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Targeted surveillance strategies following initial primary lung cancer (IPLC) treatment are currently limited. One hundred twenty patients diagnosed with IPLC who did not develop second primary lung cancer (SPLC) were matched to 121 patients who developed SPLC. Our analysis found IPLC surgical resection increases SPLC emergence risk regardless of procedure type. Increased survival after IPLC resection warrants close SPLC monitoring. Background: Increased patient survivorship following initial primary lung cancer (IPLC) diagnosis and treatment has uncovered new clinical challenges as individuals post-IPLC are at growing subsequent risk of developing second primary lung cancer (SPLC). Proper SPLC surveillance guidelines aimed at monitoring IPLC survivors are crucial to enhancing health outcomes. This study aims to categorize risk factors associated with SPLC emergence in IPLC survivors for clinical use following IPLC treatment. Materials and Methods: Using the Karmanos Cancer Institute Tumor Registry, patients diagnosed with IPLC from 2000 to 2017 were identified. Patients diagnosed with SPLC were matched to individuals who did not develop SPLC. Logistic and Cox regression analyses were performed to identify risk factors for SPLC emergence and overall survival (OS). Results: One hundred twenty-one patients diagnosed with IPLC who later developed SPLC were identified and compared with 120 patients with IPLC who did not develop SPLC. Several factors such as stage at first diagnosis, histology, age, and smoking history were not associated with SPLC risk. The median time to SPLC was 1.79 years. Patients who were treated with surgical resection had a significantly higher probability of developing SPLC. After correcting for potential immortal time bias, the median OS was 3.63 years (95% confidence interval [CI], 3.05–5.00) and 7.31 years (95% CI, 4.62–10.90) for SPLC and no SPLC groups, respectively. Conclusion: This study uncovered notable associations and lack thereof between several competing SPLC risk factors, as well as mortality. Further characterization of SPLC risk factors is essential for enhancing surveillance recommendations.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

BackgroundGEN-009 adjuvanted personalized cancer vaccine contains up to 20 neoantigens selected by ATLAS™, an ex vivo bioassay screening autologous T-cells for immune responses against both neoantigens and Inhibigens™. Inhibigen-specific T-cells suppress immunity, have been shown to accelerate tumor progression in mice, and are excluded from GEN-009. In cohort A, all patients immunized in the adjuvant setting with GEN-009 monotherapy developed immune responses. Ninety-nine percent of selected peptides were immunogenic: ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides, respectively.1 Six of 8 patients continue without progression with a median follow up >2 years.MethodsGEN-009 was administered to patients with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing. Five vaccine doses were administered over 24 weeks in combination with single agent anti-PD-1. Patients who progressed prior to vaccination received salvage therapy followed by GEN-009 in combination. Peripheral T-cell responses were measured by ex vivo and in vitro stimulated fluorospot assays. Circulating tumor (ct) DNA levels were evaluated in a subset of patients pre- and post-GEN-009 administration.Results15 patients received GEN-009 in combination with PD-1 inhibitor; 1 patient received GEN-009 monotherapy. Median number of neoantigens per vaccine was 14 (range 5–18). GEN-009-related adverse events were limited to vaccine injection site reactions, mild myalgias or fatigue. Sequential vaccination with GEN-009 had an additive effect on the magnitude of ex vivo T-cell responses, that persisted in some patients for 12+ months post first vaccine dose. An association between proportion of peptides eliciting significant cytokine responses and RECIST response is apparent. Epitope spread was detected in CD8+ T-cells from CPI-sensitive patients, but not refractory patients. Four patients who responded to PD-1 inhibition followed by disease stabilization then demonstrated further tumor reduction after GEN-009 vaccination. Seven of 9 CPI responsive patients are progression-free 7 to 18 months after first vaccine dose. Three of 7 CPI-refractory patients have experienced unexpected prolonged stable disease, with 2 PR and 1 SD after vaccination lasting up to 10 months. Plasma ctDNA kinetics mirrored RECIST responses in each tested patient; in some responders, all evidence of ctDNA disappeared, including non-targeted antigens.ConclusionsVaccination with GEN-009 alone or in combination with anti-PD-1 was well tolerated. Preliminary data demonstrate induction of robust, durable neoantigen-specific immune responses and epitope spreading in the presence of PD-1 CPI. Broad immunity against tumor specific targets and encouraging patient outcomes support further study.Trial Registration clinicaltrials.gov identifier: NCT03633110ReferencesLam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021 March;11(3):696–713.Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1

BackgroundNKTR-255 is an investigational IL-15Rα-dependent, polymer-conjugated, recombinant human IL-15 agonist designed to provide sustained pharmacodynamic (PD) responses without the need for daily dosing. NKTR-255 engages all IL-15 receptor binding complexes to expand, proliferate and activate natural killer (NK) and CD8+ T-cells. This Phase 1b/2 trial (NCT04616196) evaluates NKTR-255+cetuximab in highly refractory patients with head-and-neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC).MethodsSuccessive cohorts received escalating doses of NKTR-255 (q3w) +cetuximab (250mg/m< sup >2 weekly), 1 week after a loading dose of cetuximab alone. Safety (CTCAEv5.0; MTD/recommended Phase 2 dose [RP2D]) and efficacy (RECISTv1.1) were measured. PK/PD analyses were conducted, including assessment by flow cytometry/plasma cytokine analysis. Fold-change was calculated as treatment over baseline for NKTR-255 (baseline=1).ResultsAs of August 15, 2021, 12 patients had received ≥1 dose of NKTR-255+cetuximab; (37–70 years; 92% male; HNSCC n=4, CRC n=8; NKTR-255 1.5µg/kg n=7, NKTR-255 3.0µg/kg n=5). Patients had received a median 3.5 lines of prior therapy for metastatic disease. 11 patients had no response to the most recent prior therapy. Of the 12 patients, seven remain on treatment, with five not yet reaching first scan. RP2D has not yet been reached; dose escalation is ongoing.10 patients experienced an AE; one G5 AE occurred (due to progression). Seven patients reported NKTR-255-related AEs (all G1-2, except one G3 [which resolved in 24 hours]). Any-cause AEs in ≥20% were acneiform dermatitis, fatigue, and infusion-related reaction.Treatment-induced transient changes in inflammatory cytokines, including IFNy, MCP-1 and IL-6, at 1.5µg/kg (n=3) peaked 4 hours post-infusion and resolved by 24-48 hours. Mean T1/2 of NKTR-255 (1.5µg/kg dose, first cycle) was 27.8 hours.Dose-dependent expansion of NK and CD8+ T-cells was observed in peripheral blood. For NK cells, mean peak fold-change was ~4-fold and ~6-fold, and for CD8+ T-cells was ~2-fold and ~3-fold (1.5µg/kg and 3µg/kg dose levels, respectively). NK and CD8+ T-cells demonstrated increased Ki67+ proliferative ability.As of August 15, four patients in the 1.5µg/kg NKTR-255 dose cohort were response-evaluable: one CRC patient (4 prior metastatic treatment lines) reported a confirmed PR (–52%) after 3 cycles; two HNSCC patients reported SD.ConclusionsNKTR-255 was biologically active and led to expansion and proliferation of NK and CD8+ T-cells. Early dose-escalation data suggest that NKTR-255+cetuximab is safe and tolerable with preliminary anti-tumor activity. Updated data will be presented. NKTR-255, alone and in combination with daratumumab and rituximab, is also being evaluated in liquid tumors.AcknowledgementsThe authors thank the patients and their families involved in the trial.Trial RegistrationNCT04616196Ethics ApprovalThe study was approved by site IRBs.ConsentN/A

BACKGROUND Immune checkpoint inhibitors (ICIs) are the newest class of anticancer drugs. Pneumonitis is increasingly being recognized as a potential complication of these agents. METHODS We conducted a retrospective study of patients who received ICIs at a comprehensive cancer center. We collected data on demographics, type of malignancy, type of ICI agent, incidence of pneumonitis up to 6 weeks after receiving ICI agent, clinical characteristics, and risk factors for overall survival in patients who develop pneumonitis. RESULTS A total of 654 patients received ICIs during the study period. The most common type of cancer for which ICI was given was adenocarcinoma of the lung (29%), followed by renal cell cancer (12%) and squamous cell lung cancer (12%). Among the study patients, 41% received nivolumab and 32% received pembrolizumab. Other patients in the study received combination of ICIs or ICI plus chemotherapeutic agent, or were part of clinical trial involving ICI. Overall 42 (6.4%) patients developed pneumonitis within 6 weeks after the last dose of treatment of any ICI agent. Of these, 81% of patients had Grade ≥ 2 pneumonitis and 45% of these required hospital admission for pneumonitis, with 10% of them requiring admission to intensive care unit. Overall, patients who received pembrolizumab-containing regimen, had prior chemotherapy, or who never had cancer-related surgery had increased risk of death. CONCLUSION Our large retrospective study shows real-life data of incidence of pneumonitis in patients who are treated with ICIs for cancer treatment. Our data indicate that the incidence of pneumonitis is overall lower than that reported previously with relatively good outcomes.

