Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial

Approximately 67,000 patients are diagnosed with head and neck squamous cell carcinoma (HNSCC) in the United States every year (1). Even though the incidence of smoking-related cancers is declining, human papillomavirus (HPV)-associated cancers of the oropharynx continue to increase by about 1% annually (1). Historically, platinum-based chemotherapy was the cornerstone for recurrent and metastatic (R/M) HNSCC (2–4). Cetuximab, a human–mouse chimeric IgG1 monoclonal antibody that binds and inhibits the epidermal growth factor receptor (EGFR), improved overall survival (OS) in combination with radiation or cisplatin and 5-fluorouracil (5, 6) and was FDA approved for R/M HNSCC. However, single-agent cetuximab has shown poor overall response rates (<15%) with a response duration of <2–3 months (7).

Programmed cell death 1 (PD-1) inhibitors nivolumab and pembrolizumab have since received FDA approval for R/M HNSCC (8, 9) after platinum failure. Most recently, single-agent pembrolizumab when the combined positive score (CPS) for programmed death ligand-1 (PD-L1) is ≥1, or a combination of pembrolizumab, platinum agent, and 5-fluorouracil (5-FU) regardless of PD-L1 status has become the most accepted standard of care for patients with untreated and incurable R/M HNSCC (10). Despite recent advances and the availability of immune-checkpoint inhibitors (ICI) as a promising modality for R/M HNSCC, the prognosis remains poor, with an estimated median OS of fewer than 15 months and the overall response rate is low at <18% (8, 10, 11), necessitating exploration of novel therapeutic strategies and combinations.

Cetuximab exerts its principal effect by inhibiting EGFR signaling in cancer cells and simultaneously induces natural killer (NK) cell–mediated antibody-dependent cell cytotoxicity (ADCC; refs. 12–15). In addition, cytokines secreted from activated NK cells increase CD-8⁺ T-cell–mediated lysis of cancer cells and induce recruitment of other immune cells to the tumor microenvironment (14, 16). However, cetuximab-mediated ADCC and immune stimulation also initiate a negative feedback loop of immunosuppression [increased expression of checkpoints on tumor or immune cells, recruitment of regulatory T cells (Tregs), and myeloid-derived suppressor cells] in the TME (17). Therefore, we hypothesized that combining an ICI and cetuximab would synergize, overcoming immunosuppressive effects and resistance, leading to an increase in overall response rate (ORR) and survival. Previously, trials combining cetuximab and PD-1 inhibitors have shown encouraging response rates of up to 44% with pembrolizumab and cetuximab and 22% (in the previously treated cohort and 37% in the previously untreated cohort) with nivolumab and cetuximab (18, 19). We conducted a trial in previously treated patients with R/M HNSCC, where instead a PD-L1 inhibitor, durvalumab, was combined with cetuximab, thus making this unique compared with prior studies.

This investigator-initiated phase II study was a single-arm, open-label, nonrandomized trial that enrolled patients at the University of Cincinnati Cancer Center (UCCC). The study was conducted following the International Conference on Harmonization guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. The protocol (Supplementary Material) was approved by the institutional review board, and patients provided written informed consent for participation. This study is registered with ClinicalTrials.gov NCT03691714.

The treatment schema is described in Supplementary Fig. S1. Patients were eligible for enrollment if they were at least 18 years of age; had histologically or cytologically confirmed R/M squamous cell carcinoma of the oral cavity, oropharynx, paranasal sinuses, nasal cavity, hypopharynx, or larynx; deemed not to be candidates for curative intent therapy (i.e., surgery or radiotherapy); had an Eastern Cooperative Oncology Group (ECOG) performance status 0–2; had adequate bone marrow, renal, and hepatic function; and were able and willing to provide written informed consent. Patients with salivary gland tumors and nasopharyngeal tumors were excluded from the study. Enrolled patients were allowed prior exposure to systemic therapy for R/M HNSCC, including cetuximab and ICIs. However, patients exposed to both cetuximab and ICIs were excluded, as well as those with an active autoimmune condition requiring systemic therapy and those with active and untreated CNS metastasis. Detailed eligibility criteria are provided in the protocol (Supplementary Material).

