BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

3111 Background: Myeloid-derived suppressor cells (MDSC) are expanded in cancer and promote immune suppression. We have shown that ibrutinib inhibits migration and immunosuppressive function of MDSC. Moreover, the combination of ibrutinib and a PD-L1 inhibitor has been found to have synergistic anti-tumor effects in a multiple solid tumor mouse models. Therefore, we conducted a pilot study testing the combination of ibrutinib and nivolumab in patients with metastatic solid tumors. Methods: Sixteen patients with advanced solid tumors were recruited to this trial. Ibrutinib was dosed as an oral single agent, starting 7 days prior to cycle 1 of nivolumab and given until cycle 1, day 8 of nivolumab. Nivolumab was administered intravenously on days 1 and 15 on 28-day cycles. Patients had blood samples collected prior to initiation of ibrutinib, day 1 of cycle 1, day 8 of cycle 1, day 1 of cycle 2, and at the time of disease progression. From these specimens, we measured circulating MDSC levels, other circulating immune subsets, T cell proliferation, and cytokines/chemokines levels. Circulating MDSC levels were measured by mass spectrometry. T cell function was evaluated by CFSE to monitor proliferating cells by dye dilution and cytokine/chemokine levels were measured with a U-PLEX assay. Data were analyzed using two-tailed, paired Student's t-tests to assess statistical significance. Results: An increase in circulating MDSC (22% to 28%; SD 9.158) levels was observed following 7 days of single-agent ibrutinib compared to baseline. However, in combination therapy, MDSC levels decreased (19%; SD 13.17) prior to cycle 2. Despite increasing levels of circulating MDSC, T cell function improved throughout the study. Furthermore, plasma levels of chemokines associated with MDSC recruitment and migration significantly decreased with ibrutinib treatment (IL-12, CCL2, CCL3, and CCL4). Of the 16 patients, four achieved a partial response and four achieved stable disease. Median progression free survival was 3.5 months and median overall survival was 11.5 months. Conclusions: The combination of ibrutinib and nivolumab was well tolerated, demonstrated early signs of immune modulation, and showed preliminary signs of promising clinical activity in patients with metastatic solid tumors. Clinical trial information: NCT03525925 .

Bazex syndrome is a rare paraneoplastic dermatosis that precedes diagnosis of cancer. Awareness of this syndrome is important, as it allows early detection of underlying malignancy and may prevent misdiagnosis and delays in cancer treatment.

For patients ineligible for cisplatin with definitive radiotherapy (CP‐CRT) for locally advanced head and neck squamous cell carcinoma (LA‐HNSCC), concurrent cetuximab (C225‐RT) is a popular substitute. Carboplatin‐based chemoradiation (CB‐CRT) is another option; however, relative efficacies of CP‐CRT, CB‐CRT and C225‐RT are unclear, particularly in the human papillomavirus (HPV)‐unrelated population. We identified 316 patients with stage III‐IVB cancers of the oropharynx (24.7%), larynx (58.2%) and hypopharynx (17.1%) undergoing definitive C225‐RT (N = 61), CB‐CRT (N = 74) or CP‐CRT (N = 181). Kaplan‐Meier and cumulative incidence functions were generated to estimate overall survival (OS), locoregional failure (LRF) and distant metastasis (DM). Cox proportional hazards were used to determine the association of survival endpoints with clinical characteristics. Respectively, 3‐year cumulative incidences for CP‐CRT, CB‐CRT and C225‐RT were: LRF (0.19, 0.18 and 0.48, p ≤ 0.001), DM (0.17, 0.12 and 0.25, p = 0.32). Kaplan‐Meier estimates for 3 year OS were: CP‐CRT: 71%; CB‐CRT: 59% and C225‐RT: 54%; p = 0.0094. CP‐CRT (hazard ratio [HR] 0.336; 95% confidence interval [CI] 0.203–0.557, p < 0.01) and CB‐CRT (HR 0.279; 95% CI 0.141–0.551, p < 0.01) were associated with reduced hazard for LRF on multivariable analysis. CP‐CRT (HR 0.548; 95% CI 0.355–0.845, p < 0.01) and CB‐CRT (HR 0.549; 95% CI 0.334–0.904, p = 0.02) were associated with a reduced hazard for death on multivariable analysis. Propensity matching confirmed reduced hazards with a combined CP/CB‐CRT group compared to C225‐RT for LRF: HR 0.384 (p = 0.018) and OS: HR 0.557 (p = 0.045) and CB‐CRT group compared to C225‐RT for LRF: HR 0.427 (p = 0.023). In conclusion, CB‐CRT is an effective alternative to CP‐CRT in HPV‐unrelated LA‐HNSCC with superior locoregional control and OS compared to C225‐RT.