We examined the impact of treatment modality on gastrostomy tube dependence and patient-reported outcomes in human papillomavirus-associated oropharyngeal cancer (HPV-OPSCC). We performed systematic review and meta-analysis of functional outcomes 1-3 years after treatment. Twenty-three studies were included, reporting on 3127 patients treated for HPV-OPSCC. Gastrostomy tube dependence failed to show statistically significant difference between surgery with adjuvant therapy and chemoradiotherapy with cisplatin at 12 months (8.3% [95% CI: 3.1-15.9] vs. 4.2% [1.1-9.2], p = 0.37) and 24-36 months (10.5% [95% CI: 3.2-21.5] vs. 3.3% [2.0-4.9], p = 0.06). Surgery with adjuvant therapy was associated with worse University of Washington Quality of Life (UW-QOL) Swallowing (84 [95% CI: 80-88] vs. 89 [87-90], p = 0.03) and UW-QOL Overall scores (76 [95% CI: 72-80] vs. 84 [81-86], p = 0.001) compared to chemoradiotherapy with cisplatin at 12 months. Surgery with adjuvant therapy was associated with worse performance on certain measures of patient-reported swallow and overall function compared to chemoradiotherapy with cisplatin. Further randomized controlled trials are needed to directly compare functional outcomes after treatment for HPV-OPSCC.

Misako Nagasaka,1,2 Nadine Abdallah,3 Marcus Crosby,4 Nithin Thummala,1 Dhaval Patel,1 Antoinette J Wozniak,5 Shirish Gadgeel,6 Judith Abrams,1 Ammar Sukari1 1Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA; 2Department of Advanced Medical Innovations, St. Marianna University Graduate School of Medicine, Kawasaki, Japan; 3Department of Internal Medicine, Wayne State University, Detroit, MI, USA; 4Department of Radiation Oncology, Gundersen Health System, La Crosse, WI, USA; 5Department of Oncology, University of Pittsburgh, Pittsburgh, PA, USA; 6Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USACorrespondence: Ammar SukariDepartment of Oncology, Karmanos Cancer Institute, Wayne State University, 4100 John R, Detroit, MI 48201, USATel +1 313 576 8753Fax +1 313 576 8699Email sukaria@karmanos.orgIntroduction of hypothesis: Little information is available regarding the imaging characteristics that assist in differentiating responders from non-responders. We hypothesized that patients with higher pretreatment tumor volume (PTV) would have lower response rates and shorter overall survival (OS).Methods: Data from patients who received at least one dose of program death-1 (PD-1) inhibitors before August 31, 2016 were captured from our institution’s pharmacy database. The primary objective was to determine the association of PTV with best response, evaluated utilizing RECIST v1.1 criteria. Secondary objectives were estimation of progression-free survival (PFS) and OS. PTV was measured using the Philips Intellispace Multi-Modality Tumor Tracking application.Results: 116 non-small cell lung cancer (NSCLC) patients were evaluated. 66% patients had adenocarcinoma, 28% had squamous cell carcinoma and 5% had poorly differentiated NSCLC. Median PTV was 53.7 cm3 (95% CI: 13.3–107.9). Only one individual had no metastases and the remainder had M1 disease; 38% M1a, 10% M1b, 51% M1c. Most (79%) were previously treated. There were no complete responses; among those followed for at least 6 weeks, 26% had a partial response, 39% stable disease and 34% PD; 4% had no recorded response. There were no strong associations of PTV with any of the demographic or clinical characteristics. There was no association between PTV and OS (HR 1.2, P=0.26) or PFS (HR 1.1, P=0.47). Liver metastasis was associated with shorter survival (HR=2.8, P=0.05).Conclusion: PTV in NSCLC did not prove to be a predictor of response to PD-1 inhibitors but having liver metastasis was associated with significantly shorter survival.Keywords: non-small cell lung cancer, tumor volume, tumor burden, checkpoint inhibitors

BackgroundA majority of patients with advanced NSCLC develop disease progression with first-line immune-checkpoint inhibitors (ICI) ± chemotherapy. In the setting of ICI resistance, effective strategies to provide deep and durable responses are urgently needed. Lifileucel (LN-144) and LN-145 are centrally manufactured (cryopreserved drug-product, 22-day manufacturing process) autologous TIL products that have demonstrated activity in advanced melanoma, cervical cancer, and head and neck carcinoma.1–4 Here, we report the first safety and efficacy data for LN-145 as monotherapy in patients with advanced NSCLC.MethodsIOV-COM-202 (NCT03645928) is a phase 2 multicenter, multicohort, open-label study evaluating autologous TIL cell therapy in patients with solid tumors. We report data from Cohort 3B, investigating LN-145 monotherapy in patients with advanced or metastatic NSCLC. Eligibility required 1–3 prior lines of systemic therapy, including either ICI or oncogene-directed therapy. Treatment included nonmyeloablative lymphodepletion, TIL infusion, and ≤6 interleukin-2 doses. Primary endpoints were safety (incidence of Grade ≥3 treatment-emergent adverse events [TEAEs]) and objective response rate (ORR, investigator-assessed using RECIST v1.1). Exploratory biomarker analyses, including T-cell receptor (TCR) repertoire, were performed.ResultsAs of 24June2021, 28 patients received LN-145 (full-analysis set [FAS]; table 1) and 24 were efficacy-evaluable; all had received prior ICI. TIL were most commonly harvested from lung metastases (57.1%). Safety was consistent with the underlying disease and known TEAE profiles of nonmyeloablative lymphodepletion and interleukin-2. Grade ≥3 TEAEs in ≥30% of patients were thrombocytopenia and anemia. The ORR in the FAS and efficacy-evaluable set was 21.4% (6/28) and 25.0% (6/24; figure 1), respectively. Median duration of response was not reached and 83% (5/6) of responses were ongoing at last follow-up (median study follow-up, 8.2 months). One patient had a complete metabolic response, ongoing at 20.7 months; 2 responses occurred in patients who were PD-L1–negative. All responders received ≥2 prior lines of systemic therapy. Twenty-six patients had TIL available from the final drug-product for TCR repertoire analysis; mean (min-max) number of unique TCR clones was 13,142 (3093–35,734) and Shannon Entropy index was 7.34 (3.7–12). Updated data will be presented.Abstract 458 Figure 1Best percentage change from baseline in target lesion sum of diameters for efficacy-evaluable setAbstract 458 Table 1Baseline patient demographic and clinical characteristics; efficacy parametersConclusionsLN-145 was successfully manufactured and one-time treatment produced an expected safety profile and durable responses in heavily pretreated patients with NSCLC, regardless of PD-L1 expression. The activity of LN-145 monotherapy is encouraging and warrants further investigation of LN-145 as a single-agent and in combination in patients with NSCLC in ongoing studies IOV-LUN-202 (NCT04614103) and IOV-COM-202 Cohorts 3A and 3C (3B closed to enrollment).AcknowledgementsThis study and analysis were funded by Iovance Biotherapeutics, Inc. (San Carlos, CA, USA). Writing support was provided by Amanda Kelly (Iovance); graphics support was provided by Cognition Studio (Seattle, WA, USA).Trial RegistrationNCT03645928ReferencesSarnaik AA, et al. J Clin Oncol 2021; doi: 10.1200/JCO.21.00612.. Thomas SS, et al. J Clin Oncol 2021;39: (suppl; abstract 9537).Jazaeri A, et al. J Clin Oncol 2019;37: (suppl; abstract 2538).Jimeno A, et al. J Immunother Cancer 2020;8: (suppl; abstract A378).Ethics ApprovalThe study was approved by Advarra Institutional Review Board, approval number Pro00035064 and all study participants provided written consent via signature of the IRB-approved Informed Consent form.

