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Nivolumab in CRC
Immunotherapy for an Elderly Patient With Symptomatic, Rapidly Progressive MSI-High CRC: A Case Study

Released: May 10, 2017

Expiration: May 09, 2018

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In this case study, I discuss how I used the latest data on prognostic biomarkers and immunotherapy to optimally manage a patient with microsatellite instability (MSI)-high colorectal cancer (CRC) who progressed through adjuvant FOLFOX.

My patient was a 75-year-old woman who had presented to the emergency department with hematochezia and symptomatic anemia. CT of chest, abdomen, and pelvis revealed an 8-cm sigmoid mass but no metastatic disease, and a colonoscopy confirmed a nonobstructing mass in the sigmoid colon. She underwent a left hemicolectomy, and the pathologic assessment found a poorly differentiated adenocarcinoma that had invaded the muscularis propria and pericolonic tissue; it was present at the serosal surface with a contained focal perforation. There was lymphovascular invasion but no perineural invasion, no tumor deposits, no lymph node involvement, and negative margins. She was staged as a stage IIb, or a T4a, N0. Testing indicated loss of MLH1 and PMS2 expression, BRAF mutation, and a methylated MLH1 promoter, suggesting that she had a sporadic form of MSI-high tumor.

Given the local perforation and high-risk stage II features, she was treated with adjuvant FOLFOX, which she tolerated well. After 5 cycles, she developed abdominal pain, and restaging showed multiple, fairly large pelvic mesenteric nodules. A PET/CT scan confirmed that these were FDG-avid nodules, with an SUV up to 10 predominantly in the left quadrants, but no disease elsewhere. Given the atypical presentation of recurrence while receiving adjuvant therapy, her pelvic mass was biopsied, which confirmed the same poorly differentiated adenocarcinoma with the same markers—CK20 negative, CK7 negative, intact pan-cytokeratin.

Second-line Treatment With Nivolumab
At this point, she presented to my practice. Given her MSI-high status, I started her on the PD-1 inhibitor nivolumab with the standard every-2-week dosing regimen (3 mg/kg). She tolerated the treatment very well without any referable immune-related adverse events. After 2 months of treatment, her pelvic symptoms resolved and she no longer needed pain medication. Restaging demonstrated responding disease in the pelvic mesenteric nodules.

She has continued therapy now for approximately 8 months, and the disease has continued to regress—it is now down to 1.5 cm in maximum dimension with improvement in her tumor markers. Her tolerance remains excellent other than a slight increase of her TSH, but she maintains a normal free T4. She remains on treatment.

Fortunately for others like my patient, there are studies planned on adjuvant immunotherapy in MSI-high patients. The NCI is planning a phase III trial enrolling MSI-high patients with stage III colon cancer to randomize to combination chemotherapy with or without atezolizumab, a PD-L1 inhibitor.

Biomarkers in Immunotherapy: Key Considerations
We know that MSI in metastatic disease is a poor prognostic sign, and that a BRAF mutation is associated with aggressive, rapidly progressing disease. Thus, when we encounter symptomatic patients with these biomarkers and aggressive disease unresponsive to first-line chemotherapy, we must consider whether further therapy is warranted, especially for older patients. Fortunately, PD-1 inhibition is well tolerated in these patients. Although we may have hesitated in the past to administer further therapy, this population’s outcomes with immunotherapy have been impressive, and we now have a lower threshold for attempting immunotherapy in these patients. The PD-1–targeted antibody nivolumab has demonstrated promising clinical activity and survival (with and without ipilimumab) in patients with MSI-high metastatic CRC enrolled in the phase II CheckMate-142 trial (N = 74). In this study, the ORR to nivolumab monotherapy was approximately 30%, including 2 CRs, and an additional 40% of patients achieved stable disease. Furthermore, a 74% 12-month OS rate was noted among patients with MMR-deficient/MSI-high CRC who received single-agent nivolumab. In a phase I study of pembrolizumab, another anti–PD-1 antibody, in patients with CRC and MMR deficiency (n = 28), the ORR was 57% (including CRs in 11%) vs 0% in patients with MMR-proficient disease (n = 25). 

However, I would still administer FOLFOX first to a patient with MSI-high metastatic CRC. Currently, we lack long-term data on patients treated with PD-1 inhibitors. The latest data show higher response rates and better disease control with immune checkpoint inhibitors than other second-line or third-line options in MSI-high tumors, but it remains to be seen how PFS will compare with first-line chemotherapy like FOLFOX. Therefore, current guidelines mostly recommend nivolumab or pembrolizumab as a second-line and third-line option. Now, however, we can rapidly move patients with progression on first-line chemotherapy to immunotherapy. In addition, immune checkpoint inhibitor therapy can be offered to patients with MSI-high CRC not tolerating first-line therapy, but it is currently not standard practice to use immunotherapy in an otherwise healthy patient as first-line treatment.

To review additional guidance on immune checkpoint inhibitors, please click here for educational materials and resources on biomarkers of response to immunotherapy.

How do you use a patient’s MSI status to select a treatment regimen after progression? Share your perspective in the comment box below!

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