Patterns of Response to Immune Checkpoint Inhibitors in Association with Genomic and Clinical Features in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC)

Abstract

Background: We sought to compare patterns of response to immune checkpoint inhibitors (ICI) with respect to clinical and genomic features in a retrospective cohort of patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods: One hundred seventeen patients with R/M HNSCC treated with ICI were included in this study. Tumor growth kinetics (TGK) prior to and TGK upon immunotherapy (IO) was available for 49 patients. The TGK ratio (TGKR, the ratio of tumor growth velocity before and upon treatment) was calculated. Hyperprogression (HPD) was defined as TGKR ≥ 2. Results: HPD was documented in 18 patients (15.4% of the whole cohort). Patients with HPD had statistically significant shorter progression free survival (PFS) (median PFS 1.8 months (95% CI, 1.03–2.69) vs. 6.1 months for patients with non-HPD (95% CI, 4.78–7.47), p = 0.0001) and overall survival (OS) (median OS 6.53 months (95% CI, 0–13.39) vs. 15 months in patients with non HPD (95% CI, 7.1–22.8), p = 0.0018). In a multivariate Cox analysis, the presence of HPD remained an independent prognostic factor (p = 0.049). Primary site in the oral cavity and administration of ICI in the second/third setting were significant predictors of HPD in multivariate analysis (p = 0.028 and p = 0.012, respectively). Genomic profiling revealed that gene amplification was more common in HPD patients. EGFR gene amplification was only observed in HPD patients, but the number of events was inadequate for the analysis to reach statistical significance. The previously described MDM2 amplification was not identified. Conclusions: HPD was observed in 15.4 % of patients with R/M HNSCC treated with IO and was associated with worse PFS and OS. EGFR amplification was identified in patients with HPD.

Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer

“…By multivariate analysis, it was found that MDM2/MDM4 amplification and EGFR mutations were associated with TTF < 2 months. The presence of MDM2 amplification and EGFR mutations in patients with HPD were also found in a clinical study by Singavi et al [50] and Economopoulou et al [51] . The MDM2 protein encoded by the MDM2 gene is a major negative regulator of the p53 protein.…”

“…[ 50 ] and Economopoulou et al . [ 51 ] . The MDM2 protein encoded by the MDM2 gene is a major negative regulator of the p53 protein.…”

Unexpected response to fourth-line paclitaxel in a patient with metastatic oropharyngeal squamous cell carcinoma, immunotherapy-refractory: a case report

“…Ferrara et al ., [23] have defined HPD as progressive disease by response evaluation criteria in solid tumors criteria at first evaluation and a difference in tumor growth ratio (TGR) higher than 50% (calculated comparing pre- and postimmunotherapy TGR). Similarly, Economopoulou et al ., [24] have defined radiologic HPD as the presence of tumor growth kinetics ratio (TGK) (ratio between TGK upon treatment and TGK before treatment) >2. However, the authors observed that several patients experienced clinical HPD without meeting radiologic criteria, suggesting that HNSCC could own intrinsic features that complicate the assessment of response based only on radiologic criteria and raising the question of the incorporation of clinical benefit endpoints into the definition of response to immunotherapy.…”

Current Understanding and Future Perspectives on Hyperprogressive Disease Highlight the Tumor Microenvironment

“…22 Although HPD was found in 2016, its definition and diagnostic criteria have not been unified. It is worth noting that continuous studies have shown that HPD is associated with poor OS, 11,13,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] and may even accelerate death in bladder carcinoma and squamous cell carcinoma. 15,31 Moreover, a shorter period of PFS has a certain contribution to the prognosis and even death.…”

“…55 Some studies have also shown that patients with HPD were younger than patients with non-HPD in non-small cell lung cancer (NSCLC) and in neck squamous cell carcinoma (HNSCC). 31,34,37,56 In summary, to determine the significance of age as a clinical characteristic for HPD will require prospective studies with large samples.…”