Author: M. Alexander Otto, PA, MMS

A randomized clinical trial from India raises the possibility of huge cost savings by using much lower doses of immunotherapy.

The researchers used just 6% of the recommended dose of nivolumab instead of the full dose in their treatment of patients with advanced head and neck cancer, and the addition of this low dose to the standard regimen improved 1-year survival by 25%.

The study was published on January 10 in the Journal of Clinical Oncology and has been downloaded almost 2000 times.

The findings suggest that low doses of immunotherapy might be equivalent to the much higher doses that are approved and are currently used, two medical oncologists comment in a related editorial.

If these findings can be extrapolated to other immune checkpoint inhibitors and to other tumor types, switching to the lower doses could save healthcare systems billions of dollars, write Aaron Mitchell, MD, of Memorial Sloan Kettering Cancer Center, New York City, and Daniel Goldstein, MD, of Tel Aviv University, Israel.

Improving Access
With limited resources, the Indian healthcare system cannot afford full-dose checkpoint inhibitors, and as a result, fewer than 5% of patients have access to them, explained trial investigators led by Vijay Maruti Patil, MD, a medical oncologist at Tata Memorial Hospital, Mumbai, India.

The goal of the trial was to see whether lower, less expensive doses were effective for patients with advanced head and neck cancer. The idea is to increase access by making treatment more affordable, the authors explain.

In the trial, nivolumab 20 mg was administered every 3 weeks ― a dose far lower than the US Food and Drug Administration–approved flat dose of 240 mg every 2 weeks. Resulting treatment costs were only 5% to 9% of the cost of full-dose immunotherapy regimens.

Low-dose nivolumab was added to a treatment course recommended for advanced head and neck cancer in resource-limited settings: methotrexate 9 mg/m2 once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily.

One-year overall survival (OS) improved from 16.3% to 43.4% with low-dose nivolumab (hazard ratio, 0.545; P = .0036). Median OS improved from 6.7 months to 10.1 months (P = .0052), with associated gains in quality of life.

Patil and his team call the combination “an alternative standard of care” that can substantially reduce drug costs and increase access to immunotherapy in resource-limited settings.

There are plenty of lessons for the United States, Europe, and other resource-rich settings, Mitchell and Goldstein say.

A “Viable Solution” to Drug Costs
“Much has been written in recent years regarding the extraordinary high cost of cancer drugs,” the editorialists say, but “very few viable solutions have been provided.” With “vigorous lobbying” from drugmakers, “the status quo has been maintained, and prices remain high.

“Here, a very viable solution has been demonstrated” that runs “counter to the financial interest of the pharmaceutical industry.” The “importance extends beyond head and neck cancer and beyond nivolumab…. Many similar opportunities for dose de-escalation exist for other cancer drugs,” they write.

The example offered by this new study as well as others ― including the “well-established” practice of abiraterone dose reductions to improve access for patients with prostate cancer ― “should be used as a springboard to assess the opportunities for dose de-escalation across cancer types and pharmaceutical agents,” Mitchell and Goldstein say.

“The fact that much lower doses of nivolumab produce clinical benefit comparable with conventional doses should come as no surprise, given what has long been known regarding the underlying pharmacokinetics of this drug,” they note.

“Early phase I data found similar receptor occupancy and response rates with doses ranging from 0.1 mg/kg to 10 mg/kg once every 2 weeks,” they point out. For a 70-kg patient, 0.3 mg/kg would work out to about 20 mg per administration, which is why the dose was selected for the trial, they explain.

Study Details
The 151 adults in the trial had recurrent or newly diagnosed advanced disease and were being treated with palliative intent. Their performance scores were 0–1; most had malignancies of the oral cavity, and for more than 50% of patients, platinum-based regimens had failed.

Seventy-five patients were randomly assigned to the baseline regimen, and 76 were assigned to that regimen plus low-dose nivolumab. Conserving medication, investigators shared 40-mg vials of nivolumab between patients. The outcomes suggest that nivolumab is stable after vials have been open for a month, the investigators say.

The rate of grade 3 or worse events was about 50% in both arms, which is lower than in the phase 3 approval trials of checkpoint inhibitor regimens for head and neck cancer.

The benefit of low-dose nivolumab as add-on therapy was seen regardless of PD-L1 status and previous platinum failures.

The team concludes that their results show that “the addition of low-dose nivolumab to metronomic chemotherapy led to improved overall survival and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.”

J Clin Oncol. 2023 Jan 10;41:170-172. Full text, Editorial

The trial was funded by NATCO Pharma, INTAS Pharmaceuticals, the Mumbai Oncology Association, and Motivation for Excellence. Three investigators have disclosed relationships with industry, including Patil, who has received research funding from NATCO, INTAS, Johnson & Johnson, AstraZeneca, Eisai, and Novartis. Goldstein is an advisor for Vivio; he also has ownership interests in Vivio and TailorMed and has received research funding from Merck, BMS, and Janssen. Mitchell received a $1000 grant from Merck in 2018.