All study participants received an initial loading dose of cetuximab 400 mg/m² intravenously (i.v.) alone, followed by 250 mg/m² i.v. once weekly. Cetuximab was chosen to be administered first to capture patients who may develop an infusion reaction with cetuximab, a common occurrence in previous clinical trials (7). Durvalumab was administered at a 1,500 mg fixed dose i.v., starting with the weekly dose of cetuximab on the first day of each 4-week cycle (Supplementary Fig. S1). Cycles were repeated every 28 days until disease progression, unacceptable toxicity, or the physician or participant's decision to withdraw from the study. A fixed 500 mg dose of cetuximab every 2 weeks was allowed once this had been approved by the FDA (20). Adverse events were documented using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5, with attribution to each study drug, details of which are available in the protocol provided with the Supplementary Material.

Response was assessed using conventional imaging—CT scans or MRI—of the neck and chest (abdomen and pelvis if indicated) every 8 weeks regardless of interruptions in treatment or treatment delays. Blood correlative studies were obtained at the time of screening (before administration of either drug), after the loading dose of cetuximab, and after the first dose of durvalumab (Supplementary Fig. S1). End-of-treatment visit for clinical evaluation and safety assessment was done 28 days after (or within 7 days before or after) the last dose of the study drug, and participants who had discontinued treatment on trial were followed up every 3 months for collection of survival outcomes data.

PD-L1 expression in archival or newly obtained, formalin-fixed tumor samples was assessed by IHC using the next-generation sequencing platform from CARIS^TM. Monoclonal antibodies used included 22c3 (n = 26; PD-L1–positive defined as a CPS ≥1) and 28–8 (n = 5; PD-L1–positive defined as ≥1+ staining intensity and ≥1% of cells stained). The threshold to define tumor mutational burden-high (TMB-H) was greater than or equal to 10 mutations/MB based on the KEYNOTE-158 pembrolizumab trial (21). Where available, p16 status was determined by IHC according to standard pathologic scoring (moderate to strong cytoplasmic and nuclear staining in at least 70% of tumor cells).

The primary endpoint for this study was the ORR by 6 months, defined as the proportion of participants with a partial (PR) or complete response (CR) per RECIST (version 1.1) criteria (22). Secondary endpoints were progression-free survival (PFS), defined as the time from administration of the first dose of cetuximab to disease progression or death from any cause, whichever happened first or otherwise censored at the last date known alive; OS, defined as the time from study enrollment to death from any cause or censored at the last date known alive; disease control rate by 6 months [defined as the proportion of participants with a PR or CR and stable disease (SD)]; duration of response (defined as the time from documentation of tumor response to disease progression); and safety and tolerability (defined as the occurrence of treatment-related adverse events per NCI-CTCAE version 5). Secondary safety endpoints were grade 3 and 4 adverse events and all grade (grade 1–5) adverse events. Exploratory endpoints were PD-L1 expression (utilizing CPS) and p16 status and their association with a response by 6 months, OS, and PFS.

Correlative studies’ methodology, including peripheral blood mononuclear cell (PBMC) isolation, storage, plasma isolation, flow cytometry, and Luminex, are included with the Supplementary Material.

PBMCs isolated and frozen from patient blood were thawed in a 36°C water bath for 2 minutes. Cells were washed in 5 mL RPMI and spun at 400 × g for 5 minutes. Cells were resuspended in RPMI (Corning) + 10% FBS (Corning) at density of 1 × 10⁶ cells per mL with 100 U/mL IL2 (PeproTech). PBMCs were allowed to rest overnight at 37°C and 5% CO₂. NK cells were then isolated using CD56-negative selection (Stemcell) and cocultured at a 1:5 ratio with CellTrace CFSE Cell Proliferation Kit stained Cal27 tumor cells for 4 hours. Culture was then collected and stained for 7AAD (BioLegend) and analyzed on a flow cytometer (BD LSRFortessa, University of Cincinnati Department of Cancer Biology). NK-killed targets were determined by gating CFSE⁺ cells and then 7AAD⁺. Basal death (Cal27s with no NK cells) was subtracted to determine direct killing.

Cytokine concentrations in the sample supernatants were determined by enzyme-linked immunosorbent assay (ELISA) using a Luminex assay (R&D Systems, a Bio-Techne brand) according to the manufacturer's protocol and is also detailed in the Supplementary Material.

