Purpose:

Treatments after anti–PD-1 therapy for patients with recurrent, metastatic head and neck squamous cell carcinoma (HNSCC) are limited. Blocking PI3K signaling may lead to tumor immunomodulation and enhanced taxane sensitivity. This phase 2 trial evaluated dual, selective PI3Kδ/γ inhibition with docetaxel in patients with anti–PD-1 refractory recurrent, metastatic HNSCC.

Patients and Methods:

Patients received duvelisib (25 mg orally twice daily) with docetaxel (75 mg/m2 IV) every 21 days. The primary endpoint was overall response rate (RECIST v1.1), using a Simon two-stage design. Secondary endpoints were safety, progression-free survival, and overall survival, and exploratory endpoints were correlating immunologic and genomic parameters with outcomes.

Results:

From 11/1/21 to 10/10/23, 26 patients were enrolled (median age: 64, 96% men, 54% with human papillomavirus+ disease; primary site: 12 oropharynx, 11 oral cavity, and 3 larynx/hypopharynx. The best overall response rate was 19% [5/26; 95% confidence interval (CI), 6.8%–40.7%]. All were partial responses [median duration: 5.1 months (0.7–15.5)]; 46% (12/26) exhibited stable disease, and 32% (8/26) exhibited progression (1 unevaluable). Two patients remain on-treatment at data cutoff; 25% (6/24) came off for toxicity. Grade 3+ treatment-related adverse events were observed in 50% (13/26), most often elevated liver function tests (6, 23%). No deaths were treatment-related. At median follow-up of 6.5 months (0.7–26), median progression-free survival was 2.8 months (95% CI, 1.9–7.0); 17/26 patients had died. Median overall survival was 10.2 months (95% CI, 6.7–15.9), favoring human papillomavirus–negative patients. Greater tumor CD3+/CD8+ T-cell infiltration trended with improved outcomes.

Conclusions:

We report a favorable response rate when combining a selective PI3K pathway inhibitor and taxane in patients with anti–PD-1 refractory HNSCC.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
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Supplementary data

Supplemental Table 1

Supplemental Table 1. Overview of the multiplex immunofluorescence panel.

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Supplemental Table 2

Supplemental Table 2. Representativeness of Study Participants.

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Supplemental Table 3

Supplemental Table 3. Reasons for Treatment Discontinuation.

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Supplemental Table 4

Supplemental Table 4. Univariate odds ratio and 95% CI for logistic regression models for predictors of response.

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Supplemental Table 5

Supplemental Table 5. Univariate Hazard ratio and 95% CI for Cox proportional hazard models on overall survival.

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Supplemental Table 6

Supplemental Table 6. Results of multiplex immunofluorescence profiling on tumor specimens.

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Supplemental Table 7

Supplemental Table 7. Correlating pre-treatment tumor immune cell parameters with outcomes (N=18).

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Supplemental Appendix 1

Supplemental Appendix 1. Study protocol.

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