Long-term response with the atypical reaction to nivolumab in microsatellite stability metastatic colorectal cancer: A case report

Patient information

A 42-year-old man, never smoker, with abdominal pain accompanied by nausea was taken by ambulance to the local hospital in August 2017, where intestinal obstruction was verified. His medical history included сhronic cholecystitis, chronic pancreatitis, and mixed etiology of hepatitis. The patient underwent abdominal stoma surgery. Biopsy revealed a highly differentiated adenocarcinoma. The patient independently visited Tomsk Cancer Research Institute for further examination, where he underwent left hemicolectomy and colostomy suturing. Pathologic verification of resection specimens confirmed moderately differentiated adenocarcinoma with mucinous features and foci of severe fibrosis, as well as comedo necrosis and with an accompanying lymphocytic infiltrate and invasion into the serous membrane. The patient was diagnosed with splenic flexure colon cancer, T4N3M0, stage IIIC. However, a month later, during an additional examination in October 2017, supraclavicular lymph node metastases on both sides were detected. Due to definitive evidence of disseminated disease, the patient was upstaged to stage IV. Molecular testing of the tumor revealed the KRASp.G12D mutation.

MSS/pMMR phenotype

Immunohistochemistry analysis of MMR protein expression (MLH1, MSH2, MSH6, and PMS2) demonstrated a homogeneous pattern of their proficiency in colon tumor tissue (Fig. 1A). Polymerase chain reaction (PCR) assay confirmed the MSS phenotype for three different colon tumor specimens (Fig. 1B). With respect to PD-L1 status, a weak expression (TPS-1% and CPS-6.0) in several colon tumor specimens was independently detected by two researchers.

Chemotherapeutic intervention

Patient was started on a first-line FOLFOX plus bevacizumab regimen, which consisted of bevacizumab 5 mg/kg on day 1, oxaliplatin 85 mg/m² on day 1, leucovorin 400 mg/m² on day 1, and 5-fluorouracil 400 mg/m² bolus injection followed by 46-hour continuous infusion of 5-fluorouracil 2,400 mg/m² on day 1. After four cycles of treatment, the partial response per RECIST 1.1 was recorded. In June 2018, the patient completed 14 cycles of chemotherapy and following the chest computed tomography (CT) images showed the appearance of randomly located focal nodules of up to 7 mm in size consistent with lung metastases. The levels of tumor markers such as CEA, CA19-9, and CA242 did not exceed the normal values, being 0-3.40 ng/mL for CEA, 0-34 U/mL for CA19-9, and 0-20.0 U/mL for CA242.

Second-line treatment with FOLFIRI and aflibercept (aflibercept 4 mg/kg on day 1, irinotecan 180 mg/m² on day 1, leucovorin 400 mg/m² on day 1, 5-fluorouracil 400 mg/m² bolus injection followed by 46-hour continuous infusion of 5-fluorouracil 2,400 mg/m²) was initiated. Repeat CT images after three cycles showed no growth of focal nodules in the lung. This treatment was associated with adverse events such as of grade 2 hypertension, nausea, and thrombocytopenia. CT assessment after seven cycles of treatment confirmed a stable response. Due to an acute exacerbation of mixed etiology hepatitis (chronic hepatitis B with serum hepatitis B virus DNA titer >10⁵ copies/mL and toxic hepatitis) and an abnormal alanine aminotransferase exceeding nine times the upper limit of normal at baseline, subsequent treatment was interrupted. The patient received hepatoprotective and detoxification treatment. Approximately 2 months later, CT scans showed an increase of nodule size in the lung (Fig. 2A).

Nivolumab administration

Given the fast progression and PD-L1 status, treatment with nivolumab at a dose 240 mg was started in December 2018. Three months later, most of the previously identified focal nodules in the lung were not clearly visualized by CT, the remaining lesions decreased in size up to 1-2 mm. In May 2019, chest CT scans confirmed the reduction of lung nodules (Fig. 2B). However, a para-aortic lymph node (PALN) on the left up to 15×12 mm was found (Fig. 2C). Using the iRECIST as a modified immune RECIST criterion (10), the response was classified as a dissociated response. MSS phenotype in lymph node was further verified by PCR (Fig. 1B).

Further administration of nivolumab allowed achieving positive dynamics in terms of the disappearance of lesions in the lung (Fig. 2D) and the absence of the growth of PALN metastases in August 2019 (Fig. 2E). An immune stable disease (iSD) per iRECIST was recorded until September 2021, when we had to discontinue treatment due to the patient being infected with COVID-19. The administration of nivolumab was resumed; however, in April 2022, CT scans revealed an increase in the size of PALN by 7 mm compared with the baseline (Fig. 2F). The decision to initiate FOLFOX plus bevacizumab therapy (bevacizumab 5 mg/kg on day 1, oxaliplatin 85 mg/m² on day 1, leucovorin 400 mg/m² on day 1, and 5-fluorouracil 400 mg/m² bolus injection followed by 48 hours continuous infusion of 5-fluorouracil 2,400 mg/m² on day 1) was taken by a multidisciplinary staff. Due to the experience of hypersensitivity reaction to oxaliplatin after three cycles, the patient was switched to the bevacizumab in combination with capecitabine regimen (bevacizumab 5 mg/kg and capecitabine 2,500 mg/day, days 1 and 14). Currently, the patient has completed 10 cycles of this therapy with good tolerance.