Low-Dose Nivolumab Plus Chemotherapy an Accessible Alternative to Full-Dose Checkpoint Inhibitors in Head and Neck Cancer

Vijay Maruti Patil, MBBS, MD, DM

Low-dose treatment with nivolumab (Opdivo) in addition to triple metronomic chemotherapy (TMC) improved overall survival (OS) over TMC alone for patients with advanced head and neck cancer, according to findings published in the Journal of Clinical Oncology. These data suggest that this treatment approach may be an acceptable alternative for patients who cannot access full-dose checkpoint inhibitors.

Among 151 patients who were randomly assigned to receive either TMC alone (n = 75) or in addition to intravenous nivolumab (TMC-I; n = 76). The 1-year OS rate was 43.4% (95% CI, 30.8%-55.3%) in the TCM-I arm vs 16.3% (95% CI, 8.0%-27.4%) in the TMC arm (HR, 0.545; 95% CI, 0.362-0.820; P = .0036). The median OS in the TMC-I arm was 10.1 months (95% CI, 7.4-12.6) compared with 6.7 months (95% CI, 5.8-8.1) in the TMC arm (P = .0052). The adjusted HR in favor of the TMC-1 arm was 0.486 (95% CI, 0.311-0.758; P = .001).

“Relative to metronomic chemotherapy alone, the addition of low-dose nivolumab led to improvements in OS, progression-free survival [PFS], response rate, and certain domains of quality of life,” wrote Vijay Maruti Patil, MBBS, MD, DM, of the department of Medical Oncology at the Tata Memorial Hospital in Mumbai, India, and coinvestigators. “This was achieved without an increase in the rate of adverse events.”

In low- and middle-income countries, only 1% to 3% of patients with advanced head and neck squamous cell carcinoma are able to afford the immunotherapy regimens recommended in the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines.1 TMC has been shown to improve survival in this stating and retrospective data suggest that low-dose nivolumab may be beneficial, prompting investigators to evaluate the regimen.

The randomized, phase 3 superiority study included adult patients with recurrent or newly diagnosed, advanced head and neck squamous cell carcinoma who were being treated with palliative intent. Patients had an ECOG performance status of 0 or 1.

Participants were randomly assigned to receive either either oral methotrexate 9 mg/m2 once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily, or TMC-I at a flat dose of 20 mg once every 3 weeks. One-year OS represented the primary end point.

At a median follow-up of 10.9 months (95% CI, 10.6-12.2) and a median IQR of 9.1-12.7 months, there were a total of 99 deaths, including 58 deaths in the TMC arm and 41 deaths in the TMC-I arm.

Moreover, there were 66 PFS events in the TMC arm and 52 in the TMC-I arm for PFS. The median PFS with chemotherapy alone was 4.6 months (95% CI, 4.2-5.3) and 6.6 months (95% CI, 4.4-8.9), respectively (P = .002). Adding low-dose nivolumab decreased risk of progression or death by 44% (HR, 0.563; 95% CI, 0.389-0.816).

In 61 patients (81.3%) in the TMC arm and in 46 patients (60.5%) in the TMC-I arm, disease progression was observed as an event before death. Among patients receiving chemotherapy alone, first progression occurred in both the locoregional (n = 50; 66.7 %) or distant setting (n = 3; 4.0%), and in 8 cases (10.7%) first progression occurred in both. Among patients receiving the combination therapy, the rates of locoregional and distant progression were 51.3% (n = 39) and 3.9% (n = 3), respectively. In 4 cases, progression occurred in both sites (5.3%).

Overall, the response rates between the TMC and TMC-I arms were 45.3% (95% CI, 34.6%-56.6%) and 59.2% (95% CI, 48.0%-69.5%), respectively. The median time to best response was 2.1. months (IQR, 2.0-4.1) and 2.4 months (IQR, 21.-5.6), and the median duration of response (DOR) was 3.3 months (95% CI, 2.5-5.2) and 8.7 (5.8–not assessable; P = .003). Moreover, in the TMC-I, the median DOR was not reached among patients with a PD-L1 score greater than 50% (95% CI, 4.2-NA). For those who had a PD-L1 score below 50% or unknown, the median duration was 8.1 months (95% CI, 4.5-9.0; P = .045).

The rates grade 3 or worse AEs in the TMC and TMC-I arm was 50% (n = 74) and 46.1% (n = 76). Two patients in the TMC-I arm died during treatment one of whom developed aspiration pneumonia, where the other had a reactivation of Hepatitis B and developed the hepatorenal syndrome.

The most common any-grade AEs in the TMC arm included fatigue (100%), hyponatremia (83.8%), anemia (79.7%), mucositis (79.7%), rash (68.9%), and diarrhea (68.9%). In the TMC-I arm, the most common any-grade AES were fatigue (98.7%), hyponatremia (93.4%), anemia (89.5%), mucositis (73.7%), rash (72.4%) and diarrhea (64.5%).

Six patients in the TMC arm (8.0%) and 5 patients in the TMC-I arm (6.6%) required a dose reduction (P = .765). Specifically, erlotinib (Tarceva)reductions were needed in 5 (6.7%) and 4 patients (5.3%) in the TMC and TMC-I arms, respectively, and methotrexate dose reductions were necessary for 1 patient in each arm (P = 1.0). The median number of treatment cycles in the 2 arms was 7 (IQR, 4-10) and 8 (IQR, 5-13).

Of note, patients receiving TMC-I also performed relatively better compared with those in the TMC arm in terms of physical functioning (HR, 0.687; 95% CI, 0.479 to 0.986) and role functioning (HR, 0.692; 95% CI, 0.484-0.990).

Reference

Patil VM, Noronha V, Menon N, et al. Low-dose immunotherapy in head and neck cancer: a randomized study. J Clin Oncol. 2023;41(2):222-232. doi:10.1200/JCO.22.01015