Microbiome TOPOSCORE Does Not Predict Melanoma Response to Immunotherapy Re-Induction

Baseline gut microbiome ecosystem states classified by the TOPOSCORE framework were insufficient to predict clinical treatment outcomes in patients with primary resistant metastatic melanoma, according to an exploratory analysis of the prospective multicenter phase II PROMIT trial published in Cancer Immunology, Immunotherapy. The study evaluated whether gut microbial communities could indicate which individuals might benefit from immune checkpoint inhibitor re-induction after receiving chemotherapy.

Primary resistance to immune checkpoint inhibitors represents a substantial hurdle in the clinical care of metastatic melanoma. Prior findings from the multicenter PROMIT clinical study demonstrated that administering intermittent chemotherapy could restore therapeutic sensitivity to immune checkpoint inhibitor re-induction in a subset of patients. Based on those observations, investigators sought to determine whether specific gut microbiome ecosystem states identified through the TOPOSCORE system were associated with tumor response in this treatment sequence.

The exploratory investigation, conducted under trial identifier NCT04225390, included 24 patients with primary resistant metastatic melanoma who provided longitudinal stool samples. Participants were treated with two cycles of dacarbazine followed by re-induction therapy with immune checkpoint inhibitors. Stool specimens underwent shotgun metagenomic sequencing, and microbial ecosystems were characterized into SIG1-associated or SIG2-associated states using the TOPOSCORE framework, an analytical approach structured around species-interacting groups that are defined by ecological co-abundance patterns.

The investigators observed that neither baseline TOPOSCORE distributions nor numerical s-scores were associated with clinical outcomes. Cross-sectional analyses incorporating all available stool samples across each treatment phase similarly revealed no statistically significant differences in s-scores among patients experiencing partial response, stable disease, or progressive disease. Among nine patients who provided complete longitudinal samples across baseline, post-chemotherapy, and re-induction timepoints, six maintained their original TOPOSCORE category throughout therapy, while three patients switched categories. Within the subset of two patients achieving a partial response, one patient remained in the SIG2 category at all sampling intervals, whereas the second patient transitioned from SIG2+ to SIG1+ after dacarbazine chemotherapy before shifting back to SIG2+ during immunotherapy re-induction.

The authors concluded that baseline TOPOSCORE classification alone could not reliably forecast treatment outcomes in this patient cohort. In addition, the longitudinal ecosystem patterns observed across the cohort were heterogeneous, and the small total of nine complete longitudinal profiles precluded any definitive conclusion that chemotherapy successfully prompted a favorable microbiome transition. The researchers noted that these exploratory observations highlight the need for further evaluation of microbiome ecosystem dynamics within larger prospective cohorts.

Subject of Research: Gut microbiome TOPOSCORE and immunotherapy response in metastatic melanoma

Article Title: Microbiome-derived TOPOSCORE is associated with response to immune checkpoint inhibitor re-induction after chemotherapy in primary resistant metastatic melanoma

Article References: Haferkamp, S., Schilling, B., Baumgart, L., Gesierich, A., Glutsch, V., Drexler, K., Wein, L., Morak, M., Erdmann, M., Berking, C., Piccinno, G., Derosa, L., Zitvogel, L., Wang, Y., & Heinzerling, L. (2026). Microbiome-derived TOPOSCORE is associated with response to immune checkpoint inhibitor re-induction after chemotherapy in primary resistant metastatic melanoma. Cancer Immunology, Immunotherapy, 75(11), Article 265. https://doi.org/10.1007/s00262-026-04618-2

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04618-2

Keywords: metastatic melanoma, TOPOSCORE, gut microbiome, immune checkpoint inhibitors, dacarbazine, PROMIT trial, immunotherapy resistance, shotgun metagenomic sequencing, Microbiome-derived, associated, response, immune