Background:: Metastatic microsatellite instability-high (MSI-H) colorectal cancer (CRC) is one of the rare gastrointestinal tumors where immune checkpoint inhibitors (ICIs) have a defined therapeutic role. Single-agent nivolumab, single-agent pembrolizumab and the combination of nivolumab plus ipilimumab are all FDA-approved therapies in patients with refractory disease. Limited data exists however, on how to treat patients who progress on anti-programmed cell death protein 1 (PD-1) therapy, specifically with regards to continuing immunotherapy. We present the case of a young woman with MSI-H CRC who received nivolumab plus ipilimumab post-progression on pembrolizumab and remains in partial response. To the best of our knowledge, this is the first report of such a phenomenon in a CRC patient.
Case Presentation:: A 39-year-old female with MSI-H (loss of MSH2 and MSH6 by initial immunohistochemistry) cecal adenocarcinoma started therapy with pembrolizumab in February 2018 after progressing on a clinical trial with fluorouracil and irinotecan (FOLFIRI) plus a matrix metalloproteinase-9 inhibitor. In October 2018, although she met criteria for stable disease by RECIST 1.1 on CT scans, she began to exhibit mild growth in her lung metastases. Because she had been tolerating pembrolizumab well, she was continued on the therapy. In December 2018 she developed overt disease progression in her liver and was taken off the anti-PD-1 antibody. Given her tumor mutational burden (55 Muts/Mb) and absence of other meaningful options, her therapy was switched to nivolumab plus ipilimumab (240 mg and 1 mg/kg every 3 weeks, respectively). She received 4 doses of the combination and her first restaging scans in March 2019 demonstrated stable disease (20% tumor reduction). She was transitioned to single agent nivolumab every 2 weeks thereafter and demonstrated a partial response (30% tumor reduction) on her subsequent CT scans in June 2019.
Conclusion:: We have found no prior published reports of MSI-H CRC patients responding to combination immunotherapy with nivolumab plus ipilimumab after prior progression on anti-PD-1 antibodies. This approach has been successful in metastatic melanoma patients and warrants prospective clinical trial evaluation in MSI-H CRC patients to assess whether it can influence future post-ICI progression treatment strategies.
Keywords: Anti-cytotoxic T-lymphocyte-associated protein 4; Anti-programmed cell death protein 1; Checkpoint inhibitor progression; Metastatic colon cancer; Mismatch repair deficiency.