Nadine Abdallah,1 Misako Nagasaka,2,3 Eman Abdulfatah,4 Dongping Shi,4 Antoinette J Wozniak,2 Ammar Sukari2 1Department of Internal Medicine, Wayne State University, Detroit, MI 48201, USA; 2Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; 3Department of Advanced Medical Innovation, St. Marianna University Graduate School of Medicine, Kawasaki, Kanagawa, Japan; 4Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA Introduction: Histologic transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a well-recognized mechanism of resistance in EGFR-mutant adenocarcinoma upon treatment with TKIs, but rarely reported with programmed death1 (PD-1) inhibitors. We report two cases of potential transformation during treatment with PD-1 inhibitors.Case presentations: Case 1, a 65-year-old man was diagnosed with stage IVa lung adenocarcinoma on pleural fluid cytology. He received six cycles of carboplatin and pemetrexed, then maintained on pemetrexed. He had disease progression after nine cycles of pemetrexed and was switched to nivolumab. He progressed after five cycles of nivolumab. Core biopsy of the lung mass revealed SCLC. Case 2, a 68-year-old man was diagnosed with two primary NSCLCs and underwent resection. He had recurrence after several months and was treated with four cycles of carboplatin, paclitaxel, and pembrolizumab on clinical trial, with partial response. He was continued on pembrolizumab and had disease progression after 30 cycles. Biopsy of the new lesions showed SCLC.Discussion: Histologic transformation from NSCLC to SCLC can be explained by the presence of a common cell precursor. Proposed molecular mechanisms include loss of RB1, TP53 mutations, and MYC amplification. The distinction between transformation and mixed histology tumors is challenging, especially when pathologic material used for the initial diagnosis is limited. The possibility of a second metachronous primary lung cancer cannot be excluded in our cases.Conclusion: Histologic transformation with PD-1 inhibitors could be under-recognized. Disease progression should prompt re-biopsy to uncover new histology and change in treatment. Future studies are needed to elucidate mechanisms and predictors of transformation. Keywords: transformation, small cell lung cancer, non-small cell lung cancer, PD-1 inhibitor, resistance, checkpoint inhibitor&nbsp

Purpose: No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC. Patients and Methods: Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled. Spartalizumab was dosed 400 mg once every 4 weeks, and chemotherapy was received per investigator's choice. Results: Patients were randomized to receive either spartalizumab (82 patients) or chemotherapy (40 patients). The most common spartalizumab treatment-related adverse events were fatigue (10.3%) and pruritus (9.3%). Median PFS in the spartalizumab arm was 1.9 months versus 6.6 months in the chemotherapy arm (P = 0.915). The overall response rate in the spartalizumab arm was 17.1% versus 35.0% in the chemotherapy arm. Median duration of response was 10.2 versus 5.7 months in the spartalizumab versus chemotherapy arms, respectively. Median overall survival was 25.2 and 15.5 months in the spartalizumab and chemotherapy arms, respectively. Tumor RNA sequencing showed a correlation between response to spartalizumab and IFNγ, LAG-3, and TIM-3 gene expression. Conclusions: Spartalizumab demonstrated a safety profile consistent with other anti–PD-1 antibodies. The primary endpoint of median PFS was not met; however, median overall survival and median duration of response were longer with spartalizumab compared with chemotherapy.

BACKGROUND The standardization of quality measures has been key in advancing the aims of the National Quality Forum established to improve health outcomes. METHODS The National Cancer Database was used to identify eligible patients. Two quality metrics were evaluated including time to treatment initiation (TTI) and chemotherapy in locoregionally head and neck squamous cell carcinoma (HNSCC). RESULTS TTI was significantly associated with mortality reflected by a hazard ratio (HR) of 1.13 for 60-90 days of TTI (95% CI 1.08-1.17), 1.19 for >90 days of TTI (95% CI 1.13-1.26). Patients with locoregionally advanced HNSCC had an 87% adherence to chemotherapy, which correlated with reduced mortality (HR 0.57; 95% CI 0.55-0.59). Patients treated at high quality centers had a 9% increase in survival (HR 0.91; 95% CI 0.88-0.93). CONCLUSION We identified that both TTI and chemotherapy for locoregionally advanced HNSCC meet criteria for valid quality metrics potentially suitable for national adoption.

Background Single agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored. Methods IOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naive HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG Results Nine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached. Conclusions LN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented. Trial Registration NCT03645928 Ethics Approval The study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

Liquid biopsy is now considered a valuable diagnostic tool for advanced metastatic non-small cell lung cancer (NSCLC). In NSCLC, circulating tumor DNA (ctDNA) analysis has been shown to increase the chances of identifying the presence of targetable mutations and has been adopted by many clinicians owing to its low risk. Serial monitoring of ctDNA may also help assess the treatment response or for monitoring relapse. As the presence of detectable plasma ctDNA post-surgery likely indicates residual tumor burden, studies have been performed to quantify plasma ctDNA to assess minimal residual disease (MRD) in early-stage resected NSCLC. Most data on utilizing liquid biopsy for monitoring MRD in early-stage NSCLC are from small-scale studies using ctDNA. Here, we review the recent research on liquid biopsy in NSCLC, not limited to ctDNA, and focus on novel methods such as micro RNAs (miRNA) and long non-coding (lncRNA).

Background Immuno-STATsTM are novel, modular fusion proteins designed to selectively activate tumor-antigen-specific CD8+ T cells. Human papillomavirus (HPV) associated cancers serve as a model system to assess the safety and efficacy of the Immuno-STAT platform. CUE-101 is comprised of human leukocyte antigen (HLA) complex, HLA A*0201, a peptide epitope derived from the HPV type 16 E7 protein, and 4 molecules of a reduced affinity human interleukin-2 (IL2) designed to bind and activate HPV-specific T cells for eradication of HPV16-driven cancers. In preclinical studies CUE-101 demonstrated selective binding, activation, and expansion of HPV16 E7-specific CD8+ T cells, which translated into anti-tumor activity.1 Methods CUE-101-01 is a first-in-human (FIH) phase 1 study in patients diagnosed with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) refractory to one or more lines of therapy. Trial eligibility includes MHC class I type HLA-A*0201 and a diagnosis of an HPV16+ HNSCC, as assessed by p16 IHC and confirmed by HPV16 mRNA ISH. CUE-101 is administered intravenously over 60 minutes every 21 days. Objectives include determination of safety, pharmacodynamics (PD), pharmacokinetics (PK), recommended phase 2 dose (RP2D), and preliminary anti-tumor activity. The safety results from treated participants will be presented. Results 19 participants have received CUE-101 monotherapy as of August 7, 2020. Doses ranging from 0.06 to 1 mg/kg were determined to be safe and well-tolerated, enabling dose escalation to 2 mg/kg. Preliminary PK data demonstrate dose-dependent increases in drug exposure which are sustained upon repeat dosing, and low inter-subject variability. Preliminary data from systemic blood analyses show early signals of expansion of HPV-16 E711-20-specific CD8+ T cells. Stable disease (SD), as determined by RECIST 1.1, was observed in several participants in these early dose cohorts, with one subject maintaining SD up to 19 weeks. The maximum tolerated dose (MTD) has not yet been reached. As of May 14, 2020 (the development safety update report (DSUR) data-lock date), no dose limiting toxicities and the following adverse events were observed in the first 12 patients treated with CUE-101: fatigue (n=3), decreased appetite (n=1), arthralgia (n=1), muscular weakness (n=1), parasthesia (n=1), bullous pemphigoid (n=1), and infusion-related reactions (n=1). Conclusions CUE-101 is a novel agent that is demonstrating acceptable tolerability, favorable PK, and preliminary PD signals that support selective activation of tumor-specific T cells. Neither the MTD nor the monotherapy RP2D have been established. PD and PK analyses are ongoing as dose escalation continues. Acknowledgements The authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma. Trial Registration ClinicalTrials. gov NCT03978689 Ethics Approval This study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites; IRB reference numbers: DF/HCC IRB# 19-374 (Massachusetts General Hospital), HRPO# 201905108 (Washington University School of Medicine), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center), Advarra Pro00037736 (Moffitt Cancer Center), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), 2019-087 (Karmanos Cancer Institute), WIRB IRB00112341(Winship Cancer Institute/Emory University), WIRB 2000026098 (Yale Cancer Center), WIRB STUDY00008948 (University of Washington, Seattle ), WIRB 1908869642 (University of Arizona Cancer Center, IRB 20-073 (Memorial Sloan Kettering Cancer Center), 2019-0578 (The University of Texas MD Anderson Cancer Center), IRB 52744 (Stanford University School of Medicine). Reference Quayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc Fusion Protein, Enhances Tumor Antigen Specific T Cell Activation for the Treatment of HPV16-Driven Malignancies. Clin Cancer Res 2020;26:1953–64.

