobactam and fluids, with favourable clinical response (ECOG PS 1).

Figure 2.

(a) Case 1: CT image performed in November 2024. Perforated colonic diverticulum with free intraperitoneal air and abdominal fluid collection – direct sign of gastrointestinal perforation. (b) Case 3: CT scan performed in September 2021.2b: Unsealed diverticular perforation. (c) Subdiaphragmatic free air - direct sign of gastrointestinal perforation.

Approximately one month after interruption of alectinib, a CT scan documented disease progression with new brain lesions and suspected pancreatic involvement (according to RECIST v.1.1), therefore lorlatinib was started in December 2024. Brain radiotherapy was deferred as the metastases were small and asymptomatic. Lorlatinib treatment led to a complete response that is still ongoing, and the patient remains on treatment without significant adverse events and ECOG PS 0.

Case 2

A 56-year-old female smoker was diagnosed with a stage IIB (pT1bN1M0) lung adenocarcinoma, resected in 2021 (Figure 1b). Relevant comorbidities are dilated cardiomyopathy, with severe valvular disease and depressive disorder, concomitant medication included: edoxaban, bisoprolol, empagliflozin, furosemide, spironolactone, rosuvastatin, paroxetine.

In March 2024, a relapse was documented (pleural lesions and thoracic lymphadenopathies, and NGS (OCAplus DNA/RNA) detected a EML4 (exon 13)- ALK (exon 20) fusion with a TMB of 1.91 mutations/Mb. The patient presented with ECOG PS 1 due to G2 nausea G1 (related to chronic constipation), dyspnea and G1 chest pain, (according to to CTCAE v5.0), treated with metoclopramide, ondansetron, methylprednisolone, morphine and oxygen therapy. Alectinib 600 mg BID was started in March 2024, and after one month, the patient was admitted to the emergency department for severe G2 diarrhea (according to CTCAE v5.0), in fair clinical conditions (ECOG PS 2). A CT scan showed distal ileitis with a focal wall defect and perilesional abscess, consistent with a localized (sealed) ileal perforation G2 DR (according to CTCAE v5.0). Considering this acute event potentially related to alectinib, the treatment was discontinued. The perforation resolved on April 2024 and one month later lorlatinib 100 mg once daily was started. It was then suspended in October 2024, and subsequently restarted with the first dose reduction in January 2025, due to G2 heart failure secondary to valvular disease (non-drug related, NDR). Lorlatinib was then definitively discontinued in January 2025, after recurrence of heart failure. The patient is now on surveillance with sustained disease control (PR according to RECIST v.1.1).

Case 3

A 69-year-old female former smoker was diagnosed in June 2018 with Stage IVA (cT1aN2M1b) NSCLC, involving bone and brain lesions (Figure 1c). FISH analysis highlighted an ALK gene rearrangement in 60% of the evaluated tumor cells. Comorbidities included arterial hypertension and depression (not on pharmacological treatment).

The patient was in good clinical conditions (ECOG PS 1) and commenced alectinib 600 mg BID in July 2018, achieving a partial response with regression of both primary and metastatic sites. Regarding toxicity, treatment was temporarily withheld in October 2020 due to grade 3 drug related creatine phosphokinase (CPK) increase.

In August 2021, she developed G2 fever and G1 diffuse cramps (according to CTCAE v5.0), considered drug related, so alectinib was discontinued. Three days later she was hospitalized for septic shock (G4 according to CTCAE v5.0), and a CT scan documented diverticulitis with G2 DR intestinal perforation (according to CTCAE v5.0) and pneumoperitoneum, with an ECOG PS 2 (Figure 2b, 2c). The patient was treated conservatively with intravenous piperacillin–tazobactam, metronidazole, and parenteral nutrition, leading to complete clinical and radiological resolution. Notably, diverticulosis had not been previously diagnosed in this patient. Considering the durable disease control achieved with alectinib for nearly three years and its role as a life-saving treatment, it was resumed at the dose of 600 mg BID and continued until April 2022, when the patient was hospitalized for G3 DR (according to CTCAE v5.0) rectal diverticular perforation complicated by peritoneal abscess and fistula of the vaginal stump. She underwent rectosigmoid resection with construction of a terminal colostomy in the left lower abdomen. Subsequent radiological evaluations confirmed that the disease remained stable; the best overall response was a partial response (PR according to RECIST 1.1). Considering the high risk of further gastrointestinal perforation, the long-term disease stability and the absence of intracranial progression, brigatinib was selected as an alternative second-generation ALK-inhibitor and was started in June 2022. However, it was discontinued only one month later because of recurring G3 gastrointestinal toxicity (according to CTCAE v5.0). In August 2022, the patient underwent colonic resection with closure of the colostomy and creation of an ileostomy. Histological examination revealed chronic ulcerative inflammation, the patient was in good clinical conditions (ECOG PS 1).

