Case Presentation: A 60 year old male with stage IV lung adenocarcinoma metastatic to the brain being treated with carboplatin/pemetrexed and 3 doses of pembrolizumab presented to the emergency department with frequent watery and bloody diarrhea. He had been having >10 stools a day for 6 weeks, lost 35-40 pounds and was unable to eat due to abdominal cramping. He had previously been on 5 days of prednisone 20mg in an attempt to treat his diarrhea. He was admitted to the hospital and started on high dose IV solumedrol at 2mg/kg daily without improvement after 7 days. He underwent a flexible sigmoidoscopy to obtain biopsies as there was a concern for CMV colitis due to immunosuppression and presentation. Biopsies taken confirmed PD-1 mediated immune colitis, ruled out CMV and the patient was given an infliximab infusion with drastic improvement. He was discharged on a prednisone taper for 15 days. He was readmitted 2 weeks later on the last day of his taper for >7 bloody bowel movements a day and received his second infliximab infusion with improvement. He was discharged and planned for the third and final infliximab infusion; however, subsequently developed recurrent frequent diarrhea prior to the scheduled appointment. At that time, c diff stool antigen was positive and he was treated with vancomycin as well as high dose prednisone with a 2 week taper. He is planned for repeat flexible sigmoidoscopy to assess for recurrence of PD-1 induced colitis versus c diff colitis.
Discussion: Pembrolizumab, a humanized IgG4 antibody that targets the programmed cell death-1 receptor, was developed originally for the use in metastatic melanoma and is now approved for any unresectable or metastatic solid tumor. The drug works by inhibiting PD-1 activation, which promotes stimulation of T-cell-mediated immune responses against tumor cells as well as non-tumor cells causing immune-related adverse events. This case illustrates the potential for severe refractory immune-mediated colitis due to PD-1 inhibitor monotherapy. Diarrhea is a common side effect of immune checkpoint inhibitors, especially CTLA-4 inhibitors with an incidence of 32.8% and immune-related adverse events are known complications with these drugs. Grade 3-4 immune-mediated colitis characterized by greater than 7 watery stools a day is much less common especially in those treated with PD-1 inhibitor monotherapy with an incidence of 0.9% versus CTLA-4 monotherapy (6.8%) and CTLA-4/PD-1 combination therapy (9.4%). This case demonstrates the importance of recognizing the same degree of severe colitis in monotherapy with PD-1 inhibitors in order to prevent known fatal complications such as perforation. It also demonstrates the need for clinical correlation and further testing such as biopsy diagnosis to assess for c diff, CMV, IBD and GVHD as these conditions can be indistinguishable on presentation and can lead to refractory fatal colitis.
Conclusions: PD-1 inhibitors have recently been approved for treatment of unresectable solid tumors regardless of primary source and will be increasingly utilized in cancer treatment. Because of this it is important to recognize immune-mediated colitis as to not delay aggressive treatment that may be needed including TNF alpha inhibitors in order to shorten the course of illness, prevent fatal complications and decrease hospital stay and readmission.