Background GEN-009 is an adjuvanted personalized cancer vaccine containing up to 20 neoantigens selected by ATLAS™, an ex vivo bioassay screening autologous T cells to identify both neoantigens as well as Inhibigens™ empirically and without in silico predictions. Inhibigen-specific T cells suppress immunity and have been shown to accelerate tumor progression in mice. Inhibigens are avoided in GEN-009. Previous data from patients treated with GEN-009 monotherapy showed 99% of selected peptides generated immune responses including ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides respectively. Methods GEN-009 is being evaluated in patients (pts) with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing; they subsequently received 5 vaccine doses over 24 weeks in combination with the PD-1 inhibitor. Patients who progressed prior to vaccination could receive alternate therapy followed by GEN-009 combined with an appropriate salvage regimen. Peripheral T cell responses were evaluated pre-and post-vaccination by dual-analyte fluorospot assays measured both directly ex vivo and after in vitro stimulation. Results As of August 18, 2020, 15 pts received GEN-009 in combination with a PD-1 inhibitor. Their median TMB was 1.37Mut/mb (range 0.31–6.55), with a median of 24 (6–99) neoantigens and 16 (1–86) Inhibigens. The number of neoantigens in each manufactured vaccine ranged from 4–18 (median 13). GEN-009-related adverse events were limited to Grade 1 injection site reactions. Ex vivo T cell responses peaked after the third vaccination for IFNγ and some patients showed evidence of epitope spread. The initial 5 patients are evaluable for antitumor activity with at least 3 months follow up after first vaccination. Three patients experienced early tumor responses followed by stabilization on PD-1 inhibitor SOC and demonstrated a further reduction in tumor volume after GEN-009 vaccination (figure 1). One patient experienced a complete response prior to vaccination and the 5th patient had progression on SOC, but had a Partial Response to salvage and remains stable after vaccination. Conclusions Vaccination with GEN-009 in combination with PD-1 CPI is feasible for patients with advanced solid tumors with little additive toxicity. Preliminary data demonstrate induction of robust, neoantigen-specific immune responses and a potential expansion of stimulatory targets with epitope spreading in the presence of PD-1 inhibitor. Possible additive antitumor activity in combination with PD-1 inhibitors is suggested by tumor shrinkage following GEN-009 dosing. More mature response and immunogenicity data on 10 additional patients is anticipated for November. Trial Registration ClinicalTrials. gov NCT03633110 Ethics Approval The study was approved by Western Institutional Review Board, approval number 1-1078861-1.

BackgroundImmuno-STATsTM are novel, modular fusion proteins designed to selectively activate tumor-antigen-specific CD8+ T cells. CUE-101 is comprised of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of a reduced affinity human interleukin-2 (IL-2) and is designed to bind and activate HPV16-specific T cells for treatment of HPV16-driven cancers. In preclinical studies CUE-101 demonstrated selective binding, activation, and expansion of HPV16 E7-specific CD8+ T cells, and a murine surrogate activated anti-tumor immunity.1MethodsCUE-101-01 is a first-in-human study in HLA-A*0201 positive patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Safety of escalating monotherapy and combination doses was evaluated to establish the recommended phase 2 dose (RP2D) for expanded enrollment. Patients with R/M HNSCC refractory to 1 or more prior platinum or pembrolizumab based systemic treatments received CUE-101 monotherapy, and patients with R/M HNSCC and PD-L1 tumor expression received combination CUE-101 and 200 mg pembrolizumab as first line treatment. Study treatment was administered intravenously every 3 weeks until progression or toxicity. Objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.ResultsAs of June 30, 2021, 39 patients have received CUE-101 monotherapy ranging from 0.06 to 8 mg/kg. The maximum tolerated dose (MTD) was not identified. Based on PK, PD and clinical data, a monotherapy RP2D of 4 mg/kg was selected. The combination cohort of 1 mg/kg CUE-101 and pembrolizumab has been tested and dose escalation is ongoing. Adverse events have included CTCAE grade 2 or less fatigue (41%), anemia (31%), lymphopenia (24%), chills (21%), decreased appetite (19%) and dyspnea (17%). CUE-101 PK data demonstrate dose-dependent increases in drug exposure that are sustained upon repeat dosing. PD data demonstrate dose-dependent expansion of HPV-16 E711-20-specific CD8+ T cells, sustained increase in natural killer cells and transient increase in Treg cells. An increase in CD3+ GZMB+ tumor infiltrating T cells was observed in tissue following treatment with CUE-101 in one patient with available pre- and post-treatment biopsies. One patient at the CUE-101 monotherapy RP2D has an ongoing partial response and 8 of 33 patients have experienced stable disease ≥ 12 weeks based on RECIST 1.1 criteria.ConclusionsCUE-101 is a novel immunotherapeutic demonstrating acceptable safety and tolerability with encouraging PD signals, supporting selective activation of tumor-specific T cells, and promising antitumor activity. Enrollment continues in both monotherapy and combination cohorts.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma.Trial RegistrationClinicalTrials.gov NCT03978689ReferencesQuayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc fusion protein, enhances tumor antigen specific T cell activation for the treatment of HPV16-driven malignancies. Clin Cancer Res 2020;26:1953–64.Ethics ApprovalThis study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers: Advarra Pro00037736 (Moffitt Cancer Center), IRB 52744 (Stanford University School of Medicine), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center), HRPO# 201905108 (Washington University School of Medicine), 2019–087 Karmanos Cancer Institute, DF/HCC IRB# 19-374 (Massachusetts General Hospital), WIRB 2000026098 (Yale Cancer Center), WIRB 1908869642 (University of Arizona Cancer Center), WIRB STUDY00008948 (University of Washington, Seattle), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), WIRB IRB00112341(Winship Cancer Institute/Emory University), 2019–0578 (The University of Texas MD Anderson Cancer Center), IRB 20-073 (Memorial Sloan Kettering Cancer Center), IRB00255391 (Johns Hopkins University School of Medicine).

Extra-pulmonary small cell carcinomas (EPSCC) are rare malignancies. Like small cell lung cancer (SCLC), they are aggressive malignancies with dismal prognosis. We here report a case of a middle-aged man who presented with odynophagia and cervical lymphadenopathy. Diagnostic workup confirmed the diagnosis of locally-advanced p16-positive oropharyngeal cancer (OPC) with a surprising histology of small cell cancer, suggesting a human papilloma virus (HPV)-related oropharyngeal cancer with small cell differentiation. HPV oropharynx infection is a well-known risk factor for squamous cell carcinoma of the oropharynx, but it is unknown if it may increase the risk of other OPC histology.

With the rapid development of precision medicine, next-generation sequencing (NGS) has provided the ability to uncode tumors at the DNA level. Identifying EGFR mutations and other molecular changes has become more crucial in the management of non-small cell lung cancer (NSCLC) than ever before. Although the histologic subtypes in patients with advanced NSCLC remain valid in determining treatment options, the detection of specific molecular signatures such as de novo T790M with sensitizing EGFR mutations could be more useful than the histologic subtype itself. Germline T790M mutation should be suspected and tested for when multiple biopsies show de novo T790M mutations or when de novo T790M is found in patients with a family history of lung cancer. This case report presents a 60-year-old woman with bilateral NSCLC with 3 different distinct histologic diagnoses. Evaluating the molecular profile using NGS completely changed the diagnosis, prognosis, and management of this rare presentation of NSCLC.

Background Patients with mNSCLC without actionable driver mutation(s) who have progressed after cytotoxic chemotherapy plus immune checkpoint inhibitors (ICI) ± bevacizumab have limited treatment options and represent an unmet need. The safety and efficacy of TIL cell therapy for mNSCLC patients who failed to respond or progressed on nivolumab has been evaluated in a Phase 1 clinical trial (Creelan B., AACR 2020), demonstrating an objective response rate (ORR) of 25% including 17% durable CRs. This provides a clear rationale for initiation of IOV-LUN-202 study, evaluating Iovance Gen 2 TIL cell therapy with LN-145 in patients with mNSCLC without actionable driver mutation(s), who have progressed on or following a single line of approved systemic therapy consisting of combined ICI + chemotherapy ± bevacizumab. Trial Design IOV-LUN-202 (NCT04614103) is a prospective, open-label, multi-cohort, non-randomized, multicenter Phase 2 study. Patient cohorts (n=40 ea) based on tumor proportion score (TPS) at metastatic diagnosis prior to ICI use are Cohort 1 (TPS Table 1.IOV-LUN-202 Patient CohortsPATIENT POPULATIONCOHORTMetastatic NSCLC without an actionable driver mutation and progressive disease on or following a single line of approved systemic therapy including ICI + Chemo ± BevacizumabSAMPLE SIZE1PD-L1 TPS < 1%N = 402PD-L1 TPS ≥ 1%N = 403PD-L1 TPS < 1%/Core BiopsiesN = 154RetreatmentN = undefined Citation Format: Erminia Massarelli, Zelanna Goldberg, Alex Cacovean, Bhagyashree Yadav, Guang Chen, Madan Jagasia, Friedrich Graf Finckenstein, Maria Fardis, Ammar Sukari. A phase 2 multicenter study of autologous tumor infiltrating lymphocytes (TIL, LN-145) cell therapy in patients with metastatic non-small cell lung cancer (mNSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT246.

