A lower-cost chemoimmunotherapy approach including triple oral metronomic chemotherapy (TMC) combined with ultra-low-dose immunotherapy termed TMC-I could extend survival for patients with advanced head and neck squamous cell carcinoma in resource-limited countries, according to investigators from India who reported results with the novel regimen at the 2026 ASCO Annual Meeting.¹

Immune checkpoint inhibitors have transformed cancer care—but not everywhere in the world. Because of their expense, they have been incorporated as standards of care only in countries that can afford them, said Minit Jalan Shah, MBBS, MD, DM, of Tata Memorial Centre in Mumbai. He noted that in India, head and neck squamous cell carcinoma is the second most commonly diagnosed malignancy, yet fewer than 3% of eligible patients receive a checkpoint inhibitor.

Now, investigators from India have found an alternative: TMC-I, which combines an ultra-low dose of the PD-1 inhibitor nivolumab with an oral metronomic regimen of methotrexate, the EGFR tyrosine kinase inhibitor erlotinib, and the COX-2 inhibitor celecoxib. In a multicenter phase III study, treatment with TMC-I reduced the risk of death by 43% compared with chemotherapy with paclitaxel plus carboplatin and was associated with fewer side effects in patients with recurrent or metastatic head and neck squamous cell carcinoma.

TMC-I helps bridge the gap between efficacy and real-world access….

— MINIT JALAN SHAH, MBBS, MD, DM

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“TMC-I helps bridge the gap between efficacy and real-world access where chemoimmunotherapy may cost anywhere around $12,000 per year and cetuximab-based chemotherapy between $25,000 and $30,000 per year. TMC-I costs $2,700 per year. It offers a practical, scalable, and globally relevant first-line treatment option for advanced head and neck squamous cell carcinoma,” Dr. Shah said.

About the Study

The study enrolled 422 adults with advanced recurrent or metastatic platinum-sensitive disease, randomly assigning them to first-line palliative therapy with either paclitaxel/carboplatin or TMC-I, an oral metronomic regimen of methotrexate, erlotinib, and celecoxib combined with ultra–low-dose nivolumab (20 mg). 

Overall survival was the primary endpoint, with the trial designed to first assess the non-inferiority of TMC-I vs paclitaxel/carboplatin. A prespecified hierarchical testing strategy then allowed assessment of superiority in overall survival. Progression-free survival was a key secondary endpoint.

Key Findings

The TMC-I regimen demonstrated superior overall survival compared with paclitaxel/carboplatin. After a median follow-up of 11.9 months, patients receiving TMC-I had a median overall survival of 10.3 months compared with 6.2 months for those receiving paclitaxel/carboplatin (hazard ratio [HR] = 0.57; P < .001); 1-year survival was 46% vs 23%, respectively, Dr. Shah reported. These findings are notable given the higher-risk clinical profile of the study population, including a high proportion of patients with oral cavity primary tumors and ECOG performance status 2.

Median progression-free survival was 5.5 months with TMC-I vs 2.7 months with paclitaxel/carboplatin (HR = 0.465; P < .001). The investigators also reported a higher objective response rate with TMC-I (53.4% vs 24.1%; P < .001) and more durable responses, with median durations of response of 11.0 and 3.6 months, respectively. The survival benefit of TMC-I appeared generally consistent across prespecified subgroups, with a greater magnitude of benefit observed in patients with oral cavity tumors and tobacco-associated disease.

Daily functioning was preserved, with a trend toward better role and social functioning and reduced symptoms across several domains with TMC-I; exploratory analyses also suggested improvements in selected quality-of-life measures,” Dr. Shah added.

Another apparent advantage of TMC-I was its tolerability. The rate of grade 3 or higher adverse events was lower with the ultra–low-dose chemoimmunotherapy regimen than with paclitaxel/carboplatin: 37.1% vs 47.5% (P = .036)

No treatment-related deaths were reported, and patient-reported quality of life was preserved with TMC-I. Based on these results and those of prior studies, TMC-I has become the preferred first-line regimen in India.

“The next step is to refine and expand TMC-I, including evaluating its combination with intravenous chemotherapy in first-line treatment and in neoadjuvant approaches. We are also exploring biomarker-driven strategies to identify patients most likely to benefit from low-dose immunotherapy,” Dr. Shah said.

Expert Point of View

While TMC-I, a regimen combining an ultra-low dose of the PD-1 inhibitor nivolumab with an oral metronomic regimen of methotrexate, the EGFR tyrosine kinase inhibitor erlotinib, and the COX-2 inhibitor celecoxib, does not directly affect the contemporary management of advanced head and neck squamous cell carcinoma in the United States, the findings from a multicenter phase III study of TMC-I conducted in India have relevance in other ways, said Julie R. Gralow, MD, FACP, FASCO, ASCO’s Chief Medical Officer and Executive Vice President.¹

Julie R. Gralow, MD, FACP, FASCO

Dr. Gralow explained that the study by Shah et al reported at the 2026 ASCO Annual Meeting represents a broader effort across health-care systems to find lower-cost alternatives in the face of what many view as the unsustainable cost of cancer care. ¹

“Health-care costs in the United States and for the treatment of cancer are exceedingly high, and anything we could do to better understand the comparability across these 12 [U.S. Food and Drug Administration (FDA)]-approved PD-1/PD-L1 inhibitors are incredibly appropriate and are in the best interest of our patients as well as our health-care system,” she said.

Commenting first on treatment inequities, she noted that only about 3% of patients in India who are candidates for PD-1/PD-L1 agents receive them, primarily because of their price but also because of infrastructure issues. “These drugs are now on the World Health Organization’s [Model List of Essential Medicines] for a variety of indications, which means that an expert global panel is saying that every country should be trying to get access to them,” she said.

“Lower-cost alternatives, including lower doses or less frequent dosing, or narrowing the treatment population with more selective biomarkers, clearly help ameliorate the global problems with immune checkpoint inhibitor access, but these would need to be established by head-to-head trials using a U.S. standard of care as the comparator if they are to be accepted and change practice in the United States,” Dr. Gralow said. “Trials comparing lower doses of immune checkpoint inhibitors would be exceptionally difficult to conduct inside the United States, but prospective trials conducted abroad utilizing a U.S. standard-of-care comparator to definitively demonstrate equivalence or superiority could supply the evidence needed to safely integrate these dosing strategies into U.S. practice.” Positive results from such comparative studies could lead to more appropriate (ie, conservative) dosing of costly drugs even in high-resource settings, she pointed out.

“I am excited to tell you that there is growing momentum to do [these studies]…,” she said.

DISCLOSURE: Dr. Shah and Dr. Gralow had no relevant disclosures.

REFERENCE

1. Shah MJ, Noronha V, Menon NS, et al: Ultra-low-dose immunotherapy plus oral metronomic chemotherapy versus paclitaxel-carboplatin in platinum-sensitive recurrent or metastatic head and neck squamous cell carcinoma: A randomized phase III trial. 2026 ASCO Annual Meeting. Abstract LBA6007. Presented May 31, 2026.