PD-L1/IDO1–Targeted Vaccine Therapy Is Safe and Effective in Advanced Melanoma

Although the addition of the cancer vaccine IO102-IO103 to pembrolizumab (Keytruda) failed to provide a statistically significant progression-free survival (PFS) benefit vs pembrolizumab alone in the first-line setting in patients with advanced melanoma, this vaccine shows the potential to bolster the efficacy of evolving frontline melanoma therapies, according to Jessica C. Hassel, MD.

In the phase 3 IOB-013/KN-D18 trial (NCT05155254), at a median follow-up of 23 months, the median PFS was 19.4 months (95% CI, 9.7-not reached) with the combination (n = 203) vs 11.0 months (95% CI, 6.0-14.8) with pembrolizumab monotherapy (n = 204; HR, 0.77; 95% CI, 0.58-1.00; P = .0558).¹ Notably, the statistical significance threshold for the study had a P value of .045.

“What would be wise is to [use this vaccine] on top of what we have to further increase the efficacy [of standard therapies],” Hassel said in an interview with OncLive® during the 2025 European Society for Medical Oncology (ESMO) Congress.

In the interview, Hassel discussed the unique mechanism of action of the IO102-IO103 vaccine, expanded on the implications of key efficacy data from the trial, and noted that additional research is exploring the vaccine’s activity in other cancer types.

For instance, she referenced the investigation of the vaccine added to first-line pembrolizumab in a phase 2 basket trial (NCT05077709) in patients with advanced solid tumors. Final results also presented at ESMO 2025 showed that at a median follow-up of 32.3 months in patients with non–small cell lung cancer (n = 31), the overall response rate (ORR) was 48.4% (95% CI, 30.2%-66.9%), the median PFS was 8.1 months (95% CI, 4.2-17.7), and the median overall survival (OS) was 22.6 months (95% CI, 16.6-not evaluable [NE]).² In the cohort of patients with squamous cell carcinoma of the head and neck (n = 18), at a median follow-up of 23.8 months, the ORR was 44.4% (95% CI, 21.5%-69.2%), the median PFS was 7.0 months (95% CI, 2.0-13.1), and the median OS was 22.3 months (95% CI, 9.4-NE).

Hassel is a dermato-oncologist at Heidelberg University Hospital, as well as head of the Section of Dermato-Oncology of the Department of Dermatology at the National Center for Tumor Diseases in Germany.

OncLive: What is the mechanism of action of the IO102-IO103 vaccine?

Hassel: IO102-IO103 is an immune modulatory off-the-shelf vaccine, and it consists of 2 peptides, IDO1 and PD-L1. It’s administered subcutaneously, and then the peptides are taken up by antigen-presenting cells. Those present the peptides and then activate and expand T cells that are reactive against IDO and PD-L1. These T cells can detect IDO and PD-L1–positive cells in the tumor microenvironment [TME], but also immunosuppressive cells, such as myeloid-derived suppressor cells, M2 macrophages, and regulatory T-cells, and thereby eliminate these immunosuppressive cells and facilitate in the TME the activation of tumor-active T cells.

What was the rationale for investigating IO102-IO103 plus pembrolizumab in advanced melanoma?

In cutaneous melanoma, we have good immunotherapies already. We have immune checkpoint blockade either with PD-1–directed monotherapy or double checkpoint blockade with a CTLA-4–directed antibody. Nevertheless, [patients can] have resistance to PD-1–targeted therapy.

The aim [of this trial] was to generate new tumor-specific responses because immune checkpoint blockers work only in patients who have an immune response already; then you can activate this immune response. But with a vaccine, you want to create new immune responses to lift the [response] level a bit higher in cutaneous melanoma. [This interaction] was the reason why, in the trial, PD-1–directed therapy was combined with this cancer vaccine and compared with PD-1–directed monotherapy.

What was the design of the IOB-013/KN-D18 trial?

This was a randomized trial including 407 patients with advanced melanoma in the first-line setting.¹ The patients were allowed to have received adjuvant or neoadjuvant pretreatment, if it was concluded more than 6 months [prior to study enrollment]. Otherwise, it was a normal first-line setting, and patients received either the combination of IO102-IO103 plus pembrolizumab at 200 mg every 3 weeks or pembrolizumab alone for up to 2 years. The primary end point was PFS by blinded independent central review. Secondary end points included ORR, duration of response, OS, and safety.