Background TIL (especially CD8+ T cells) in the tumor microenvironment is associated with survival outcomes in many solid tumors, including melanoma (Mel), head and neck squamous cell carcinoma (HNSCC), and non-small cell lung cancer (NSCLC). Lifileucel (LN-144), has shown efficacy with durable responses in advanced melanoma (Mel) (Sarnaik et al., ASCO 2020), metastatic cervical cancer (Jazaeri et al., ASCO 2019), and LN-145 + pembrolizumab in HNSCC (Jimeno et al., SITC 2020). TIL therapy has shown evidence of efficacy in metastatic NSCLC in a Phase 1 study (Creelan et al., ASCO 2020). Methods IOV-COM-202 (NCT03645928) is a Phase 2 global, open-label multi-cohort, non-randomized study designed to evaluate the safety and efficacy of TIL therapy as a single agent or in combination with immune checkpoint inhibitors. All patients receive either, lifileucel, LN-145 or LN-145-S1 (PD-1 select TIL), which is manufactured at centralized GMP facilities generating a cryopreserved infusion product which is shipped to the treatment centers. Cohort 1, 2 and 3 enroll Mel, HNSCC and NSCLC patients, respectively (Table 1). Patients undergo a nonmyeloablative lymphodepletion (NMA-LD) regimen prior to TIL infusion, followed by up to 6 doses of intravenous IL-2. Patients in Cohorts 1A, 2A, and 3A start pembrolizumab following tumor harvest for TIL generation, but prior to NMA-LD. Pembrolizumab is dosed per label. Patients in Cohorts 1B, IC and 3B receive LN-145-S1, lifileucel, and LN-145, respectively. Cohort 3C patients receive a dose of ipilimumab and nivolumab prior to tumor harvest, with nivolumab continuing Q4W for up to 2 years, or until progression or unacceptable toxicity. Key eligibility includes: ≥ 18 years of age; RECIST measurable disease; ≥ 1 lesion(s) available for TIL generation; ECOG PS 0-1. The primary endpoint: ORR per RECIST v1.1. Secondary endpoints: safety, CR rate, DOR, DCR, PFS, and OS. Table 1.IOV-COM-202 Study DesignCohortTIL ManufacturingCohort 1A: Melanoma PD-1/ PD-L1 Naïve LN-144 + Pembrolizumab N=12LN-144: 22-day manufacturingCohort 1B: Melanoma ≥1 prior systemic therapies LN-145-S1 N up to 27LN-145-S1: PD-1 selected TILCohort 1C: Melanoma ≥1 prior systemic therapies LN-144 Gen 3 N up to 27LN-144 Gen 3: 16-day manufacturingCohort 2A: Head and Neck PD-1/ PD-L1 Naïve LN-145 + Pembrolizumab N=19LN-145: 22-day manufacturingCohort 3A: NSCLC PD-1/ PD-L1 Naïve LN-145 + Pembrolizumab N=12LN-145: 22-day manufacturingCohort 3B: NSCLC ≥1 prior systemic therapies LN-145 N=12LN-145: 22-day manufacturingCohort 3C: NSCLC 1 prior systemic therapy TIL + Ipilimumab / Nivolumab N up to 26 Citation Format: Scott Gettinger, Harriet Kluger, Adam Schoenfeld, Allison Betof-Warner, Kai He, Ammar Sukari, Bernard Doger de Speville Uribe, Sylvia Lee, Simon Haefliger, Zelanna Goldberg, Alex Cacovean, Rana Fiaz, Guang Chen, Madan Jagasia, Friedrich Graf Finckenstein, Maria Fardis, Antonio Jimeno. A Phase 2, multicenter study of autologous tumor infiltrating lymphocytes (TIL, LN 144/LN-145/LN-145-S1) in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT235.

e18050 Background: Adenoid cystic carcinoma (ACC) is a rare malignancy of glandular tissue with a high rate of local recurrence and metastatic disease for which clinical behavior varies widely. Currently, no standard therapy exists, and available therapies have low response rates. Therefore, prognostic biomarkers to determine optimal treatment strategies are urgently needed. Here we investigate the molecular landscape and therapeutic targets of ACC. Methods: ACC samples were analyzed using next generation sequencing (NGS) (NextSeq, 592 gene panel) or whole exome sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Pathogenic fusion events were detected using whole transcriptome sequencing (NovaSeq). Statistical significance was determined using the Chi-square test and adjusted for multiple comparisons. Tumor infiltrating Immune cell fractions were determined using the QuanTIseq deconvolution algorithm and WTS data. Results: 327 ACC patients were identified, median age of 58 years, 62% female and 62% metastatic disease. The most frequent mutations (excluding indeterminate results) involved genes in the NOTCH pathway ( NOTCH1 16% [41 of 298 cases]), chromatin remodeling ( ARID1A 24.3% [27 of 138 cases], KDM6A 12.5% [28 of 224 cases], KMT2C 10.7% [21 of 197 cases]) and TP53 10.2% (25 of 246 cases). Chromatin remodeling genes were co-mutated with NOTCH1. NOTCH1 mutations were found in 41 cases, 18 primary and 23 metastatic were associated with reduced median overall survival (mOS 1.8 years vs 3.8 years, p = 0.01). Mutations were most frequent in the PEST (n = 35), NRR (n = 18), PEST+NRR (n = 16) and EGF-like domains (n = 11). PEST domain mutations were found exclusively in ACC originating from the head and neck (H&N). GSEA showed that MYC, E2F and G2M target pathways were enriched in NOTCH1 mutated ACC regardless of the presence of MYB fusions. All three pathways were enriched in PEST domain mutations whereas only MYC targets were enriched in NRR and NRR+PEST domain mutations indicating that PEST domain mutations drive transcriptomic changes in NOTCH1 mutated ACC. MYC gene expression was significantly upregulated in NOTCH1 mutated ACC. Fusion events were detected in 45% (104/231). MYB:NFIB was the most common fusion (40%) and was more frequent in H&N origin than other sites. There was no difference in the mOS between MYB fusion positive and negative ACC (4.4 years vs 5.5 years, p = 0.14). M2-polarized macrophages, myeloid dendritic cells and neutrophils were significantly higher in metastatic compared to primary ACC while NK cells were more abundant in primary tumor. Conclusions: ACC is a genetically heterogenous disease with an immune-excluded microenvironment. NOTCH1 mutations were associated with worse, while MYB:NFIB fusion was not associated with prognosis. Our study shows that M2 macrophages and MYC are potential novel therapeutic targets in ACC.

6031 Background: Salvage surgery for locally recurrent head and neck squamous cell carcinoma (rHNSCC) results in local control rates of 33-50% but only 20-40% of patients achieve long-term survival necessitating additional therapy (Haque et al., Oral Oncol. 2019). Many patients are ineligible for re-irradiation and chemotherapy alone after salvage surgeryhas shown no survival benefit. The clinical activity and tolerability of immune checkpoint inhibitors has been demonstrated in metastatic HNSCC, but the benefit after salvage surgery (SS) has not been studied. Here we report the results of a multi-center phase II investigation of nivolumab, a PD-1 inhibitor, after SS in recurrent HNSCC (NCT03355560). Methods: HNSCC patients undergoing curative-intent SS were enrolled to receive 6 months of nivolumab beginning 4-11 weeks after surgery. All received radiation with or without chemotherapy as prior definitive therapy and had no other curative treatment options at the time of surgery. Key exclusion criteria included: distant metastatic disease, gross residual disease, or a history of immunodeficiency, autoimmunity, or pneumonitis. The primary endpoint was 2-year disease-free survival (DFS) measured by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Results: 39 patients were enrolled. Median age was 68 years (range, 49-85). 12/39 (31%) were female. 34/39 (87%) were white. Disease sites included oropharynx 9/39 (23%), oral cavity 14/39 (36%), and larynx 16/39 (41%). P16 status was 26% (+), 48% (-), and 26% (unknown). 17/39 (44%) had high risk pathologic features (positive margins or extranodal spread) at time of SS. 28/39 (72%) patients experienced treatment-related adverse events (TRAE), the most common of which were fatigue (26%), hypothyroidism (10%) and acneiform rash (13%). Grade 3-4 TRAEs were rare, occurring in 3/39 (8%) patients and included diarrhea, oral pain, neck pain, productive cough, stridor, and COPD exacerbation. 3/39 (8%) required treatment discontinuation and there were no grade 5 events. The 2-year DFS was 60% (95%CI 0.39-0.91). 2-year overall survival was 74% (95% CI 0.54-1). In single-cell multiplex cytokine analysis, patients who relapsed following adjuvant nivolumab had a significantly higher proportion of peripheral blood CD8 T cells which displayed a polyfunctional cytokine profile. IFN-γ and Granzyme were the dominant CD8 cytokines in both responders and non-responders, however CD8 expression of MIP1a and TNF-α were significantly higher in patients who ultimately relapsed. Conclusions: Nivolumab after salvage surgery in rHNSCC is well tolerated and shows promising antitumor activity in this high-risk patient population with unmet need. Immunotherapy after salvage surgery should be studied in randomized clinical trials. Clinical trial information: NCT03355560.

