Purpose: Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective phosphoinositide-3-kinase (PI3K)-γ inhibitor with anti-tumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (MARIO-1; NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors. Patients and Methods: Dose-escalation cohorts received eganelisib 10–60 mg as monotherapy (n=39) and 20–40 mg when combined with nivolumab (n=180). Primary endpoints included incidence of dose-limiting toxicities (DLTs) and adverse events (AEs). Results: The most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious adverse events occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Anti-tumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors. Conclusions: Based on the observed safety profile, eganelisib doses of 30 mg and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.

BACKGROUND: Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO. METHODS: We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient's histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology. RESULTS: The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node (n = 58), liver (n = 40), lung (n = 37), bone (n = 24), and brain (n = 8). Most patients (80.7%) were RMH good risk. Most patients (n = 62) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17-0.84, p = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41-1.19, p = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p = 0.0048). CONCLUSIONS: Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.

Human papilloma virus (HPV) causes a subset of head and neck squamous cell carcinomas (HNSCC) of the oropharynx. We combined targeted DNA- and genome-wide RNA-sequencing to identify genetic variants and gene expression signatures respectively from patients with HNSCC including oropharyngeal squamous cell carcinomas (OPSCC). DNA and RNA were purified from 35- formalin fixed and paraffin embedded (FFPE) HNSCC tumor samples. Immuno-histochemical evaluation of tumors was performed to determine the expression levels of p16INK4A and classified tumor samples either p16+ or p16-. Using ClearSeq Comprehensive Cancer panel, we examined the distribution of somatic mutations. Somatic single-nucleotide variants (SNV) were called using GATK-Mutect2 (“tumor-only” mode) approach. Using RNA-seq, we identified a catalog of 1,044 and 8 genes as significantly expressed between p16+ and p16-, respectively at FDR 0.05 (5%) and 0.1 (10%). The clinicopathological characteristics of the patients including anatomical site, smoking and survival were analyzed when comparing p16+ and p16- tumors. The majority of tumors (65%) were p16+. Population sequence variant databases, including gnomAD, ExAC, COSMIC and dbSNP, were used to identify the mutational landscape of somatic sequence variants within sequenced genes. Hierarchical clustering of The Cancer Genome Atlas (TCGA) samples based on HPV-status was observed using differentially expressed genes. Using RNA-seq in parallel with targeted DNA-seq, we identified mutational and gene expression signatures characteristic of p16+ and p16- HNSCC. Our gene signatures are consistent with previously published data including TCGA and support the need to further explore the biologic relevance of these alterations in HNSCC.

Objectives: The patterns of care for salivary gland adenoid cystic carcinomas (ACC) are unknown. We sought to assess predictors of receiving postoperative radiation and/or chemotherapy for patients with nonmetastatic, definitively resected ACC, as well as report unexpected nodal disease. Methods: The National Cancer Data Base was queried for definitively resected nonmetastatic ACC from 2004 to 2014. Logistic regression, Kaplan-Meier, and Cox proportional-hazard models were utilized. Propensity-score matched analysis was employed to reduce confounding variables. Results: A total of 3,136 patients met entry criteria: 2,252 (71.8%) received postoperative radiation, with 223 (7.4%) also receiving concurrent chemotherapy. Median follow-up was 4.87 years. In clinically lymph node negative (cN0) patients, 7.4% had pathologically positive lymph nodes (pN) + after elective neck dissection. Patients who lived closer to their treatment facility and had positive margins were more likely to receive postoperative radiation. Black patients and uninsured patients were less likely to receive radiation. Older age, male sex, advancing stage, and positive surgical margins were associated with worse overall survival (OS). With limited follow-up, receipt of radiation or chemotherapy was not associated with OS. Conclusion: Postoperative radiation was frequently given for resected ACC, with a minority receiving chemotherapy. Black patients and uninsured patients were less likely to receive radiation. Postoperative radiation and/or chemotherapy had no association with OS but were given in greater frequency in more advanced disease, and our series is limited by short follow-up. The disparity findings for this rare disease need to be addressed in future studies. Level of Evidence: 2c Laryngoscope, 129:377–386, 2019.

