Impact of Neoadjuvant Durvalumab with or without Tremelimumab on CD8+ Tumor Lymphocyte Density, Safety, and Efficacy in Patients with Oropharynx Cancer: CIAO Trial Results

Abstract

Purpose: In oropharyngeal squamous cell carcinoma (OPC), high CD8⁺ tumor-infiltrating lymphocyte (CD8⁺TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab + tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8⁺TIL density, safety, and efficacy in patients with OPC.

Patients and methods: Patients with newly diagnosed stage II-IVA OPC or locoregionally recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab + tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8⁺TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes.

Results: Of 28 eligible patients (14/arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8⁺TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P = 0.97; 95% CI: -1.07-2.28). In each group, 6 patients (43%, 95% CI: 17.66-71.14) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8⁺TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8⁺TIL change in patients with a MPR was seen (P = 0.059; 95% CI: -0.33-3.46). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence.

Conclusions: Durvalumab + tremelimumab did not increase CD8⁺TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.

Trial registration: ClinicalTrials.gov NCT03144778.

Figure 1.. Study schema.

*Per the 7th edition of the AJCC Cancer Staging Manual. **Only an option for patients with recurrent disease and ≤50% viable tumor in the surgical specimen. Patients randomized to receive durvalumab plus tremelimumab as neoadjuvant therapy would receive two more cycles of the combination followed by durvalumab as a single agent for up to 1 year; those randomized to receive single-agent durvalumab would receive durvalumab for up to 1 year. CPI, checkpoint inhibitor; CT, chemotherapy; DFI, disease-free interval; OPC, oropharyngeal squamous cell carcinoma; PS, performance status; RT, radiotherapy.

Figure 2.. Impact of checkpoint inhibitor therapy on CD8⁺ tumor-infiltrating lymphocytes (CD8⁺TIL).

Ratio of posttreatment to pretreatment CD8⁺TIL density by treatment arm (n=23).

Figure 3.. Efficacy of neoadjuvant durvalumab (durva) ± tremelimumab (treme).

(A) Percentage change from baseline in target lesions per RECIST 1.1 (n=28). (B) Percentage of viable tumor cells in the surgical specimen at the primary tumor site (n=25) and in the nodal metastases (n=19).

Figure 4.. CD8⁺ tumor-infiltrating lymphocyte (CD8⁺TIL) changes by pathologic response.

(A) Ratio of posttreatment to pretreatment CD8⁺TIL density by pathologic response (n=8). (B) Representative images showing increase in CD8⁺TIL density between before (Pre) and after (Post) checkpoint inhibitor administration.