Analyses for evaluating ORR included participants who had received at least one dose of durvalumab following the loading dose of cetuximab. Those who received only the loading dose of cetuximab and died or withdrew from the study before receiving the first dose of durvalumab and did not have a scan to assess tumor response were excluded from the response analysis. However, for the secondary endpoints of PFS and OS, all enrolled participants (intention-to-treat population), who had received at least one loading dose of cetuximab (regardless of whether they were able to receive durvalumab) were included in the survival analysis. Similarly, if a patient had received the loading dose of cetuximab but died or withdrew from the study before durvalumab was started, they were included in the safety analyses as well. The null hypothesis for this study was that the ORR with durvalumab and cetuximab at a 6-month follow-up would not be higher than 14% (which was based on an assumed ORR of 14% with cetuximab (7). In our study, where we proposed to combine durvalumab and cetuximab, we expected to reach over 84% power to detect an ORR of 35% against a null overall response rate of 14%, using Simon's two-stage design method in power calculation. The Kaplan–Meier method was used to analyze PFS and OS, and the median PFS and OS with its associated 95% CI were calculated. The secondary endpoint for adverse events was summarized using frequencies and proportions. The safety population included all participants who received at least one dose of durvalumab.

For the exploratory analyses, all statistics were performed in Prism V9. Two-way match ANOVA was utilized for time point analyses. One-way ANOVA analyzed responder comparisons. A type I error rate of 0.05 was used to determine statistical significance. All endpoint analyses were done in R version 4.2.1.

Raw data are available as a supplementary table and are available upon request from the corresponding author.

Between October 2018 and October 2021, 35 patients were enrolled, of whom 33 received at least 1 dose of durvalumab (consort diagram; Supplementary Fig. S2) and were included in response analysis. Data cutoff date for the analysis was April 8, 2022. Baseline demographics, information on the primary disease site, and type of prior therapies administered are shown in Table 1. The median age was 64 years (range, 47–81 years), and the majority of patients were male (N = 24; 68%) and White (N = 33; 94%). Oropharyngeal (N = 12; 35%) and oral cavity (N = 11; 31%) were the most common primary sites. Among the 12 patients with oropharyngeal primaries, 5 (42%) were p16 positive. Majority of patients (54%) had received some form of systemic therapy for R/M HNSCC in the past. Eleven patients out of the 33 included in the response analysis (33%) had received prior platinum-based chemotherapy for R/M HNSCC, 10/33 patients (30%) had received an ICI, and 1/33 (3%) patients had received cetuximab in the past (Table 1). Archival tissue specimens were available from 31 (93%) patients for PD-L1 testing, of which 22 patients (71%) were PD-L1 positive.

The median duration of follow-up from the initiation of study treatment to data cutoff or death, whichever occurred first, was 7.5 months (range, 1–38.7 months). The primary endpoint of improved ORR was met in 13 of 33 patients available for efficacy analysis (39%; Fig. 1A and B), thus indicating that the null hypothesis could be rejected. Ten had a PR, and three had a CR. In addition, 7 patients had SD (20%), and 13 patients had progressive disease (PD; 39%) as their best response. Five patients discontinued treatment before the first follow-up scan could be performed (one due to an immune-related adverse event and three due to complications related to their cancer) and were classified as having PD for this analysis. The median duration of response for patients who had a PR or CR was 8.6 months (95% CI: 6.5–16.8; Fig. 1C). In these patients, the median time to first observed radiographic response was 1.91 months (range, 1.8–9.3 months). Notably, four patients with a CR or PR continue to respond to the regimen at the 6-month follow-up time point (Fig. 1C). The disease control rate was 60% (20/33 patients). In the intention-to-treat population (35 patients), the median PFS was 5.8 months (95% CI: 3.7–14.1), and the median OS was 9.6 months (95% CI: 4.8–16.3) (Fig. 1D and E).

Of note, among the 10 patients who had previously received ICI (pembrolizumab or nivolumab) for R/M HNSCC, three patients derived clinical benefit with the combination. These three patients had been treated with pembrolizumab, with a response lasting for 5 months (patient 1), 7 months (patient 2), and 5 months and 6 weeks (patient 3). Durvalumab and cetuximab in the current clinical trial were administered to them as the immediate next line of therapy and they attained SD as their best response. Although there was no difference in the PFS or OS between patients who had received any prior systemic therapy or chemotherapy for R/M HNSCC (Supplementary Figs. S3 and S4), the OS was better for patients who had not received prior ICI [median OS 7.1 months; 95% CI: 2.8–not reached (NR) vs. 13.9 months; 95% CI: 4.8–NR; Fig. 2A and B].