Given the encountered toxicity and the maintained disease response, it was decided to discontinue the treatment. Extracranial disease has remained controlled, whereas intracranial disease required stereotactic radiotherapy for single lesions in October 2024, January and July 2025.

Discussion

In this series, three females with ALK-rearranged NSCLC developed gastrointestinal (GI) perforation related to alectinib, after durable disease control. Latency was heterogeneous, from one month to more than three years. Two patients had diverticulosis, whereas the third one had no GI comorbidities. All patients discontinued alectinib at perforation, two were managed conservatively while one required surgical resection. Post-event strategies varied: lorlatinib yielded deep and durable response in one case and disease control in another, while brigatinib was stopped early for recurrent GI toxicity. One patient maintained long-term control without systemic therapy, with Stereotactic Body Radiation Therapy (SBRT) for oligoprogression.

Evidence from the literature

The existing literature comprises only a few case reports of alectinib-associated GI perforation. One report described a 79-year-old woman who developed a descending colon perforation after ten months of alectinib therapy, despite no previous history of gastrointestinal disease; she underwent partial colectomy with colostomy, recovered, and ultimately chose to continue treatment. ⁵ In a retrospective Italian series analyzing eight patients with drug-related pneumatosis intestinalis or perforation, a 57-year-old woman with ALK-rearranged NSCLC treated with alectinib was identified; in this case, ileal pneumatosis was incidentally detected during follow-up imaging and managed conservatively, without progression to perforation. ⁶ More recently, Qiu et al. reported a 62-year-old woman who developed pancolitis and multiple ileal and ileocecal ulcers after nearly four years of alectinib treatment; this grade 3 adverse event was successfully managed with discontinuation of alectinib and oral mesalazine, followed by a switch to ceritinib, with no recurrence of gastrointestinal symptoms. ⁷ Another case involved a 62-year-old woman with ALK-rearranged NSCLC who developed a contained perforated duodenal ulcer after one month of alectinib therapy; she was not a surgical candidate and was therefore managed conservatively, with permanent discontinuation of alectinib and subsequent switch to brigatinib, which was well tolerated without recurrence of gastrointestinal toxicity or disease progression. ⁸ It is also reported the case of a 74-year-old woman with ALK-rearranged metastatic NSCLC who developed pneumoperitoneum approximately two weeks after initiating alectinib therapy. She was managed conservatively without surgery and ultimately died seven months later from cancer-related complications. ⁹ Finally, in the pivotal phase II trial of alectinib in crizotinib-refractory ALK-positive NSCLC, four patients (3%) died from treatment-related adverse events, including one case of intestinal perforation considered possibly related to alectinib ¹⁰ (Table 1).

Table 1.

Described cases of GI perforation/ulcers in patients affected by ALK-rearranged NSCLC.

Reference	Sex, Age (years)	GI event	Timing from start	Management	Outcome/Follow-up
Li et al. 5	Female, 79	Descending colonic perforation	10 months	Partial colectomy + colostomy	Recovered; alectinib resumed; no recurrent GI toxicity.
Brocchi et al. 6	Female, 57	Ileal pneumatosis	Asymptomatic (unknown)	Conservative management	No GI recurrence
Qiu et al. 7	Female, 62	Pancolitis + ileal/ileocecal ulcers (G3)	4 years	Discontinued alectinib + oral mesalazine, switched to ceritinib	Resolution, no recurrent GI toxicity
Patel et al. 8	Female, 62	Contained perforated duodenal ulcer	1 month	Conservative management, permanent discontinuation, switched to brigatinib	No recurrent GI toxicity
Maina et al. 9	Female, 74	Pneumoperitoneum	2 weeks	Conservative management	Discharged to rehabilitation facility
Ou et al. 10	Unknown	Intestinal perforation	Unknown	Unknown	Death