3584 Background: Patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed on ≥2 prior therapies have limited treatment options, with median OS ranging from 6-9 months (mo). In the dose-escalation phase of this first-in-human multicohort study (NCT02720068), the anti-lymphocyte activation gene (LAG)-3 antibody favezelimab (fave) was well tolerated alone and with pembrolizumab (pembro) across all dose levels (Lakhani, SITC, 2018, abstract O26). Here, we evaluate the safety and efficacy of fave alone or in combination with pembro in pts with advanced MSS CRC from the dose confirmation phase. Methods: Eligible pts with MSS PD-1/PD-L1-treatment-naïve mCRC that progressed on prior standard-of-care (3L+) were enrolled (cohort A) to receive the RP2D of 800 mg fave alone (Arm 1), 800 mg fave + 200 mg pembro (Arm 2C), or 800 mg fave + 200 mg pembro (MK-4280A) co-formulation (Arm 5), all Q3W. Treatment continued for 35 cycles or until progression, unacceptable toxicity, or investigator/pt decision. Pts with confirmed progression per irRECIST v1.1 on fave alone could crossover to 800 mg fave + pembro. Safety was assessed in all treated pts; efficacy in the full analysis set (FAS) of all treated pts with baseline scan. Objectives included safety (primary), ORR (RECIST v1.1 by investigator [secondary]), and DOR, PFS, and OS (exploratory). Interim analysis data cut-off was: Oct. 23, 2020. Results: A total of 20 pts received fave (Arm 1); 89 pts (including 9 crossover) received fave + pembro (Arms 2C+5); 12 pts (Arm 1) and 36 pts (Arms 2C+5), had PD-L1 CPS ≥1 tumors. At data cut-off, median follow-up was 5.8 months (mo) in Arm 1 and 6.2 mo in Arms 2C+5. Treatment-related adverse events (TRAEs) were 65% with fave (Arm 1) and 65.2% with fave + pembro (Arms 2C+5). Grade ≥3 TRAEs were 15% (Arm 1), and 20% [Arms 2C+5]). No grade 5 TRAEs were reported. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15%) with fave, and fatigue (16.9%) with fave + pembro. Confirmed ORR was 6.3% (4PR, 1CR) with fave + pembro (Arms 2C+5). No pt receiving fave alone responded. In Arms 2C+5, median DOR was 10.6 mo (range, 5.6-12.7). ORR, OS and PFS by PD-L1 status are reported in the Table. Conclusions: Favezelimab alone or in combination with pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, including with MK-4280A, compared with monotherapy most notably in pts with PD-L1 CPS ≥1 tumors. Clinical trial information: NCT02720068. [Table: see text]

e18026 Background: Previous studies have consistently shown that p16+ oropharynx squamous cell cancer (OPSCC) patients have better outcomes. The significance of molecular and transcriptional signatures and its correlation with p16 expression remains unclear. Methods: We queried the Caris Life Sciences database to assess the molecular and transcriptional signatures related to p16+ and p16- head and neck squamous cell cancer (HNSCC) patients. Comprehensive molecular profiling including whole exome sequencing (WES), targeted Next-Generation Sequencing (NGS), and immunohistochemistry (IHC) 22c3 for PD-L1 was performed (CPS ≥1 considered positive) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. A standard cut-off of 2+, > 70% p16 staining was used. HPV16/18 was tested using WES. Patients were considered smokers if they had > 15 pack-years. Real world overall survival (rwOS) was obtained from insurance claims data and Kaplan-Meier estimates were calculated from the date of start of treatment to the date of last contact. Results: 948 cases of OPSCC were identified in the Caris database. 41% (82/199) were smokers. Where p16 and HPV data was available, 41% were p16+ (171/420) while HPV positivity rate was 52% (71/148). We noted a small number of patients with discordant p16 and HPV status (7 p16+/HPV-, 8 p16-/HPV+) in 327 patients who had HPV status available. Most common mutations were TP53 (33%), PIK3CA (17%) and KMT2D (10.6%). 87% were PD-L1 positive (342/394), with high expression in both p16+ and p16- subgroups, 90% and 85% respectively. 10% had TMB≥10/Mb (48/463). TP53 mutations were more common in p16- (49%) tumors in contrast to p16+ (10%) (p < 0.0005), while no statistical difference was detected in TMB≥10/Mb between the groups. CDKN2A, TERT and NOTCH1 mutations were more prevalent in tumors that were p16- or HPV- in contrast to tumors that were p16+ or HPV+ (p < 0.05). FGF3, CCND1, FGF4, FGF19 copy number alterations (CNA) were less common in p16+ OPSCC compared to p16- or HPV16- OPSCC (p < 0.0005). P16+ patients had longer rwOS when compared to p16-, 47 months versus 20 months (HR = 0.55, p = 0.014) respectively. Conclusions: Higher frequency of CDKN2A, TERT and NOTCH1 mutations among p16- (versus p16+) raise the possibility of potential targets for treatment in this group with poor prognosis. However, it remains unclear if these can serve as independent predictors of survival.[Table: see text]

e18056 Background: Adenoid cystic carcinoma (ACC) is a rare malignancy of glandular tissue with a high rate of local recurrence and metastatic disease. Despite being regarded as an indolent disease, the clinical course of recurrent and metastatic ACC (R/M ACC) is highly variable. Responses to chemotherapy (chemo) are uniformly poor. Several multi-targeted tyrosine-kinase inhibitors (mTKIs), EGFR inhibitors (EGFRi) and other targeted agents have been studied in single-arm early phase trials with response rates ranging from 0-16% and progression free survival ranging from 2.5-17 months. However, there have been no comparative clinical trials and it is not known if one treatment strategy is superior. We undertook this retrospective study to assess the real-world clinical outcomes in patients with adenoid cystic carcinoma using the Caris Life Sciences database. Methods: Real world overall survival (rwOS) for cases of ACC was obtained from insurance claims data and Kaplan-Meier estimates were calculated from the date of collection to the date of last contact. Cases were divided into subgroups based on treatment received – chemo (including platinum agents, taxanes, 5FU, topoisomerase inhibitors, anthracyclines), EGFRi (cetuximab, erlotinib, lapatinib), mTKIs (pazopanib, axitinib, sunitinib, cabozantinib, lenvatinib, sorafenib) and immune checkpoint inhibitors (ICIs) (atezolizumab, ipilimumab, pembrolizumab, nivolumab). Results: 368 patients (pts) were identified with ACC, 16 were locally recurrent and 216 tumors were taken from metastatic sites. 50 pts received chemo, 6 were treated with EGFRi and 15 with mTKIs. Pts who received combination EGFRi and chemo or mTKI and chemo were excluded. The median overall survival (mOS) all patients with metastatic ACC was 2.8 years (yrs). The mOS of pts with R/M ACC was 3 yrs for chemo, 2.9 yrs for EGFRi and 1.5 yrs for mTKIs. There was no significance in mOS between chemo vs mTKIs (HR 0.85, 95% CI 0.3 - 2, p = 0.72) and chemo vs EGFRi (HR = 0.88, 95% CI 0.3 - 2.5, p = 0.78). We further compared the outcomes of those treated with EGFRi (n = 8) with mTKIs (n = 19) in the entire cohort. For most pts, these agents were given as front line therapy. 25% (2/8) of patients had received treatment prior to EGFRi and 20% (4/9) prior to mTKIs (p = 1). There was no significant difference in mOS with HR 0.6 (95% CI 0.16 - 2.6), p = 0.6. We also compared the mOS of patients who received ICIs (n = 22) with those who did not (n = 346) but there was no significant difference (mOS 3.19 vs 3.17 yrs respectively, HR 0.87, 95% CI 0.47- 1.61, p = 0.65). Conclusions: There was no significant difference in the mOS between pts with R/M ACC who were treated with chemo, EGFRi or TKIs and in those who received ICIs compared to those who did not in our limited patient population. This highlights the need for predictive biomarkers for better patient selection with the goal of personalizing treatment strategies for this disease.

Purpose As Syria enters its fifth year of conflict, the number of civilians killed and injured continues to rise sharply. Along with this conflict comes the rapid decline of medical care, specifically cancer care. To determine physician and equipment availability, cancer screening and management, and possible solutions relative to various major cities, a survey was distributed to physicians inside Syria through the help of the humanitarian organization Syrian American Medical Society. Methods Online surveys were distributed to both certified oncologists who work in cancer clinics and general physicians who work in rural and mobile clinics inside Syria. Variables assessed were physician specialty, location, population, cost, regional situation (besieged versus government controlled), and resource availability and access. Results were stratified by location and physician specialty. Results Survey results revealed a large shortage of specialized physicians and inhibited accessibility to screening and management options in besieged areas compared with government-controlled regions. Physicians within both government-controlled and besieged cities reported limited or no targeted agents, radiation therapy, clinical trials, bone marrow transplantation, positron emission tomography scans, magnetic resonance imaging, and genetic testing. Conclusion The Syrian civil war has resulted in suboptimal oncology care in the majority of the region. In consideration of specific deficiencies in cancer care, we recommend several solutions that may better the level of care in Syria: patient education on medical documentation and self-examination; online consultation; and cheap, effective screening methods. The implementation of these recommendations may change the course of cancer care in a country that has deteriorated into the worst humanitarian crisis of the century.

