Impact of neoadjuvant durvalumab with or without tremelimumab on CD8⁺ tumor lymphocyte density, safety, and efficacy in patients with oropharynx cancer: CIAO trial results

Purpose: In oropharyngeal squamous cell carcinoma (OPC), high CD8^þ tumor-infiltrating lymphocyte (CD8^þTIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab þ tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8^þTIL 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 þ tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8^þTIL 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^þTIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P ¼ 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^þTIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8^þTIL change in patients with a MPR was seen (P ¼ 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 þ tremelimumab did not increase CD8^þTIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.