Highlights
The PROMIT trial investigated a novel approach to overcome primary resistance to immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma. Key highlights include:
- An overall objective response rate (ORR) of 18% following dacarbazine priming and ICI rechallenge.
- A disease control rate (DCR) of 37% in a patient population with previously progressive disease.
- The treatment was well-tolerated, with grade 3 or higher adverse events occurring in only 10% of participants.
- Evidence suggesting that short-term, intermittent alkylating chemotherapy may reset the tumor microenvironment for immunotherapy.
Background: The Challenge of Primary ICI Resistance
The advent of immune checkpoint inhibitors, specifically those targeting PD-1 and CTLA-4, has revolutionized the treatment landscape for metastatic melanoma. However, a significant subset of patients—particularly those with BRAF wildtype tumors—exhibit primary resistance. These patients show disease progression at the very first radiological assessment, leaving clinicians with limited evidence-based options beyond palliative chemotherapy or clinical trials. Primary resistance remains a formidable barrier, often associated with a ‘cold’ tumor microenvironment characterized by low mutational burden, poor T-cell infiltration, or immunosuppressive metabolic pathways.
Historically, chemotherapy was viewed purely as a cytotoxic fallback. However, emerging evidence suggests that certain cytotoxic agents, particularly alkylating agents like dacarbazine, may possess immunomodulatory properties. By inducing DNA damage, increasing mutational load, and potentially altering the tumor microenvironment or gut microbiome, chemotherapy might ‘prime’ the immune system to respond to ICIs that were previously ineffective. The PROMIT trial was designed to prospectively test this hypothesis in a clinical setting.
Study Design and Methodology
The PROMIT trial (NCT04225390) was a prospective, multicentre phase II study conducted across four specialized German skin cancer centers. The study targeted a specific and difficult-to-treat demographic: patients with histologically confirmed BRAF wildtype metastatic melanoma who demonstrated primary resistance to ICI therapy (either pembrolizumab or the combination of ipilimumab and nivolumab).
Primary resistance was strictly defined as radiological evidence of disease progression during the first staging after initiating ICI. The intervention involved a unique ‘intermittent’ chemotherapy schedule. Patients received two doses of dacarbazine at 850 mg/m² intravenously, administered on days 1 and 21. One week after the second dose of dacarbazine, patients were rechallenged with the exact same ICI regimen to which they had previously failed to respond. This design sought to isolate the effect of the chemotherapy ‘intermission’ as the sensitizing factor.
Key Findings: Efficacy and Response Rates
Of the 53 patients enrolled, 38 were evaluable for efficacy, having completed at least one dose of the ICI re-exposure phase. The results provide a compelling signal for clinical utility in a refractory population.
Objective Response and Disease Control
The overall objective response rate (ORR) was 18% (95% CI: 0.08–0.34). Specifically, 7 out of 38 patients achieved a confirmed partial response (PR). While no complete responses were recorded during the study period, the achievement of partial responses in patients who had previously progressed on the same immunotherapy is statistically and clinically significant. Furthermore, the disease control rate (DCR), which includes patients with stable disease, reached 37%. For patients who had previously seen their tumors grow unchecked, this stabilization represents a meaningful clinical window.
Safety and Tolerability
Safety is a paramount concern when combining or sequencing cytotoxic and immunotherapeutic agents. The PROMIT protocol proved to be remarkably well-tolerated. Treatment-related adverse events (TRAEs) of CTCAE grade 3 or higher were observed in only 10% of the cohort. Most toxicities were consistent with the known profiles of dacarbazine (e.g., transient hematological suppression or nausea) and ICIs. Importantly, no new safety signals were identified, and the intermittent nature of the chemotherapy likely contributed to the low toxicity burden compared to continuous chemotherapy regimens.
Mechanistic Insights: How Chemotherapy Breaks Resistance
The success of the PROMIT trial invites questions regarding the biological mechanisms at play. Several hypotheses exist to explain how dacarbazine might sensitize tumors to ICIs:
1. Induction of Neoantigens
Alkylating agents cause DNA damage. In some cases, this damage leads to new somatic mutations which, when transcribed and translated, create neoantigens. These ‘foreign’ proteins can be recognized by T-cells, effectively making a ‘cold’ tumor appear ‘hot’ to the immune system.
2. Immunogenic Cell Death (ICD)
Certain chemotherapies trigger a form of cell death that releases danger-associated molecular patterns (DAMPs). This process recruits dendritic cells to the tumor site, enhancing the priming of tumor-specific T-cells.
3. Depletion of Suppressor Cells
Low-dose or intermittent chemotherapy has been shown in various models to selectively deplete myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs), thereby lifting the ‘brakes’ on the local immune response.
Expert Commentary
The PROMIT trial addresses a critical unmet need. While the ORR of 18% might seem modest compared to first-line ICI results, it is vital to remember that these patients had already failed the gold-standard treatments. In the context of primary resistance, any strategy that restores sensitivity to PD-1/CTLA-4 blockade is a major step forward.
However, some limitations must be noted. The sample size, while appropriate for a phase II trial, is relatively small, and the study lacked a randomized control arm (e.g., dacarbazine alone or ICI rechallenge without dacarbazine). Future research should focus on identifying biomarkers—such as changes in the tumor mutational burden (TMB) or T-cell receptor (TCR) repertoire—that can predict which patients are most likely to benefit from this ‘chemo-priming’ approach.
Conclusion
The PROMIT trial provides evidence that primary resistance to checkpoint inhibitors is not necessarily an irreversible state. By utilizing short-term, intermittent dacarbazine as a sensitizing agent, clinicians may be able to ‘reset’ the immune-tumor interface, allowing subsequent ICI therapy to succeed where it previously failed. This approach offers a low-toxicity, cost-effective, and readily available therapeutic option for patients with BRAF wildtype metastatic melanoma who have exhausted standard first-line options. As we move toward more personalized oncology, the sequencing of traditional and modern therapies will likely become a cornerstone of overcoming drug resistance.
Funding and clinicaltrials.gov
This study was supported by various academic and clinical grants from the participating German skin cancer centers. Clinical trial registration: NCT04225390.
References
- Haferkamp S, Schilling B, Berking C, et al. Breaking primary checkpoint inhibitor resistance with intermittent alkylating chemotherapy in patients with metastatic melanoma: results of a multicentre phase II trial. Br J Dermatol. 2026;194(2):216-224. doi:10.1093/bjd/ljaf350.
- Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-2532.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23-34.
- Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinventing antitumor immunity. Immunity. 2013;39(1):74-88.