The median number of cycles administered for durvalumab and cetuximab were 3 (range, 0–26 cycles) and 4 (range, 0–26), respectively. A detailed summary of all adverse events is available in Supplementary Tables S1 and S2. For clear immune-related toxicities (e.g., colitis) that were attributed to durvalumab, cetuximab was continued and vice versa. Most of these treatment continuation decisions were at the discretion of the treating investigator in consultation with the principal investigator. There were 16 grade 3 treatment-related adverse events (TRAE) and one grade 4 TRAE (Table 2). The most common TRAEs were dermatologic (acneiform rash) in 77% of patients, including one patient with grade 3 rash, fatigue in 46%, hypomagnesemia in 31% (including one patient with grade 3 hypomagnesemia), and nausea in 31% of patients. There were no treatment-related deaths. Immune-related adverse events from durvalumab were seen in six patients (17%). They included grade 3 elevation of AST/ALT and bilirubin, grade 3 colitis, grade 3 hyperglycemia, diabetes ketoacidosis and acute kidney injury in the same patient, grade 3 pleural and pericardial effusions, grade 4 uveitis, and grade 2 arthralgias. Of these, two patients discontinued treatment because of treatment-related adverse events (one due to grade 3 colitis and one due to grade 3 pleural and pericardial effusion). Dose reduction for cetuximab secondary to dermatological toxicity and fatigue was required in two (6%) patients.

Post hoc correlative analysis included an association of PD-L1 status with PFS and OS. Of the 31 patients who had PD-L1 status available, tumors from six (19%) were from metastatic/recurrence site, four (12%) were from nodes, and the remaining 21 (69%) were from the primary lesion. PD-L1 was positive in 11 of 13 patients who had a PR or CR to the combination (all three patients who had a CR were PD-L1 positive; Fig. 3A). There was no statistically significant difference between median PFS in PD-L1–negative versus –positive patients [2.99 months (95% CI: 1.8–NR) and 8.3 months (95% CI: 3.7–NR); Supplementary Fig. S5A]. Similarly, median OS was also not significantly different between the two groups [4.8 months (95% CI: 3.5–NR) in PD-L1–negative vs. 13.9 months (95% CI: 7.1 to 21) in PD-L1–positive; Supplementary Fig. S5B].

Four patients (11%) were p16 positive, whereas the remaining 31 (89%) patients either had p16-negative tumors or non-oropharyngeal tumors where p16 status was unavailable. Of the p16-positive tumors, one patient with oropharyngeal cancer had a PR (Fig. 3B). Of the 13 responders, p16 was unknown in 6 patients. In the remaining 7 patients, p16 was negative in all but 1 patient. Also noteworthy was that the majority of the p16-negative responders had oral cavity cancers (one p16-negative responder had a laryngeal primary; Supplementary Fig. S6A and S6B).

Evaluation of TMB was done in 27 (77%) patients and revealed that two patients who derived clinical benefit from the regimen (one with CR and one with SD) had a high TMB (>10 mutations/MB). The remaining patients had a low TMB, including the remaining 11 patients with clinical benefit to the durvalumab/cetuximab combination.

Flow cytometry analysis of the NK cells in the NK cell assay revealed a significant increase in the NK cytotoxic activity upon treatment with cetuximab, which was further enhanced in some patients upon the addition of durvalumab, though not significantly (Fig. 4), especially in patients who derived clinical benefit (described as responders; included patients with PR, CR, and SD). Patients with PD had the lowest NK cell cytotoxicity.

Cytokine analysis by Luminex showed that cetuximab alone decreased protumorigenic IL6 levels and increased IP-10 (Supplementary Fig. S7A and S7B); however, these cytokines were not significantly changed between responders (those with CR, PR, SD) and nonresponders. The full panel of tested cytokines, shown in Supplementary Fig. S7C, did not significantly change upon administration of either drug and was not different between responders and nonresponders.

This study presents safety and efficacy data from a phase II clinical trial combining cetuximab and the PD-L1 inhibitor durvalumab in R/M HNSCC. The ORR of 39% with the combination, including three patients who had a CR, is promising with improvement over the published response rates with ICIs or cetuximab administered as single agents (7–9).