// Priscila H. Goncalves 1 , Lance K. Heilbrun 1 , Michael T. Barrett 2 , Shivaani Kummar 4, 8 , Aaron R. Hansen 3 , Lillian L. Siu 3 , Richard L. Piekarz 4 , Ammar W. Sukari 1 , Joseph Chao 5 , Mary Jo Pilat 1, 6 , Daryn W. Smith 1 , Lindsay Casetta 1 , Scott A. Boerner 1, 7 , Alice Chen 4 , Elizabeth Lenkiewicz 2 , Smriti Malasi 2 , Patricia M. LoRusso 1, 7 1 Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA 2 Mayo Clinic Arizona, Scottsdale, AZ, USA 3 Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada 4 Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA 5 Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA 6 Eugene Applebaum College of Pharmacy and Health Sciences, Physician Assistant Studies, Wayne State University, Detroit, MI, USA 7 Current address: Yale Cancer Center, New Haven, CT, USA 8 Current address: Stanford University, Palo Alto, CA, USA Correspondence to: Priscila H. Goncalves, email: priscila.goncalves@nih.gov Keywords: adenoid cystic, salivary gland tumor, vorinostat, suberoylanilide hydroxamic acid, SAHA Received: February 09, 2017 Accepted: March 14, 2017 Published: March 22, 2017 ABSTRACT Purpose: Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial. Methods: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients. Results: Thirty patients were enrolled. Median age of patients was 53 years (range 21–73). Median number of cycles was 5 (range 1-66). Lymphopenia ( n = 5), hypertension ( n = 3), oral pain ( n = 2), thromboembolic events ( n = 2) and fatigue ( n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC. Conclusion: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.

Despite a considerable expansion in our therapeutic repertoire for management of other malignancies, mortality from head and neck cancer (HNC) has not significantly improved in recent decades. Upon normalizing National Institutes of Health–awarded R01 and R01-equivalent grants by incidence, thyroid cancer ($214) and HNC ($1329) received the fewest funding dollars. Upon adjusting funding totals by mortality, HNC was 7th out of 9 cancers evaluated ($6138). These findings highlight HNC as an underfunded disease versus other cancers. As data detailing grant applications (including unsuccessful grants) are not publicly available, it is not clear if these disparities stem from fewer applications or fewer opportunities. Our hope is that this commentary will spur further investigation into strategies to increase HNC inquiry and funding for trainees as well as early-stage and established investigators.

Background Surgical salvage is often the only potentially curative treatment in patients with recurrent head and neck squamous cell carcinoma (HNSCC). However, local control rates after salvage remain at 33-50% with a dismal long term overall survival of 20-40%. Many patients are ineligible for re-irradiation and chemotherapy alone has no survival benefit after salvage surgery necessitating new therapies. Although immune checkpoint inhibitors have demonstrated clinical activity in the metastatic setting, immunotherapy has not been explored after salvage surgery. Therefore, we initiated a multi-center Phase II investigation of adjuvant nivolumab after salvage resection in HNSCC patients (NCT03355560) supported by BMS. Methods HNSCC patients who failed definitive radiation, subsequently treated with curative intent salvage resection, were enrolled to receive 6 months of nivolumab beginning 4 to 11 weeks after surgery. Safety was evaluated with CTCAE v5.0 and disease free survival (DFS) was evaluated using time to event endpoints and Kaplan-Meier curves. Results Eighteen of 35 planned patients have been enrolled. Median age is 70 years (range, [45-85]), 4/18 (22%) were female, 17/18 (94%) were white, disease sites included oropharyngeal 3/18 (17%), oral cavity 8/18 (44%) and larynx 7/18 (39%), and 5/18 (28%) had high risk (positive margins or extranodal spread) pathological features. Four patients have recurred with DFS estimated at 55% at 10.2 months. Although estimated DFS is less than the predicted 62.3% DFS at 10.2 months (extrapolated from 2-year DFS of 33%), the chi-square p-value was 0.861 suggesting there is not enough evidence to reject the null hypothesis and the trial should proceed to the 2nd stage. Most common adverse events included fever (22%), fatigue (17%), arthralgias (22%), cough (28%) and infections (28%) most of which were unrelated. Grade 3 related events included arthralgia and cough. Conclusions Adjuvant nivolumab after salvage surgery in HNSCC patients is safe however, increased enrollment is required to establish efficacy. Clinical trial identification NCT03355560. Legal entity responsible for the study Trisha Wise-Draper. Funding BMS. Disclosure T. Wise-Draper: Research grant / Funding (self): BMS; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Merck; Research grant / Funding (institution): Tesaro. All other authors have declared no conflicts of interest.

This report describes highlights the dramatic responses seen in patients who were given paclitaxel post progression on immunotherapy. There are multiple mechanisms by which synergistic effects of immunotherapy and chemotherapy occur. Further prospective studies on chemotherapy and immunotherapy are eagerly awaited.

Background Data on the characteristics of patients who are likely to experience adverse events, both immune-related and non-immune-related, from programmed cell death-1 (PD1) inhibitors are limited. Patients and methods Data from patients who received ≥1 dose of single-agent PD1 inhibitor between August 3, 2011 and August 31, 2016 were obtained from our Institution's pharmacy database. AEs were graded using Common Terminology Criteria for Adverse Events version 4. Results One hundred and eighty-two patients received at least one dose of single-agent PD1 inhibitor prior to data cut-off. After excluding 14 patients with uncommon malignancies, the total number of patients were 168. The median age was 63 (range=24-92) years. There were 87 (52%) cases of non-small cell lung cancer (NSCLC), 35 (21%) of renal cell carcinoma (RCC), 12 (7%) of melanoma, 18 (11%) of Hodgkin's lymphomas, eight (5%) of head and neck squamous cell carcinoma (HNSCC) and eight (5%) of small cell lung cancer. Considering grade 2 or more AEs, 30 (18%) patients had kidney injury, 34 (20%) hypothyroidism, 36 (21%) transaminitis, 20 (12%) pneumonitis, and 18 (11%) colitis. Patients with RCC had higher odds of experiencing grade 2 or more kidney injury than patients with other primary tumor types (adjusted p=0.025), whereas patients with Hodgkin's lymphoma and HNSCC had higher odds of grade 2 hypothyroidism (adjusted p=0.005). Patients with NSCLC had higher risk of death with pneumonitis than those whose primary cancer was not NSCLC (adjusted p=0.005). Discussion The increased odds of patients with Hodgkin's lymphoma and HNSCC experiencing grade 2 or more hypothyroidism may be related to previous radiation exposure. Most patients with RCC had undergone nephrectomy, making them more susceptible to acute kidney injury. When pneumonitis occurred in patients with primary NSCLC, the overall survival was significantly worse. The duration of PD1 therapy was significantly associated with onset of pneumonitis (p=0.007). Conclusion The site of primary tumor or metastasis may help predict the most common AEs in patients treated with PD1 inhibitors.

Introduction JNJ-64041757 (JNJ-757) is a live, attenuated, double-deleted Listeria monocytogenes–based immunotherapy expressing human mesothelin. JNJ-757 was evaluated in patients with advanced NSCLC as monotherapy (phase 1) and in combination with nivolumab (phase 1b/2). Methods Patients with stage IIIB/IV NSCLC who had received previous therapy were treated with JNJ-757 (1 × 108 or 1 × 109 colony-forming units [CFUs]) alone (NCT02592967) or JNJ-757 (1 × 109 CFU) plus intravenous nivolumab 240 mg (NCT03371381). Study objectives included the assessment of immunogenicity, safety, and efficacy. Results In the monotherapy study, 18 patients (median age 63.5 y; women 61%) were treated with JNJ-757 (1 × 108 or 1 × 109 CFU) with a median duration of 1.4 months (range: 0–29). The most common adverse events (AEs) were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours. Peripheral proinflammatory cytokines and lymphocyte activation were induced posttreatment with transient mesothelin-specific T-cell responses in 10 of 13 biomarker-evaluable patients. With monotherapy, four of 18 response-evaluable patients had stable disease of 16 or more weeks, including one patient with a reduction in target lesions. In the combination study, 12 patients were enrolled (median age 63.5 y; women 33%). The most common AEs with combination therapy were pyrexia (67%) and chills (58%); six patients had grade 3 AEs or greater, including two cases of treatment-related fatal pneumonitis. The best overall response for the combination was stable disease in four of nine response-evaluable patients. Conclusions As monotherapy, JNJ-757 was immunogenic and tolerable, with mild infusion-related fever and chills. The limited efficacy of JNJ-757, alone or with nivolumab, did not warrant further investigation of the combination.