Background: Myeloid-derived suppressor cells (MDSC) are a naturally occurring population of immature myeloid cells with immune suppressive function that curtail inflammatory processes. In cancer, these cells abnormally expand and migrate to tumor/lymphoid regions where they negatively impact antigen specific and innate immune effector cells. Circulating MDSC levels have also been associated with the higher tumor burden and decreased survival of patients with solid tumors. Preclinical studies performed by our group demonstrated that ibrutinib (PCI-32765), an irreversible inhibitor of Bruton’s tyrosine kinase, is capable of inhibiting MDSC generation and their immunosuppressive function (A. Stiff, CA Res, 2016). We also found that the combination of ibrutinib and a PD-L1 inhibitor worked synergistically in a mouse model of mammary carcinoma. Based on these results, targeting MDSC with ibrutinib has the potential to enhance the efficacy of immune checkpoint inhibitors such as nivolumab in patients with advanced solid tumors. Materials and Methods: This pilot study will assess the effect of single agent ibrutinib and ibrutinib in combination with nivolumab on levels and function of circulating myeloid-derived suppressor cells in 15 patients with advanced solid tumors. Eligible patients are required to have metastatic malignancy and be eligible for treatment with nivolumab as determined by the treating physician. Study subjects will be treated with ibrutinib at 420 mg given orally once daily. Nivolumab will be given at a standard dose of 240 mg IV over 30 minutes on days 1 and 15 on 28-day cycles. Ibrutinib dosing will be started 7 (+/-2) days prior to cycle 1 of nivolumab therapy and will be given until cycle 1, day 8 of nivolumab or total of 15 days (whichever comes first). Peripheral blood will be collected just prior to initiation of ibrutinib (at day -7), prior to day 1 of cycle 1, prior to day 8 of cycle 1, prior to day 1 of cycle 2 and at the time of disease progression. The primary objective is to evaluate the effect of the ibrutinib therapy on circulating levels of myeloid-derived suppressor cells (MDSC). The safety of the study combination, effect of ibrutinib/nivolumab on immune cell subsets and the length of progression-free survival will also be assessed. Conclusion: The study opened to accrual on August 10, 2018 and is currently enrolling the target 15 patients. To date 9 patients are on study. Citation Format: Brooke Benner, Megan Duggan, Andrew Stiff, Bhavana Konda, Robert D. Rupert, Paul Monk, Claire Verschraegen, Hiral Shah, Anne Noonan, William E. Carson, Robert Wesolowski. Pilot study testing the effects of BTK inhibitor ibrutinib and nivolumab on levels and function of myeloid-derived suppressor cells and other immune subsets in patients with metastatic solid tumors (NCT03525925) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT169.

Objectives: Randomized trials evaluating cisplatin versus cetuximab chemoradiation (CRT) for p16+ oropharyngeal cancer (OPC) have yet to report preliminary data. Meanwhile, as a preemptive step toward morbidity reduction, the off-trial use of cetuximab in p16+ patients is increasing, even in those who could potentially tolerate cisplatin. The purpose of this study was to compare the efficacy of cisplatin versus cetuximab CRT in the treatment of p16+ OPC and to identify prognostic factors and predictors of tumor response. Materials and methods: Cases of p16+ OPC treated with cisplatin or cetuximab CRT at our institution from 2010 to 2014 were identified. Recursive partitioning analysis (RPA) classification was used to determine low-risk (LR-RPA) and intermediate-risk (IR-RPA) groups. Log-rank/Kaplan-Meier and Cox Regression methods were used to compare groups. Results: We identified 205 patients who received cisplatin (n=137) or cetuximab (n=68) CRT in the definitive (n=178) or postoperative (n=27) setting. Median follow-up was 3 years. Cisplatin improved 3-year locoregional control (LRC) [92.7 vs 65.4%], distant metastasis-free survival (DMFS) [88.3 vs 71.2%], recurrence-free survival (RFS) [86.6 vs 50.6%], and overall survival (OS) [92.6 vs 72.2%] compared to cetuximab [all p <.001]. Concurrent cisplatin improved 3-year OS for LR-RPA (97.1 vs 80.3%, p <.001) and IR-RPA (97.1 vs 80.3%, p <.001) groupings. Conclusion: When treating p16+ OPC with CRT, the threshold for substitution of cisplatin with cetuximab should be maintained appropriately high in order to prolong survival times and optimize locoregional and distant tumor control. When cetuximab is used in cisplatin-ineligible patients, altered fractionation RT should be considered in an effort to improve LRC.

6046 Background: Cisplatin ( Cis) is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Little is known about the incidence of hearing loss when using different cisplatin schedules in patients receiving concomitant CRT. We, therefore, assessed prospectively the incidence of ototoxicity in patients receiving weekly or triweekly Cis concomitantly with radiation. Methods: Head and Neck Squamous Cell Cancer patients receiving definitive or adjuvant cisplatin-based CRT were included. Cisplatin was administered weekly (40 mg/m2 weekly, 7 cycles) or triweekly (100 mg/m2 every three weeks, 3 cycles). Radiation was administered to a total dose of 70 Gy as definitive treatment or 66 Gy as adjuvant treatment (2 Gy/fraction). Intensity-modulated radiation therapy was used in all cases. Pure-tone air-conduction audiometry was performed in all pts before starting and after completion of CRT. The primary endpoint of the analysis was Common Terminology Criteria for Adverse Event (CTCAE v4.0) hearing change ≥3 at the end of CRT. Results: A total of 96 pts (M:77/F:19) were included (oropharynx 56 pts, other 40). Age: 55y (26-78). 68 pts received weekly cis and 28 triweekly regimen. 58 pts received definitive treatment and 38 adjuvant treatment. Nine pts receiving weekly cis (13%) experience G3 ototoxicity vs 14 pts (50%) receiving triweekly cis (P < 0.001, OR = 6.4, 95% CI 2.1-20.7). Risk of ototoxicity was not associated with age, cis cumulative dose, sex, tumor primary site, or CRT modality (definitive vs. adjuvant). After adjusting for these factors in a multivariable model cis schedule remained significant (OR = 8.7, 95% CI 2.31-32.75, p = 0.001). With a minimum follow-up of three months, the complete response rate after treatment was 84% for weekly CRT and 86% for triweekly CRT. Conclusions: Triweekly Cis-based CRT increases the risk of irreversible severe ototoxicity. This risk should be discussed with patients that are candidates for cis-based CRT.