IO102-IO103 Plus Pembrolizumab Demonstrates Favorable Activity in PD-L1–High HNSCC and NSCLC

October 29, 2025

Jonathan Riess, MD, discusses data for IO102-IO103 plus pembrolizumab in advanced HSNCC and NSCLC with high PD-L1 expression.

The emergence of therapeutic cancer vaccines represents a promising evolution in immuno-oncology, aiming to extend the benefits of checkpoint inhibition to a broader patient population, according to Jonathan Riess, MD.

This concept was reflected in a phase 2 basket trial (NCT05077709) presented by Reiss and colleagues at the 2025 ESMO Congress, which evaluated first-line IO102-IO103 plus pembrolizumab (Keytruda) in patients with advanced non–small cell lung cancer (NSCLC) who had a PD-L1 tumor proportion score of at least 50% and patients with advanced head and neck squamous cell carcinoma (HNSCC) with a PD-L1 combined positive score of at least 20.1

In terms of efficacy, the primary end point of overall response rate (ORR) was met in patients with HNSCC (n = 18) at 44.4% (95% CI, 21.5%-69.2%). Similar activity was observed in the NSCLC cohort, where the ORR was 48.4% (95% CI, 30.2%-66.9%). The median progression-free survival (PFS) was 7.0 months (95% CI, 2.0-13.1) in the HNSCC cohort and 8.1 months (95% CI, 4.2-17.7) in the NSCLC group, with 18-month PFS rates of 22% (95% CI, 7%-43%) and 31% (95% 16%-48%), respectively. Median overall survival (OS) was 22.3 months (95% CI, 9.4-not evaluable [NE]) in patients with HNSCC and 22.6 months (95% CI, 16.6-NE) in those with NSCLC, with corresponding 18-month OS rates of 61% and 64%, respectively.

“[The study] showed [that the combination was] safe and tolerable. Toxicity was in line with what you’d expect with single-agent pembrolizumab. There were some injection-site reactions, but [these were] very manageable in patients who received IO102-IO103. The primary end point, of ORR was met [in patients with] HNSCC, and [the regimen] also showed favorable activity in NSCLC,” Reiss explained. “[A similar benefit was seen] when looking at the secondary end points such as progression-free survival; [results] compared favorably with single-agent pembrolizumab, but [these findings] will need to be confirmed in future randomized studies.”

In an interview with OncLive, Reiss expanded on the design of the basket trial and the implications of the findings. Reiss currently serves as the Medical Director of Thoracic Oncology at the University of California Davis Health in Sacramento.

OncLive: What was the scientific rationale for evaluating the IO102-IO103 cancer vaccine in combination with pembrolizumab as first-line treatment for patients with advanced solid tumors in this phase 2 basket trial?

Reiss: At ESMO this year, I presented [data from] a phase 2 basket trial of IO102-IO103, which is a vaccine against PD-L1 and IDO—an immunomodulatory peptide. [IO102-IO103] was given in conjunction with pembrolizumab in patients with advanced metastatic HNSCC and NSCLC. The rationale [for the study] was that there has been some promising data in melanoma, including a phase 3 study [NCT05155254] that was presented at [ESMO 2025].2

This single-arm basket [trial was designed] to probe for efficacy in PD-L1–high advanced squamous head and neck cancer and NSCLC.

What were the key design features and objectives of the phase 2 basket trial?

In this basket trial, patients with advanced or metastatic NSCLC and HNSCC [were enrolled]. They were [required to have] PD-L1–high [tumors], where a standard of care is single-agent pembrolizumab. The idea was to use this immunomodulatory peptide [targeting] IDO and PD-L1 to make the tumors “hotter” and to determine whether this approach could elicit a stronger signal of activity in HNSCC and NSCLC.

Were any specific gene expression signals or molecular signatures identified in the analysis that correlated with clinical response to the combination?

In terms of some of the correlative studies that were done, patients who cleared their circulating tumor DNA tended to do better. We looked at gene expression signatures, and some findings could be prognostic, [but require further study]. The most important translational component that we presented was that patients developed antibodies to IDO and PD-L1 after vaccine administration.

What are the implications of these findings for the future study of IO102-IO103 in combination with checkpoint inhibition, and how might these results inform the design of subsequent randomized trials?

We need to do randomized studies. [IO102-IO103 may] address an unmet need, even among patients with PD-L1–high HNSCC and NSCLC. There are patients [in these populations whose responses are suboptimal or of shorter duration], even though these are typically the target population for anti–PD-1 efficacy. There is still room for improvement [in the PD-L1–high populations], and we can also examine populations with lower PD-L1 expression.

References

Riess JW, Spicer J, Seiwert T, et al. IO102-IO103 cancer vaccine plus pembrolizumab for first-line (1L) treatment of advanced solid tumors: final results of a phase 2 basket trial. Presented at: ESMO 2025 Congress; October 17-20, 2025; Berlin, Germany. Poster 1557.
Hassel JC, Arance AM, Carlino MS, et al. IO102-IO103 cancer vaccine plus pembrolizumab for first-line (1L) advanced melanoma: primary phase III results (IOB-013/KN-D18. Presented at 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA53.