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Background Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors. Methods Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high. Results The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control. Conclusions Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors. Trial registration number NCT04510129.

PURPOSE Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell–like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL. PATIENTS AND METHODS Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS). RESULTS Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell–like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% ( P = .06) and 73% ( P = .43) in the R2CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio [HR], 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided P = .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided P = .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided P = .1. CONCLUSION In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.

3509 Background: FOLFIRI or FOLFOX are 1st-line treatments (Rx) for MCRC. Cetuximab is an IgG1 Mab that targets the epidermal growth factor receptor (EGFR) and is approved as monotherapy or in combination with irinotecan in irinotecan-refractory, EGFR + pts with MCRC. CALGB 80203 randomized untreated MCRC pts to FOLFOX or FOLFIRI ± cetuximab (independent of EGFR status.) Methods: Pts with performance status 0–1 with tumor blocks available for EGFR analysis received either irinotecan 180 mg/m2 over 1.5 hours (h) or oxaliplatin 85 mg/m2 over 2h combined with LV 400 mg/m2 over 2h and 5FU 400 mg/m2 bolus, then 46–48h CI 5FU 2400 mg/m2 q o w. Cetuximab dose: 400 mg/m2 loading dose, then 250 mg/m2 qw. Rx continued until progression or toxicity; subsequent Rx was not mandated although information was collected on such rx. Accrual goal was 2200 pts with intended 1° endpt of overall survival (OS). 80203 closed administratively in 1/05 (due to slow accrual) with 238 pts accrued. 2° endpts of response rate (RR), progression free survival (PFS), duration of R and toxicity are now able to be analyzed. Results: Accrual: FOLFIRI (A) - 61; FOLFIRI + cetuximab (B) - 59: FOLFOX (C) - 60; FOLFOX + cetuximab (D) - 58; approx median follow-up (f/u) is 12 months. RR (CR + PR, not all yet confirmed): A - 34%; B - 42%; C - 32%; D - 55%. RR was similar in the FOLFIRI or FOLFOX arms (A+B v. C+D; 38% v. 43%, p=0.44; chi-square) while C225 containing arms (B+D) v. non-C225 arms (A+C) had a superior RR (49% v. 33%; p=0.014, chi-square) It is too early to tell if there are differences in PFS, duration of response or OS. No significant differences in gr III diarrhea or any gr IV toxicities were seen. Conclusions: These results suggest that FOLFIRI and FOLFOX are similar in efficacy for pts with untreated MCRC and that adding cetuximab to either in1st-line Rx appears to increase response rates. PFS and duration of response do not appear different at this analysis. Further f/u and an analysis of prospective companion correlative studies may help to further clarify these results. [Table: see text]

BACKGROUND: Patients with cirrhosis are growing older and the overlap between hepatic encephalopathy (HE) & pre-dementia mild cognitive impairment (MCI) is unclear. HE affects visuospatial/psychomotor speed while MCI affects memory. Aim: Determine the performance of elderly cirrhotics on tests for HE and dementia and their impact on quality of life (QOL). METHODS: Outpatient cirrhotics and controls ages 65–95 years were recruited at 4 centers. Subjects had to have MMSE > 25, no current HE or dementia to be eligible. All subjects got tests for HE (psychometric hepatic encephalopathy score, PHES: 5 tests & low score = poor, EncephalApp, OffTime + OnTime, high score = poor) and QOL: Sickness Impact profile (SIP, high score = poor QOL). Cirrhotics also got tests for MCI; RBANS (tests immediate memory, delayed memory, language, visuo-spatial & attention). A neuro-psychologist evaluated results and divided cirrhotics into (A) unimpaired (B) MCI only (C) HE only & (D) (MCI/HE overlap). Demographics, MELD, alcohol etiology, and SIP were compared. Finally, age, gender and education-adjusted norms were created for PHES and EncephalApp based on the controls. Presence of MHE and sensitivity of EncephalApp for MHE diagnosis were evaluated. RESULTS: 109 cirrhotics and 100 non-cirrhotic subjects were included. Demographics/education levels were statistically similar between centers. Controls were older than cirrhotics (74.9 ± 6.6 vs 70.5 ± 4.4, P < 0.05) and had similar education/gender distribution. Despite this, controls performed better than cirrhotics on all tests (PHES 2.9 ± 12.4 vs −4.5 ± +4.5, P < 0.001, EncephalApp Off+On 181.4 ± +71.9 vs 218.2 ± +80.0, P = 0.03) and had a better QOL (SIP total 3.8 ± +7.1 vs 7.9 ± +9.5, Psych 3.3 ± +8.4 vs 7.2 ± +11.1, Phys 3.0 ± +6.2 vs 6.7 ± +9.5, all P < 0.001). Within cirrhosis subgroups (Table 1), demographics, MELD/alc & MMSE were similar. Pts with both MCI/HE had worse cognition on all tests, which translated into a worse QOL compared to other groups. Presence of HE, with/without MCI, contributed towards poor QOL. Norms for PHES/EncephalApp: Adjusting for age, gender & education, 17% (n = 17) patients were positive for MHE on PHES compared to controls. On EncephalApp, 49% (n = 47) patients were positive. AUC for EncephalApp using PHES as the gold standard was 0.86 (0.78-0.95 CI). CONCLUSIONS: In this multi-center study, adjusted norms defining the high sensitivity of EncephalApp to diagnose HE in older individuals were created. Presence of HE regardless of MCI contributed towards poor cognition and QOL in patients >65 years.

Hepatic encephalopathy (HE) is a major cause of morbidity in cirrhosis. However, its severity assessment is often subjective, which needs to be studied systematically. The aim was to determine how accurately trainee and nontrainee practitioners grade and manage HE patients throughout its severity. We performed a survey study using standardized simulated patient videos at 4 US and 3 Canadian centers. Participants were trainees (gastroenterology/hepatology fellows) and nontrainees (faculty, nurse practitioners, physician assistants). We determined the accuracy of HE severity identification and management options between grades <2 or ≥2 HE and trainees/nontrainees. In total, 108 respondents (62 trainees, 46 nontrainees) were included. For patients with grades <2 versus ≥2 HE, a higher percentage of respondents were better at correctly diagnosing grades ≥2 compared with grades <2 (91% versus 64%; P < 0.001). Specialized cognitive testing was checked significantly more often in grades <2, whereas more aggressive investigation for precipitating factors was ordered in HE grades >2. Serum ammonia levels were ordered in almost a third of grade ≥2 patients. For trainees and nontrainees, HE grades were identified similarly between groups. Trainees were less likely to order serum ammonia and low‐protein diets, more likely to order rifaximin, and more likely to perform a more thorough workup for precipitating factors compared with nontrainee respondents. There was excellent concordance in the classification of grade ≥2 HE between nontrainees versus trainees, but lower grades showed discordance. Important differences were seen regarding blood ammonia, specialized testing, and nutritional management between trainees and nontrainees. These results have important implications at the patient level, interpreting multicenter clinical trials, and in the education of practitioners. Liver Transplantation 24 587–594 2018 AASLD.