Our data add to the previous studies that have explored EGFR inhibition in combination with ICIs in R/M HNSCC. Although previous studies utilized PD-1 inhibitors, ours is the first to combine a PD-L1 inhibitor with cetuximab, thus making this unique. Moreover, we allowed patients who had previously been treated with both chemotherapy and an ICI (>50% of patients had been treated with either or both drugs). The previously published phase II trial that evaluated the combination of pembrolizumab and cetuximab, which resulted in an ORR of 45% and a median OS of 18 months (18). Importantly, in this study, 88% of the included patients had not received any systemic therapy in the R/M setting, which may account for the superior response rate compared with our study. Subsequently, another phase II study of 24 ICI-naïve patients evaluated the efficacy of the EGFR inhibitor, afatinib, in combination with pembrolizumab in patients with platinum-refractory recurrent metastatic HNSCC (23) and reported an ORR of 41.4%. In the treated cohort of the phase II trial combining nivolumab and cetuximab, the ORR was lower at 22% (19). Some differences in outcomes could be driven by the differences in how adverse events and dose reductions were handled between each study. Regardless, our study, where we report an ORR of 39% in previously treated patients with R/M HNSCC, not only adds to the previous literature on this combination but also presents proof of concept for efficacy of a PD-L1 inhibitor when combined with cetuximab.

Previously, durvalumab has been evaluated in a large phase III trial, where patients previously treated with multiple lines of therapy (n = 736) were randomized in a 1:1:1 manner to receive durvalumab, durvalumab plus the CTLA-4 inhibitor tremelimumab, or standard-of-care chemotherapy (cetuximab, a taxane, methotrexate, or a fluoropyrimidine; ref. 24). The ORR (17.9% for durvalumab, 18.2% for durvalumab plus tremelimumab, and 17.3% for standard chemotherapy regimens) and the 12-month OS rates (37.0% vs. 30.4% vs. 30.5% for durvalumab, durvalumab plus tremelimumab, and standard-of-care chemotherapy, respectively) were not significantly different between the groups. However, here we demonstrate that the combination of a PD-L1 inhibitor with the EGFR monoclonal antibody, cetuximab, is just as likely to lead to a clinical benefit as are the PD-1 inhibitors. Further, as we report clinical benefit in patients who had previously been treated with an ICI, this combination may be considered for patients previously treated with an ICI. This is important to consider with the approval of pembrolizumab alone or in combination with chemotherapy in the first-line setting in R/M HNSCC. Although the combination of pembrolizumab and cetuximab has been incorporated in guidelines (25), durvalumab and cetuximab may be a useful addition, especially in those who have already received prior systemic therapy.

The adverse event profiles when combining durvalumab and cetuximab were within reasonable limits, and side effects were as expected from the two individual drugs. The most common TRAEs were dermatologic (acneiform rash), fatigue, hypomagnesemia, and nausea. In a previous study by Sacco and colleagues (pembrolizumab + cetuximab; ref. 18), oral mucositis was the most common grade 3–4 TRAE, whereas we observed oral mucositis in only three patients (all with grades 1–2). Grade 3 skin-related toxicity was comparable in the two studies (6% in the study by Sacco and colleagues, 2% in ours). Similar to our study, the study reported recently by Chung and colleagues (nivolumab + cetuximab) did not report any grade 3–4 oral mucositis in either cohort and reported a higher grade 3 skin toxicity in 9% and 14% of the enrolled patients in the 2 cohorts, respectively. Overall, like previous studies, the combination was safe and well tolerated.

Exploratory analysis of PD-L1 status showed that despite no survival difference between PD-L1–positive or –negative patients, most of the responders were PD-L1 positive (83%), and all of the patients who achieved a CR had PD-L1 CPS >1. The lack of survival difference between the PD-L1–positive or –negative patients could be due to the small cohort size in our study. Previous studies reported higher response rates and better survival when using ICIs in patients with PD-L1–positive tumors (10, 26). Importantly, we noted that two responders to durvalumab and cetuximab were PD-L1–negative, thus raising the question if there are additional tumor characteristics that are responsible for a response requiring evaluation in larger studies.

Although we cannot reliably ascertain the association of outcomes with p16 from our study due to the small number of patients with p16-positive tumors (n = 4), it is important to underline that previous studies, including a meta-analysis, have shown better efficacy of the combination of an EGFR inhibitor with an ICI in terms of better ORR and 1-year OS rate than an ICI monotherapy regimen in HPV-negative disease (27). Moreover, EGFR inhibitor monotherapy, either cetuximab or afatinib, has also resulted in lower efficacy in HPV-positive than HPV-negative disease in previously published clinical trials of R/M HNSCC (28–30). A higher number of p16-negative patients in our study may explain the high response rate to the combination of cetuximab and durvalumab. These and prior data thus highlight that tumor HPV status should be considered in the design of future trials utilizing cetuximab with an ICI in R/M HNSCC.

