Dr Akhade on Building the Evidence Base for Low-Dose Immunotherapy

The challenge is not of the trial design, or the challenge is not of enrolling the patient. The challenge is to get the funds, because such academically initiated trials are difficult to get the funds for.

In an interview with OncLive, Amol Akhade, MD, a medical oncologist at Fortis Hospitals in Mumbai, discussed the evidence supporting reduced-dose checkpoint inhibition and what would be needed to move the approach into treatment guidelines.

Pharmacokinetic modeling has indicated that receptor occupancy is achieved at doses well below those approved, providing a rationale for de-escalation.1 In the phase 3 DELII trial, 500 patients with relapsed or refractory solid tumors treated at Tata Memorial Hospital in Mumbai between June 2020 and February 2024 were randomly assigned to nivolumab at 20 mg every 2 weeks or to docetaxel or paclitaxel; ultra-low-dose nivolumab improved overall survival. Investigators at the same center have also reported a survival benefit with ultra-low-dose nivolumab plus oral metronomic chemotherapy in recurrent/metastatic HNSCC.

Akhade traced the concept back roughly a decade, to work by Daniel A. Goldstein, MD, on the pharmacoeconomic rationale for dose de-escalation. Receptors saturate at a given exposure, he said, and additional drug beyond that point may add little. Most supporting data remain retrospective or drawn from real-world experience, and no randomized comparison of approved vs reduced dosing has been conducted.

A checkpoint inhibitor that is effective in a given setting appears to work regardless of dose, Akhade said, whereas one that fails because of tumor biology or resistance fails at any dose. He cited MSI-high colorectal cancer, where reduced dosing performed comparably with full dose, and characterized these observations as hypothesis generating.

Guideline adoption would require a phase 3 non-inferiority trial, with margins varying by setting — narrower in early-stage triple-negative breast cancer than in metastatic disease, he said. The obstacle is funding rather than trial design or accrual, given the cost of an approved-dose control arm. DELII was randomized against chemotherapy rather than full-dose nivolumab for that reason, according to Akhade.