Platinum-based chemotherapeutics represent a mainstay of cancer therapy, but resistance limits their curative potential. Through a kinome RNAi screen, we identified microtubule-associated serine/threonine kinase 1 (MAST1) as a main driver of cisplatin resistance in human cancers. Mechanistically, cisplatin but no other DNA-damaging agents inhibit the MAPK pathway by dissociating cRaf from MEK1, while MAST1 replaces cRaf to reactivate the MAPK pathway in a cRaf-independent manner. We show clinical evidence that expression of MAST1, both initial and cisplatin-induced, contributes to platinum resistance and worse clinical outcome. Targeting MAST1 with lestaurtinib, a recently identified MAST1 inhibitor, restores cisplatin sensitivity, leading to the synergistic attenuation of cancer cell proliferation and tumor growth in human cancer cells and patient-derived xenograft models. Jin et al. show that cisplatin dissociates cRaf from MEK1 to inhibit the MAPK pathway and identify MAST1 as a main cisplatin resistance driver that replaces cRaf to reactivate the MAPK pathway. They further show that inhibition of MAST1 by the multi-kinase inhibitor lestaurtinib restores cisplatin sensitivity.

We explored potential associations of the PD-1/PD-L1/PD-L2 pathway with clinical characteristics, outcome, and expression of EGFR, HER2, HER3 in oropharyngeal squamous cell carcinoma (OPSCC) using an institutional database. Protein expression was assessed by IHC on tissue microarray sections (EGFR, HER2, HER3) or whole tissue sections (PD-1/PD-L1/PD-L2). Expression of EGFR, HER2, HER3, PD-L1, and PD-L2 was quantified on tumor cells. Maximum density of PD-1 positive lymphocytes was measured on a scale of 0 to 4 within the tumor mass and peritumoral stroma. Associations between biomarkers and patient outcomes were tested using descriptive and inferential statistics, logistic regression, and Cox proportional hazards models. We analyzed tissue samples from 97 OPSCC cases: median age 59 years, p16þ (71%), male (83.5%), never smokers (18%), stage 3 to 4 disease (77%). Twenty-five percent of cases were PD-L1 positive. The proportion of PD-L1þ tumors was higher in p16þ (29%) than p16 OPSCC (11%, P ¼ 0.047). There was no correlation between PD-L1, PD-L2, PD-1, EGFR, HER2, or HER3 expression. Positive PD-L1 status correlated with advanced nodal disease on multivariate analysis (OR 5.53; 95% CI, 1.06–28.77; P ¼ 0.042). Negative PD-L2 expression was associated with worse survival (HR 3.99; 95% CI, 1.37–11.58; P ¼ 0.011) in p16 OPSCC. Lower density of PD-1 positive lymphocytes in peritumoral stroma was associated with significantly increased risk of death on multivariate analysis (HR 3.17; 95% CI, 1.03–9.78; P ¼ 0.045) after controlling for prognostic factors such as stage and p16 status. PD-L1 expression on tumor cells correlates with p16 status and advanced nodal status in OPSCC. PD-1 positive lymphocytes in peritumoral stroma serve as an independent prognostic factor for overall survival.

BACKGROUND: To the authors' knowledge, the practice patterns for patients aged more than 80 years with stage III non–small cell lung cancer (NSCLC) is not well known. The purpose of the current study was to investigate factors predictive of and the impact on overall survival (OS) after concurrent chemoradiation (CRT) among patients aged ≥80 years with American Joint Committee on Cancer stage III NSCLC in the National Cancer Data Base (NCDB). METHODS: In the NCDB, patients aged ≥80 years who were diagnosed with stage III NSCLC from 2004 to 2013 with complete treatment records were identified. Multivariable logistic regression and Cox proportional hazard models were generated and propensity score-matched analysis was used. RESULTS: A total of 12,641 patients met the entry criteria: 6018 (47.6%) had stage IIIA disease and 6623 (52.4%) had stage IIIB disease. The median age at the time of diagnosis was 83.0 years (range, 80-91 years). A total of 7921 patients (62.7%) received no therapy. Black race (odds ratio [OR], 1.23; 95% confidence interval [95% CI], 1.06-1.43) and living in a lower educated census tract of residence (OR, 1.20; 95% CI, 1.03-1.40) were found to be associated with not receiving care, whereas treatment at an academic center (OR, 0.80; 95% CI, 0.70-0.92) was associated with receiving cancer-directed therapy. Receipt of no treatment (hazard ratio [HR], 2.69; 95% CI, 2.57-2.82) or definitive radiation alone (HR, 1.15; 95% CI, 1.07-1.24) compared with CRT was associated with worse OS. On propensity score matching, not receiving CRT was found to be associated with worse OS (HR, 1.58; 95% CI, 1.44-1.72). CONCLUSIONS: In this NCDB analysis, approximately 62.7% of patients aged ≥80 years with stage III NSCLC received no cancer-directed care. Black race and living in a lower educated census tract were associated with not receiving cancer-directed care. OS was found to be improved in patients receiving CRT. Cancer 2018;124:775-84. © 2018 American Cancer Society.

