Case report: reinitiating pembrolizumab treatment after small bowel perforation

Abstract

Background: Immune checkpoint inhibitors (ICIs) have emerged as paradigm shifting treatment options for a number of cancers. Six antibodies targeting the immune checkpoint proteins programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) or cytotoxic T-lymphocyte associated protein 4 (CTLA4) have been approved. In some cases, response rates have been impressive, but not uniformly so and not consistently; similarly, toxicity to this class of therapeutic is often unpredictable and can be life threatening. Predicting treatment response and toxicity are two main obstacles to truly individualize treatment with ICIs. One of the most severe and life-threatening adverse events is colitis induced colonic perforation, estimated to occur in 1.0 to 1.5% of patients treated with ICIs. An important question to address is, under what circumstances is it appropriate to reinitiate ICI treatment post-bowel perforation?

Case presentation: The patient is a 62-year-old woman, who presented with stage IV lung cancer. Immunohistochemical staining indicated that 80% of the patient's tumor cells expressed PD-L1. The patient was started on a three-week cycle of pembrolizumab. Subsequent reducing in tumor burden was observed within ten weeks. Initially, pembrolizumab was tolerated fairly well, with the exception of immunotherapy related hypothyroidism. However, the patient experienced a second, more serious immune-related adverse event (irAE), in the form of enteritis, which led to small bowel perforation and necessitated exploratory laparotomy. The concerning part of the small bowel was resected, and a primary anastomosis was created. Based on the pathological and surgical findings, the patient was diagnosed with pembrolizumab-associated small bowel perforation. The patient recovered well from surgery and, considering the patient's remarkable response to treatment, a collective decision was made to reinitiate pembrolizumab on post-operative day twenty-eight. The patient is continuing her immunotherapy with ongoing partial response and is able to continue her full-time job.

Conclusions: This case report highlights the challenges of identifying patients likely to respond to ICIs and those that are likely to experience irAEs and it discusses the impressive work that has been done to start to address these challenges. Lastly, the topic of reinitiating pembrolizumab treatment even after colonic perforation is discussed.

Keywords: Bowel perforation; CTLA4; Cancer; Immune checkpoint inhibitors; Immune-related adverse events; Immunotherapy; PD-1; PD-L1; Pembrolizumab; Toxicity.

Fig. 1

Consideration of PD-L1 and/or tumor-mutation burden in clinical trials of immune checkpoint inhibitors in non-small cell lung cancer. Shown are response rates, progression free survival (PFS) and overall survival (OS) based on PD-L1 expression levels and/or tumor-mutation burden for twelve published clinical trials (See Supplemental Materials for complete references). The x-axis indicates tumor mutation burden and/or percentage of PD-L1 positive cells (tumor cells unless otherwise indicated). HNS = high nonsynonymous # of mutations (median of 324), LNS = low nonsynonymous # of mutations (median of 122), HE = high exonic # of mutations (median of 494), LE = low exonic # of mutations (median of 190); Q3W = 10 mg/kg of pembrolizumab every 3-weeks, Q2W = 10 mg/kg of pembrolizumab every 2-weeks; TC0 (percent of PD-L1 positive tumor cells, < 1%) or IC0 (percent of PD-L1 positive tumor-infiltrating immune cells, < 1%), TC1 (≥1 and < 5%) or IC1 (≥1 and < 5%), TC2 (≥5 and < 50%) or IC2 (≥5 and < 10%), TC3 (≥50%) or IC3 (≥10%); 1Q12W = ipilimumab every12-weeks, 1Q6W = ipilimumab every 6-weeks; HTB = high tumor-mutational burden (≥243 somatic missense mutations), L/MTB = low/medium tumor-mutation burden (low = < 100 somatic missense mutations; medium = 100–242 somatic missense mutations)

Fig. 2

Diagnosis of PD-L1 positive, metastatic NSCLC and pre-treatment PET/CT imaging. a. Hematoxylin and eosin (H&E) stained neck mass biopsy showing adenocarcinoma cells consistent with primary lung disease. Scale bar = 20 mm. b. Thyroid transcription factor 1 (TTF-1) positive (dark brown staining) tumor cells. Bar = 20 mm. c. Immunohistochemical staining of the patient’s biopsy sample for PD-L1 (Dako 22C3). In the representative image, greater than 80% of tumor cells were PD-L1 positive (brown staining). Scale bar = 20 mm. d. Transverse computed tomography (CT) images with matching positron emission tomography (PET) images below. Detected lesions: a = anterior left upper lung lobe, b = right paratrachel region, c = left lung hilum, d = single splenic lesion

Fig. 3

Post-treatment CT images of the lungs and spleen and abdominal images indicating small bowel perforation. a. Transverse CT images of the chest and abdomen showing significant reduction of the (a) anterior left upper lung lobe lesion, (b) left lung hilar lesion and (c) single splenic lesion. b. Transverse CT image showing submucosal edema (“target sign”) of the small bowel (red circle). c. Transverse CT image showing foci of non-dependent extraluminal air adjacent to the bowel (red circle)

Fig. 4

Microscopy evaluation of small bowel perforation. a. Hematoxylin and eosin (H&E) stained slides of normal small intestine (left panel), low magnification of perforated small intestine showing ulceration and perforation (center panel) and high magnification of perforated small intestine showing acute inflammation and mucosal ulceration (right panel). b. H&E slides of medium (left panel) and small (left and right panel) vessels associated with the small intestine. No evidence of vasculitis is seen. c. Section of small intestine H&E and trichrome stained showing ulceration with perforation through the serosa (arrow heads) with loss of muscularis propria (arrows) and acute and chronic inflammation and fibrosis