Nivolumab Received FDA Approval for Stage 4. Colon and Rectal Cancer

On 31 July 2017, the United States Food and Drug Administration, FDA, granted accelerated approval after disease continued progressing following fluoropyrimidine, oxaliplatin and irinotecan treatment, in patients with deficient DNA repair genes (Mismatch Repair System, dMMR) and high microsatellite instability (MSI-H) who were aged 12 or older with metastatic colorectal cancer, for the immunotherapy drug Nivolumab (trade name Opdivo).

Microsatellites: DNA is copied by matching each nucleotide with its partner (for example, adenine (A) with thymine (T); cytosine (C) with guanine (G)). Some errors (such as mismatches) can occur during replication involving 3 billion nucleotide matches. DNA repair genes normally detect and repair them. In some cancers, however, mismatches cannot be repaired, and this is called a mismatch repair defect in terminology. Microsatellites are these unmatched DNA sequences, which repeat and accumulate, causing mutations that lead to genomic instability as a result.

This FDA approval is based on data involving patients identified through genetic analysis as dMMR or MSI-high whose disease progressed during or after fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy despite treatment, or who could not tolerate it, totaling 53 metastatic colorectal ( large intestine ) cancer patients in a multicenter, open-label, single-arm study. They constituted most of the study's 74 metastatic colorectal cancer patients who had previously received fluoropyrimidine combined with oxaliplatin or irinotecan at least once for metastatic disease.

All patients received 3 mg/kg nivolumab by intravenous infusion every two weeks until unacceptable side effects or radiologically demonstrated continuing disease progression.

In the 53 patients previously receiving fluoropyrimidine, oxaliplatin and irinotecan, the objective response rate assessed by an independent radiological review committee was %28 (n=15 patients). In %67 of patients, responses reportedly lasted at least 6 months. One patient had a complete response and 14 had partial responses. Among all 74 patients, the objective response rate was %32 (n = 24 patients).

Nivolumab has not been studied in pediatric (child) patients. For adolescents with MSI-high or dMMR stage 4. colorectal cancer (aged 12 and older), effectiveness was extrapolated from results in the corresponding adult population.

The most common side effects of single-agent nivolumab are fatigue, rash, musculoskeletal pain, itching, diarrhea, nausea, cough, difficulty breathing, constipation, decreased appetite, lower back pain, joint pain, upper respiratory tract infection and fever.

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• What are immunotherapy side effects, and how are they managed?

For this indication, the recommended nivolumab doseis every 2 weeks at 240 mg.

What Is Nivolumab's Mechanism of Action?

Nivolumab is an immunotherapy drug and immune checkpoint inhibitor enabling immune cells to attack cancer cells more effectively. By targeting the PD-1/PD-L1 interaction, it prevents immune cells from perceiving cancer cells as “friends”.

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• The immunotherapy drug pembrolizumab ( Keytruda ) had previously also received FDA approval for patients with MMR-deficient and MSI-H cancer.