Across the reported cases, as in ours, the time to onset of GI events appears highly variable, ranging from a few weeks after treatment initiation to late events occurring after many months or even years. In most patients, management is primarily conservative, based on interruption or discontinuation of alectinib and supportive care. Surgery is reserved for confirmed perforation or complicated clinical courses.

Although no other clinical trials have reported this specific toxicity, gastrointestinal adverse events are a recognized component of alectinib safety profile across key studies.

The two phase III trials ALEX and J-ALEX studies described nausea, diarrhea and vomiting, along with less frequent events such as stomatitis, oesophagitis and upper abdominal pain.^11,12 Similar GI toxicities were also described in the adjuvant ALINA trial. ² They mainly consist of G1-G2 events. Notably, pharmacovigilance signals link ALK inhibitors to severe GI events, including obstruction and perforation. ¹⁴

Biological basis of GI perforation

It has been hypothesized that gastrointestinal perforation during alectinib treatment may be correlated with plasma drug concentration and local intestinal exposure. Alectinib is eliminated almost exclusively via the hepatobiliary pathway (~98%), resulting in sustained exposure of gastrointestinal mucosa to elevated local concentrations, potentially contributing to toxicity. Additional predisposing factors include age-related intestinal wall fragility, Non-Steroidal Anti-Inflammatory Drugs (NSAID)- induced mucosal damage, and increased intraluminal pressure due to constipation. Proposed mechanisms encompass direct cytotoxicity with intestinal wall necrosis and microvascular disruption, as well as intraluminal distension secondary to impaired motility. These effects, compounded by age-related degeneration, may ultimately converge to trigger perforation in susceptible patients. ⁵

More recently, pathological evidence has suggested an additional immune-mediated component: intestinal biopsies from affected patients showed apoptotic bodies, crypt distortion and atrophy, consistent with inflammatory injury. These changes, in the absence of viral infection, were attributed to the immunomodulatory properties of ALK inhibitors, supporting the hypothesis that autoimmune mechanisms may also contribute to gastrointestinal toxicity. ⁷

Management

In clinical practice, awareness of rare but potentially life-threatening complications such as gastrointestinal perforation may be important in patients receiving alectinib. In patients presenting with persistent abdominal pain or altered bowel habits, abdominal imaging may be warranted to exclude relevant gastrointestinal complications. ⁵ In selected high-risk patients, such as those with pre-existing gastrointestinal comorbidities, baseline gastrointestinal assessment might be considered on an individual basis, particularly in the adjuvant setting, although evidence to support this approach remains limited.

In patients who discontinue alectinib due to gastrointestinal perforation, subsequent therapeutic options should be tailored according to both efficacy and safety profiles. Lorlatinib and brigatinib may represent reasonable alternatives in the advanced setting, given the absence of reported gastrointestinal perforation events.^13,14 Nonetheless, gastrointestinal toxicity could be monitored with brigatinib as well, as a patient (Case 3) experienced a recurrence of GI toxicity during treatment.

Given the rarity of this toxicity and the limited available data, no definitive conclusions can be drawn regarding the optimal sequencing of ALK inhibitors. However, individual patient factors, including gastrointestinal comorbidities, may be considered when selecting subsequent therapies.

A final consideration relates to the increasing use of lorlatinib in the first-line setting, as established in the CROWN trial. ¹⁴ This evolving treatment landscape may influence treatment sequencing and patterns of exposure to ALK inhibitors. However, the potential impact on the incidence of rare adverse events such as gastrointestinal perforation remains unknown.

Conclusion

Our case series highlights that gastrointestinal perforation represents a rare but potentially serious toxicity of alectinib. Awareness is warranted in patients with pre-existing gastrointestinal comorbidities, where the risk of complications may be higher. Therapeutic choices must consider not only the efficacy but also the spectrum of potential toxicities.