What efficacy findings were seen with the IO102-IO103 vaccine in the IOB-013/KN-D18 trial?

When you look at the Kaplan Meier curves, you can see that they separate as early as the first staging. The median PFS with the combination was 19.4 months; it was 11.0 months with pembrolizumab alone. [We saw] an improvement in PFS [with the combination]. Unfortunately, this trial narrowly missed its significance, so the [upper bound of the] 95% CI [for HR] was 1.00, and the P value was .5658. Nevertheless, in the subgroup analysis, across all the subgroups, the combination was favored, especially in patients with BRAF-mutant tumors, PD-L1–negative tumors, or elevated lactate dehydrogenase levels.

When you look at the Kaplan Meier curves separated for PD-L1–positive and –negative tumors, there is a profound effect [with the combination], especially in patients with PD-L1–negative tumors, where pembrolizumab alone is not doing much. The median PFS was 3.0 months [with pembrolizumab alone], and it increased to 16.6 months with the combination. That was one of the most interesting results. In addition, patients who had received no neoadjuvant or adjuvant pretreatment with PD-1–directed therapy had a better PFS [with the combination compared with those who had been previously treated].

What is the safety profile of the IO102-IO103 vaccine plus pembrolizumab?

The safety findings were straightforward. [The vaccine did not add] systemic toxicity to the known safety profile of pembrolizumab. We saw the normal rashes and arthralgia that we know from [the safety profile of] PD-1–directed therapy. The only toxicity that was added was local toxicity in [the form of] injection site reactions, such as redness, swelling, and itchiness at that site. We also saw granulomas, but these were seen in half of the patients, only mild—CTCAE grades 1 and 2; there was only 1 grade 3 case noted.

Although the IOB-013/KN-D18 trial missed its primary end point, what might still be learned about the role of the IO102-IO103 vaccine in cutaneous melanoma?

What this trial shows is that cancer vaccines can be effective in metastatic cancer, [maybe beyond] melanoma. This vaccine changes the TME, so it’s not aiming for the tumor cells, but for immunosuppressive cells. This is new, and it shows that [this vaccine] might be [a good effort for managing cancer].

There are other trials recruiting patients with lung cancer and head and neck cancer. There was a poster [at ESMO 2025] where [the vaccine] was given in the first-line setting in combination with PD-1–directed therapy [in patients with solid tumors]. There were responses there, as well, and vaccine-specific immune responses in the peripheral blood. [These data] are motivating. I hope [this vaccine] will be further developed.

Based on current data, where might the IO102-IO103 vaccine play a role in the melanoma treatment paradigm going forward?

When we [consider] the treatments we have, for example, relatlimab/nivolumab [Opdualag] and ipilimumab [Yervoy]/nivolumab [Opdivo], in subgroup analyses, the PD-L1–negative patients mainly benefit from these treatments. These are the patients in need. [The vaccine] will fit [into the treatment paradigm] in this group.

We don’t add systemic toxicity if we use it as an add-on [to standard treatment]. The question is: What is our first-line treatment at the moment? It’s probably not PD-1–directed therapy anymore, as [it was when the IOB-013/KN-D18] trial was planned. It’s now combinations, for example, relatlimab plus nivolumab.

References

1. Hassel JC, Arance AM, Carlino MS, et al. LBA53: IO102-IO103 cancer vaccine plus pembrolizumab for first-line (1L) advanced melanoma: primary phase III results (IOB-013/KN-D18). Ann Oncol. 2025;36(suppl 2):S1712-S1713. doi:10.1016/j.annonc.2025.09.065
2. Riess JW, Spicer J, Seiwert T, et al. 1557P IO102-IO103 cancer vaccine plus pembrolizumab for first-line (1L) treatment of advanced solid tumors: final results of a phase II basket trial. Ann Oncol. 2025;36(suppl 2):S929. doi:10.1016/j.annonc.2025.08.2187