Ultra-Low-Dose Immunotherapy May Benefit Cancer Patients in Low-Resource Countries

CHICAGO — Triple oral metronomic chemotherapy combined with ultra-low-dose immunotherapy (TMC-I) may be a promising first-line treatment for patients in low-resource countries with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), an open-label phase III trial suggested.

TMC-I extended median overall survival (OS), the primary endpoint, to 10.3 months from 6.2 months in patients randomized to paclitaxel plus carboplatin, corresponding to a 43% lower risk of death (HR 0.565, 95% CI 0.439-0.728; P<0.001), Minit Jalan Shah, MBBS, MD, of the Tata Memorial Centre in Mumbai, India, reported at a press conference during the American Society of Clinical Oncology (ASCO) annual meeting.

The survival benefit of TMC-I was consistent across subgroups, with a greater benefit observed in those with oral cavity cancer and those who used or had used tobacco, Shah added. There also were fewer serious adverse events in patients randomized to TMC-I.

The findings could allow patients from low-resource countries to access immunotherapy at a fraction of the cost of the standard dosages used in higher-resource settings, Shah noted.

TMC-I “offers a practical, scalable, and globally relevant first-line treatment option for advanced head and neck squamous cell carcinoma,” he said. The cost of TMC-I is approximately $2,700 per year, compared with about $12,000 per year for chemotherapy plus standard-dose immunotherapy, and about $30,000 per year for cetuximab (Erbitux)-based therapy, he observed.

HNSCC is disproportionately common in low- and middle-income countries, where access to immune checkpoint inhibitors remains limited. In India, for example, less than 3% of eligible patients receive an immunotherapy. More than 80% of patients with HNSCC have had exposure to tobacco, more than 65% have advanced disease at presentation, and as many as half will have a recurrence despite treatment of curative intent.

Prior studies in predominantly platinum-refractory HNSCC showed that TMC-I improved OS compared with TMC alone, with acceptable toxicity.

In the study by Shah’s group, 422 patients with platinum-sensitive HNSCC who had palliative-intent treatment were randomized to TMC-I or IV paclitaxel, 175 mg/m², plus IV carboplatin, once every 21 days. Treatment continued until disease progression or unacceptable toxicity.

The TMC-I regimen used in the study was oral methotrexate, 9 mg/m² once weekly, plus oral erlotinib (Tarceva), 150 mg once daily, plus oral celecoxib (Celebrex), 200 mg twice daily, and IV nivolumab (Opdivo), 20 mg, with all agents cycled once every 21 days.

Patient characteristics reflected a high-risk group, Shah noted. Most participants (85%) were male. Median age was 49.5 years, about 87% had tobacco exposure, 76.3% had cancer in the oral cavity, and about 31% had an ECOG performance status of 2. A total of 45% had clinical stage T4b disease, 39.1% had stage N3b disease, and 25.6% had metastatic disease. Prior treatments included surgery in 39.6%, radiotherapy in 42.7%, and chemotherapy in 25.8%.

At 1 year, the OS rate in the TMC-I group was double that of the chemotherapy group (46% vs 23%). The 6-month OS rate was 69.2% vs 52.3%, and the 1-year OS rate was 46.4% vs 23.2%, both in favor of TMC-I.

Compared with the chemotherapy arm, the TMC-I group was superior on media progression-free survival, objective response rate, median duration of response, and disease control rate.

Fewer patients randomized to TMC-I had serious side effects: 37.1% had a grade 3 or higher adverse event versus 47.5% of those in the chemotherapy group. The most common side effects in the TMC-I group were elevated liver enzymes (8.9%), excess bilirubin (4.5%), and rash (8.4%).

There were no meaningful differences between the patient arms in quality-of-life metrics, and symptoms remained similar over time, with a trend towards a lower symptom burden in the TMC-I group.

“This study is important in that it represents a potential therapy option for patients in resource-limited parts of the world, including India, where the research was conducted,” said ASCO expert Glenn Hanna, MD, of the Dana-Farber Cancer Institute in Boston, in a statement.

“The median overall survival was improved in the triple oral metronomic chemotherapy combined with ultra-low-dose immunotherapy arm when compared with chemotherapy. However, the comparator regimen would not be a standard first-line option in the U.S., and the overall survival is lower than what we observe with standard first-line U.S. agents,” Hanna pointed out.

ASCO Chief Medical Officer Julie Gralow, MD, also noted that head-to-head comparisons between TMC-I and standard-dose immunotherapy could be beneficial, but would likely need to be conducted in a low-resource setting.