Nivolumab Plus FOLFOXIRI/Bevacizumab Elicits Promising Responses in RAS/BRAF-Mutated mCRC

The addition of nivolumab (Opdivo) to FOLFOXIRI and bevacizumab (Avastin; FOLFOXIRI-B) resulted in encouraging responses when used as frontline treatment in patients with advanced or metastatic colorectal cancer (mCRC) harboring RAS or BRAF mutations, irrespective of microsatellite status, according to data from the phase 2 NIVACOR trial (NCT04072198).¹

The findings presented during the 2022 ASCO Annual Meeting showed that at a median follow-up of 14.3 months, the regimen induced an objective response rate (ORR) of 76.7% in the intention-to-treat (ITT) population (n= 73), meeting the primary end point of the trial.

Among those who responded to treatment, 9.6% achieved a complete response (CR) rate was 9.6% and 67.1% experienced a partial response (PR). Additionally, 20.6% of patients had stable disease, and 57.5% experienced disease progression. The median duration of response (DOR) was 8.4 months (range, 7–not evaluable [NE]), and the disease control rate was 97.3%.

In the subgroup of patients with MSS disease (n = 52), the combination elicited an ORR of 78.9%, with a median DOR of 7.59 months (range, 6.21-11.43); in these patients, the DCR achieved with the regimen was 96.2%.

“Nivolumab plus FOLFOXIRI/bevacizumab showed promising activity, also in the MSS subgroup, with a manageable safety profile,” lead study author Angela Damato, MD, PhD, of the Medical Oncology Unit, Azienda USL-IRCCS Reggio Emilia, and colleagues, wrote in a poster on the data.

FOLFOXIRI-B is the standard of care for the frontline treatment of patients with mCRC. However, the efficacy of immune checkpoint inhibitors, such as nivolumab, has been limited to patients with mismatch repair–deficient (dMMR)/microsatellite instable (MSI) disease. Prior research showed that the combination of anti-VEGF antibodies and immune checkpoint inhibitors lead to immune stimulation and vascular remodeling.²

For the multicenter, single-arm, open-label NIVACOR study, investigators sought to examine the efficacy of nivolumab in combination with FOLFOXIRI-B as a frontline treatment in patients with mCRC harboring RAS/BRAF mutations. The trial enrolled patients between 18 and 75 years of age who presented with untreated, advanced mCRC that harbored a RAS/BRAF mutation.³ Moreover, participants were required to have an ECOG performance status of 0 or 1. Patients were enrolled irrespective of microsatellite status.

The trial accrued 73 patients between October 2019 and March 2021, and the data cut-off was December 31, 2021. All patients received induction treatment, which was comprised of 240 mg of nivolumab, 5 mg/kg of bevacizumab, and FOLFOXIRI, administered every 2 weeks for 8 cycles. FOLFOXIRI was comprised of 165 mg/m2 of irinotecan, 165 mg/m² of oxaliplatin, 200 mg/m² of leucovorin, and 3,200 mg/m² of 5-fluouracil over the course of 48 hours.

Patients who achieved a CR, PR, or stable disease with induction treatment then went on to receive nivolumab plus bevacizumab as maintenance therapy, given every 2 weeks until disease progression or unacceptable toxicity.

In addition to the primary end point of ORR per RECIST v1.1 criteria, key secondary end points included progression-free survival (PFS), overall survival (OS), time to progression, and safety.

The median age of enrolled patients was 60 years (range, 51-65), and 50.7% were male. Moreover, 50.7% of patients had their primary tumor on the right side, 43.8% had it on the left side, and 5.5% had it in the transversum.

Metastases were located in the liver (56.2%), peritoneum (32.9%), lymph nodes (35.6%), and lungs (17.8%). Additionally, 87.7% of patients had tumors that harbored a RAS mutation, 16.2% harbored a BRAF mutation, and 4.5% harbored both. The microsatellite status of 15.1% of patients was not available at baseline. Among the 62 evaluable patients, 16.2% had dMMR/MSI disease, and 83.8% had mismatch repair–proficient/MSS disease.

Additional data showed that in the overall ITT population, nivolumab plus FOLFOXIRI-B resulted in a median PFS of 10.1 months (95% CI, 9.4-NE). In the subset of evaluable patients with MSS disease (n = 36/52), the median PFS with the regimen was 9.82 months (95% CI, 8.18-15.24); the median PFS was NE (95% CI, 14.2-NE) in the subset of evaluable patients with MSI disease (n = 2/10).

The most frequent treatment-related adverse effects (TRAEs) of any grade associated with FOLFOXIRI included diarrhea (60.3%), neutropenia (53.4%), fatigue (52.1%), nausea/vomiting (45.2%), and paresthesia (43.9%). Grade 3 or 4 neutropenia and diarrhea due to FOLFOXIRI occurred in 37% and 19.2% of patients, respectively.

Common any-grade TRAEs linked to bevacizumab included hypertension (15.1%), other non-hematological TRAEs (8.2%), and proteinuria (4.1%). Grade 3 or 4 hypertension and other non-hematological effects due to bevacizumab were experienced by 6.9% and 1.4% of patients, respectively.

The most common any-grade TRAEs associated with nivolumab included diarrhea (31.5%), fatigue (23.3%), other immune-related TRAEs (22%), hypothyroidism (15.1%), and hyperthyroidism (6.9%). Grade 3 or 4 TRAEs due to the immunotherapy included diarrhea (6.9%), fatigue (2.8%), and other immune-related effects (2.8%).

References

1. Damato A, Bergamo F, Antonuzzo L, et al. Phase II study of nivolumab in combination with FOLFOXIRI/bevacizumab as first-line treatment in patients with advanced colorectal cancer RAS/BRAF mutated (mut): NIVACOR trial (GOIRC-03-2018). J Clin Oncol. 2022;40(suppl 16):3509. doi:10.1200/JCO.2022.40.16_suppl.3509
2. Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018;15(5):310-324. doi:10.1038/nrclinonc.2018.9
3. Nivolumab plus FOLFOXIRI/bevacizumab in first line chemotherapy of advanced colorectal cancer RASm/BRAFm patients (NIVACOR). ClinicalTrials.gov. Updated July 31, 2020. Accessed July 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04072198