Pembrozulimab Induced Collagenous Colitis Mokshya Sharma 1, MD, Santhosh Ambika 2, MD University of Nevada, Reno SOM
Background Immune modulating therapy that targets PD1 pathway such as pembrozulimab is at the frontier of breakthrough cancer treatment 1
Significance As these immune modulating therapies become more common, it will be important to have treatment guidelines to monitor and treat potential side effects. To the best of our knowledge, this is the second reported case of pembrozulimab induced collagenous colitis and first case with development of side effects early on in the treatment cycle(cycle 2 vs. cycle 14 in the previous case report).
Pembrozulimab
Pembrozulimab Adverse Reactions Immune mediated pneumonitis Immune mediated hepatitis Immune mediated hypophysitis Renal failure and immune mediated nephritis Immune mediated hyperthyroidism and hypothyroidism Other immune mediated adverse reactions: optic neuritis, myasthenic sx
Immune mediated colitis Melanoma trial: 31/1567 Grade 2-.5% Grade 3-1.1% Grade 4-.1% NSCLC trial: 4/550 Grade 2-.2% Grade 3-.4%
Pembrozulimab Adverse Reaction Management Tool Grade 2 or 3 withhold medication, trial of prednisone 1mg/kg/day or equivalent followed by a taper Grade 4-permanently discontinue, initiate prednisone Resume tx when adverse reaction remains at grade 1 or less, after following prednisone taper over 1 month Discontinue if any life threatening adverse reaction or unable to reduce prednisone dose to 10mg/day or less within a 12 week duration
Case 78 yo female with past medical history significant for tobacco abuse(15py) who was discovered to have cavitary lesions in her right upper lobe on surveillance CT scan, biopsy showed poorly differentiated squamous cell carcinoma.
Timeline Staging PET scan was done which showed uptake only in this nodule and surgical resection of the lesion with lymph node sampling was performed. Postoperative pathology showed liver paratracheal lymph node involvement. She had a 3 cm poorly differentiated squamous cell carcinoma with negative margins.
Timeline After surgery, palpable subcutaneous nodule at the incision site was found and she was referred back to surgery. Excision of the mass-poorly differentiated metastatic squamous cell carcinoma involving subcutaneous and skeletal muscle tissue. Surgical margins were free of tumor however it did show 90% PD-L1 expression. Restaging PET scan was done and is negative for any other metastatic disease.
Timeline Stage IIIa poorly differentiated RUL squamous cell lung carcinoma with isolated recurrence near chest wall incision. Difficult postoperative course, age and reluctance to consider chemotherapy, decision for surveillance initially. Given the very high chance of recurrence and the fact that she already had chest wall recurrence, the option of trying Keytruda for 6 cycles in a pseudoadjuvant fashion for risk reduction was discussed.
Timeline As per NCCN guidelines for NSC lung cancer, initiated on pembrozulimab After completion of cycle 2, complained of some abdominal cramping and loose stools-approximately 8 episodes/day Was scheduled to get cycle 3, however given ongoing diarrhea and concern for possible colitis, treatment was held and patient was initiated on steroids. 60 mg of prednisone daily 1 week, followed by a slow taper over 10 days. F/u in 1 week-improvement in bowel movements. Normal, formed stools 1/day. Plan to resume pembrozulimab cycle 3 if symptoms resolve. 2 week f/u.
Timeline 2 week f/u: finished prednisone day before appointment and started having diarrhea symptoms again, having about 4-5bm/day, loose, associated with abdominal cramping. Rule out C. dificile-negative. Placed back on 40 mg of prednisone for the next 7 days. Prednisone taper once again initiated with instructions to take Imodium as needed.
Timeline Off Imodium and prednisone for 1 week and started having diarrhea again-6-7 bm/day, right after eating. Pale, muddy brown and undigested food particle. Prescription sent to pharmacy for Imodium and referral to GI for persistent diarrhea for consideration for colonoscopy.