From flow cytometry, it was evident that NK cellular cytotoxic activity increased upon treatment with cetuximab, which was further increased upon the addition of durvalumab, especially in patients who responded to the combination, although we acknowledge that peripheral NK cell cytotoxic activity may not be reflective of NK cell infiltration and activity in the tumor. NK cell–mediated ADCC from cetuximab is well known, and trials are under way to enhance the efficacy of NK cell function with cetuximab by combining with agents such as immunogenic cytokines (e.g., IL12; ref. 31). Our findings support an approach to enhance the innate immunity of a tumor with cetuximab, followed by targeting the suppressive tumor microenvironment with an ICI to sustain greater antitumor effects of the NK cells.

Our study has limitations. The open-label design and the nonrandomized single-arm nature of this clinical trial with a small number of patients from a single enter warrants evaluation of the combination of durvalumab and cetuximab in a larger phase III randomized trial for confirmation of results. A follow-up of 6 months was chosen as previous studies have shown that patients with R/M HNSCC tend to relapse within this time window. However, we did note responses that lasted beyond 6 months. Furthermore, five patients who discontinued treatment before the first follow-up scan were counted as having PD, which may have affected the results.

In conclusion, we present promising data from a phase II clinical trial, which is unique from previous studies in that this is the first study reflecting the efficacy of a PD-L1 inhibitor in combination with cetuximab in R/M HNSCC. With an impressive response rate of 36% and durable responses, the study adds to the avenue of “chemotherapy-free” options. It provides evidence for use even in patients who have previously been treated with chemotherapy and or immune-checkpoint–based therapies. Our correlative studies provide evidence of a higher response rate but similar OS between PD-L1–positive and –negative patients. Further evaluation of this combination in a large phase III trial is warranted.

S. Gulati reports grants from AstraZeneca during the conduct of the study, as well as other support from EMD Serono and AVEO outside the submitted work. V. Takiar reports grants from VA Grant: BX004360 and NIH T32 CA117846 outside the submitted work. M. Lehn reports grants from AstraZeneca during the conduct of the study. T.M. Wise-Draper reports grants from AstraZeneca during the conduct of the study; T.M. Wise-Draper also reports grants from Merck & Co, BMS, Janssen, and Tesaro/GSK, as well as personal fees from Caris Life Sciences outside the submitted work. No disclosures were reported by the other authors.

S. Gulati: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. M. Crist: Investigation, visualization, methodology. M.K. Riaz: Investigation, visualization. V. Takiar: Investigation, writing–review and editing. M. Lehn: Investigation, visualization, methodology, writing–original draft. I. Monroe: Investigation. S. Palackdharry: Investigation, methodology. N. Kurtzweil: Investigation, methodology. R. Jandarov: Software, methodology. N. Harun: Software, formal analysis, visualization, methodology, writing–review and editing. T.M. Wise-Draper: Conceptualization, resources, supervision, funding acquisition, investigation, visualization, methodology, project administration, writing–review and editing.

The authors would like to thank the patients who participated in this trial. We would also like to thank Ilaina Monroe, Nicky Kurtzweil, Allison Forsythe, and the rest of the research coordinator team at the University of Cincinnati Cancer Center. Funding for this study was provided by AstraZeneca and awarded to Shuchi Gulati and T.M. Wise-Draper. Shuchi Gulati was supported by the National Center for Advancing Translational Sciences of the NIH, under Award Number (2KL2TR001426-05A1); NCI under Award Number K08CA273542 and in part by the ASCO/Conquer Cancer Foundation Career Development Award during the conduct of this study. Trisha Wise-Draper was supported by an NIH/Translational Science Award KL2 Training Grant TR001426, a Research Scholars Grant, RSG-19-111-01-CCE from the American Cancer Society, Wiltse philanthropic funds and by start-up funds provided by the University of Cincinnati. Vinita Takiar is partially supported by a Career Development Award, IK2 BX004360, from the United States Department of Veterans Affairs, Biomedical Laboratory Research and Development Service, the Dr. Bernard S. Aron fund, and NCI T32 CA117846.

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