Background Significant controversy remains regarding the care of patients with clinical stage III (N2‐positive) NSCLC. Although multimodality therapy is effective, the roles of surgery, chemotherapy, and radiotherapy are not fully defined and the optimal treatment approach is not firmly established. We analyzed outcomes and predictors associated with trimodality therapy (TT) in the National Cancer Database. Materials and Methods The NCDB was queried from 2004 to 2014 for patients with NSCLC diagnosed with stage III (N2) disease and treated with chemotherapy and radiation (CRT). Three cohorts of patients were studied: CRT only/no surgery (NS), CRT plus lobectomy (LT), and CRT plus pneumonectomy (PT). The univariate and multivariable analyses (MVA) were conducted using Cox proportional hazards model and log‐rank tests. Results A total of 29,754 patients were included in this analysis: NS 90.1%, LT 8.4%, and PT 1.5%. Patient characteristics: median age 66 years; male 56% and white 85%. Patients treated at academic centers were more likely to receive TT compared with those treated at community centers (odds ratio: 1.85 [1.53–2.23]; p < .001). On MVA, patients that received TT were associated with better survival than those that received only CRT (hazard ratio: 0.59 [0.55–0.62]; p < .001). The LT group was associated with significantly better survival than the PT and NS groups (median survival: 62.8 months vs. 51.8 months vs. 34.2 months, respectively). In patients with more than two nodes involved, PT was associated with worse survival than LT and NS (median survival: 51.4 months in LT and 39 months in NS vs. 37 months in PT). The 30‐day and 90‐day mortality rates were found to be significantly higher in PT patients than in LT. Conclusion TT was used in less than 10% of patients with stage III N2 disease, suggesting high degree of patient selection. In this selected group, TT was associated with favorable outcomes relative to CRT alone. Implications for Practice This analysis demonstrates that trimodality therapy could benefit a selected subset of patients with stage III (N2) disease. This plan should be considered as a treatment option following patient evaluation in a multidisciplinary setting in experienced medical centers with the needed expertise.

Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and overall survival and performed correlative studies with PDL-1 and combined positive score, CD8+ T cell infiltration and tumor mutational burden. A total of 50 patients were screened and 36 were enrolled with 33 evaluable for response. The primary end point was met, with 17 out of 33 patients having a partial response (52%) and 13 (39%) stable disease with an overall clinical benefit rate of 91%. Median and 1-year overall survival were 22.3 months (95% confidence interval (CI) = 11.7–32.9) and 68.4% (95% CI = 45.1%–83.5%), respectively. Median and 1-year progression-free survival were 14.6 months (95% CI = 8.2–19.6) and 54% (95% CI = 31.5%–72%), respectively. Grade 3 or higher treatment-related adverse events included increased aspartate aminotransferase (n = 2, 5.6%). In 16 patients (44.4%), the dose of cabozantinib was reduced to 20 mg daily. The overall response rate correlated positively with baseline CD8+ T cell infiltration. There was no observed correlation between tumor mutational burden and clinical outcome. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC. Further investigation of similar combinations are needed in RMHNSCC. The trial is registered at ClinicalTrials.gov under registration no. NCT03468218.

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confi-dence interval (CI), 26.0–52.4], and median progression-free survival was 8.2 (95% CI, 4.4–8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI–resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. SIGNIFICANCE: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.