Colonoscopy She was seen by gastroenterology and had a colonoscopy done which showed colonic ulceration and friable mucosa favoring collagenous colitis.
Colonoscopy images
Pathology Enhanced collagen table beneath the superficial epithelium, as well as intraepithelial lymphocytosis.
Pathology This shows how the superficial epithelium can strip off as a result of the thickened collagen.
Timeline Developed acute kidney injury during her f/u lab appointment- serum creatinine 3.06(baseline 1.06 a month prior), thought to be secondary to dehydration. Admitted to the hospital for hydration and close monitoring. Initiated on budesonide 9mg/day and cholestyramine 8g/day. Completed a 3 days of therapy in the hospital with marked improvement in her symptoms.
Final Diagnosis Persistent diarrhea secondary to collagenous colitis from Pembrolizumabsignificant improvement with cholestyramine and budesonide. Completed a 6 week therapy of budesonide and cholestyramine with resolution of her symptoms.
Treatment Active disease: 3 stools or 1 watery stool daily, persistent diarrhea despite antidiarrheals: budesonide 9mg/d for 4 weeks Clinical remission: Taper budesonide to 6 mg for two weeks, followed by 3 mg for another two weeks, and then discontinue therapy. If the symptoms are not controlled or if symptoms recur on tapering, the dose of 9 mg can be continued for 12 weeks or longer before tapering budesonide.
Refractory treatment Failure to respond to budesonide, but with mild symptoms: concomitant therapy with loperamide and cholestyramine If patients fail to respond to a short, 2 week trial of cholestyramine, bismuth salicylate(limited availability and data). Recurrent sx-if recurrent sx after initial tx with budesonide, can either be retreated with budesonide as intermittent therapy or as continuous maintenance therapy at the lowest dose that maintains clinical remission
Discussion As pembrozulimab gets approved for use in a variation of different cancers, with recent approval in September for gastric cancer as per keynote study 059 2, it will be important to monitor for its side effects and have effective surveillance and treatment strategies moving forward in the future. Usually, PD1 inhibitor associated colitis is thought to be immune mediated and prednisone is initiated which controls the symptoms.
Conclusion However, if not improving, low threshold for obtaining a colonoscopy to rule out collagenous colitis as treatment regimen would vary. Prednisone leads to reduction in the inflammation in the colon, however does not act on reducing the thickness of the collagen band. In studies, it was noted that prednisone had lower response(53 vs. 83%), higher relapses and more side effects when compared to budesonide.
Questions?
References Bonderup OK, Hansen JB et. al. Budesonide treatment of collagenous colitis: a randomised, double blind, placebo controlled trial with morphometric analysis. Gut. 2003;52(2):248. Chande N., MacDonaldJ.K., McDonaldJ.W. Interventions for treating microscopic colitis: a Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group systematic review of randomized trials. Am J Gastroenterology104, 2009, 235-241 Miehlke S, Madisch A, et.al. Long-term follow-up of collagenous colitis after induction of clinical remission with budesonide. Aliment Pharmacol Ther. 2005;22(11-12):1115. Sloth, H et. al. Collagenous colitis: a prospective trial of prednisolone in six patients. J Intern Med. 1991;229(5):443 Gentile NM, Abdalla AA et.al Outcomes of patients with microscopic colitis treated with corticosteroids, a population based study. Am J of Gastroenterol Feb 2013. 108(2):256-9 Weijie Ma, Barbara M. Gilliga, et.al. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. Journal of Hematology and Oncology 2016. 9:47 Baroudjian B, Lourenco N et. al. Anti-PD1-induced collagenous colitis in a melanoma patient. Melanoma Research 2016, June: 26(3):308-11 https://www.keytruda.com/hcp/mechanism-of-action/
Thank you! Special thank you to Dr. Ambika, Dr. Matteoni and Dr. Usera