Objectives: The objectives of the study were to report long-term experience with percutaneous thoracic cryoablation, including both malignant pleural and primary pulmonary tumors, assessing factors affecting complications and local recurrence rates. Material and Methods: After Institutional Review Board approval and Health Insurance Accountability Act compliance, a retrospective review of 50 patients who underwent 85 CT fluoroscopic-guided percutaneous cryoablation procedures for 116 masses, consisting of non-small cell lung cancer (n = 61), small cell lung cancer (n = 1), mesothelioma (n = 16) and malignant profile fibrous tumors (n = 38) was performed. Tumor size and location (central vs. peripheral) were noted in relation to major vasculature. Hydrodissection and/or esophageal warming balloons were utilized for the protection of crucial structures. Complications were graded according to standardized Common Terminology Criteria for Adverse Events criteria. Patients were followed by CT and/or MRI at 1, 3, 6, 12, 18, and 24 months and yearly, thereafter. Results: Mean tumor diameter was 3.3 cm and 3.0 cm for primary lung tumors (PLTs) and malignant pleural tumors (MPTs), respectively. The mean number of cryoprobes utilized was 3.7 per tumor, which produced ablation zones with CT visible ice mean diameters of 5.3 cm. Hydrodissection and/or warming balloon protections were used in 15.3% (n = 13/85). Grade ≥3 complications were limited to tumors >3 cm (8.2% = 7/85; P = 0.0042), but did not appear significant for central location. At a mean follow-up of 17.0 months, overall local tumor recurrence was 6.9% (n = 8/116). Pleural tumors had lower recurrence rates than PLTs (1.8% [n = 1/54] vs. 11.3% [n = 7/62], respectively; P < 0.21). Tumors >3 cm or central location had statistically significant higher recurrence rates, (P = 0.021) and (P = 0.039), respectively. Central recurrences occurred predominantly in tumors >3 cm (20%, n = 5/25). Conclusion: With appropriate pre-treatment, evaluation, and procedural criteria, percutaneous cryoablation of both primary lung and pleural tumors is safe and produces very low local recurrence rates, especially for tumors ≤3 cm.

BACKGROUND Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was sought to evaluate the activity of dalantercept in RM-SCCHN. METHODS Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments. RESULTS Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia. CONCLUSIONS In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016. © 2016 American Cancer Society.

Background Although larynx preservation affords patients improvements in laryngectomy-free survival, little has been reported regarding the functional outcomes after larynx preservation. The purpose of this study was to report the predictive value of pretreatment CT-gross tumor volume (GTV) for persistence of tracheostomy and percutaneous endoscopic gastrostomy (PEG) tube in larynx preservation patients. Methods Each patient had a CT scan before initiation of therapy and the GTV was contoured. Results Using recursive partitioning analysis (RPA), threshold GTVs of 27.16 cc and 12 cc were identified for association of time with tracheostomy and PEG tube, respectively. Median (95% confidence interval [CI]) times above and below these thresholds were 1.84 (1.06–not reached [NR]) and 0.75 (0.63–1.26) years, respectively (p = .03) for time with tracheostomy and 1.75 (1.34–NR) and 0.84 (0.46–NR) years, respectively (p = 0.10) for time with PEG tube. Conclusion This study demonstrates that pretreatment CT-GTV is predictive of an approximately 2.5-fold and approximately 2-fold, respectively, increase in time with tracheostomy and PEG tube. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

Cancer cachexia is a debilitating metabolic syndrome accounting for fatigue, an impairment of normal activities, loss of muscle mass associated with body weight loss eventually leading to death in majority of patients with advanced disease. Cachexia patients undergoing skeletal muscle atrophy show consistent activation of the SCF ubiquitin ligase (F-BOX) family member Atrogin-1 (also known as MAFBx/FBXO32) alongside the activation of the muscle ring finger protein1 (MuRF1). Other lesser known F-BOX family members are also emerging as key players supporting muscle wasting pathways. Recent work highlights a spectrum of different cancer signaling mechanisms impacting F-BOX family members that feed forward muscle atrophy related genes during cachexia. These novel players provide unique opportunities to block cachexia induced skeletal muscle atrophy by therapeutically targeting the SCF protein ligases. Conversely, strategies that induce the production of proteins may be helpful to counter the effects of these F-BOX proteins. Through this review, we bring forward some novel targets that promote atrogin-1 signaling in cachexia and muscle wasting and highlight newer therapeutic opportunities that can help in the better management of patients with this devastating and fatal disorder.

In recent years, cancer immunotherapy has emerged as the fourth pillar of cancer therapy alongside surgery, chemotherapy and radiotherapy. We here report an unusual scenario of a patient with advanced metastatic non-small cell lung cancer who was lost to follow up after two cycles of chemo-immunotherapy who later returned to clinic with complete response; suggesting that in some, all that was needed may have been just a few doses of therapy to "release the breaks."

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin malignancy. We report here a case of localized MCC achieving pathologic complete response upon treatment with avelumab in the neoadjuvant setting. Preclinical and clinical studies have revealed a close relationship between MCC and the immune system, thus supporting a role for PD-1/PD-L1 inhibitors in MCC. This neoadjuvant use of PD-1/PD-L1 inhibitors can avoid potentially disfiguring surgery in MCC. As the incidence of MCC is rising, clinical trials are needed to evaluate the efficacy and safety of immunotherapy in resectable disease.

Importance Immunotherapy for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8 (TLR8) agonist motolimod may stimulate innate and adaptive immunity. Objective To determine whether motolimod improves outcomes for R/M SCCHN when combined with standard therapy. Design, Setting, and Participants The Active8 study was a multicenter, randomized, double-blind, placebo-controlled clinical trial enrolling adult patients (age ≥18 years) with histologically confirmed R/M SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx between October 2013 and August 2015. Follow-up ended September 2016. Analysis for the present report was conducted between June 2016 and December 2017. Interventions Combination treatment with platinum (carboplatin or cisplatin), fluorouracil, cetuximab (the EXTREME regimen), and either placebo or motolimod, each administered intravenously every 3 weeks. Patients received a maximum of 6 chemotherapy cycles, after which patients received weekly cetuximab with either placebo or motolimod every 4 weeks. Main Outcomes and Measures Progression-free survival (PFS) as determined by independent central review using immune-related RECIST (Response Evaluation Criteria in Solid Tumors). Key secondary end points included overall survival (OS) and safety. Results Of 195 patients enrolled, 85% were men (n = 166); 82% were white (n = 159); median age was 58 years (range 23-81 years). Median PFS was 6.1 vs 5.9 months (hazard ratio [HR], 0.99; 1-sided 90% CI, 0.00-1.22;P = .47), and median OS was 13.5 vs 11.3 months (HR, 0.95; 1-sided 90% CI, 0.00-1.22;P = .40) for motolimod vs placebo. Increased incidence of injection site reactions, pyrexia, chills, anemia, and acneiform rash were noted with motolimod. Of 83 cases oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV) positive. In a prespecified subgroup analysis of HPV-positive participants, motolimod vs placebo resulted in significantly longer PFS (7.8 vs 5.9 months; HR, 0.58; 1-sided 90% CI, 0.00-0.90;P = .046) and OS (15.2 vs 12.6 months; HR, 0.41; 1-sided 90% CI, 0.00-0.77;P = .03). In an exploratory analysis, patients with injection site reactions had longer PFS and OS (median PFS, 7.1 vs 5.9 months; HR, 0.69; 1-sided 90% CI, 0.00-0.93;P = .06; and median OS, 18.7 vs 12.6; HR, 0.56; 1-sided 90% CI, 0.00-0.81;P = .02). Conclusions and Relevance Adding motolimod to the EXTREME regimen was well tolerated but did not improve PFS or OS in the intent-to-treat population. Significant benefit was observed in HPV-positive patients and those with injection site reactions, suggesting that TLR8 stimulation may benefit subset- and biomarker-selected patients. Trial Registration ClinicalTrials.gov identifier:NCT01836029.

Purpose: We conducted a Phase II, clinical trial to evaluate the efficacy and safety of a biweekly gemcitabine and paclitaxel (GEMTAX) regimen as second-line treatment in patients with recurrent or metastatic unresectable, squamous cell carcinoma of the head and neck (SCCHN). The primary endpoint was response rate. Patients and Methods: Patients with recurrent unresectable or metastatic platinum refractory SCCHN, who had performance status ≤2 and adequate organ function, were eligible. Gemcitabine (3000 mg/m 2 intravenous) and paclitaxel (150 mg/m 2 intravenous) was given on days 1 and 15of 4 weeks cycle, until patients had disease progression or unacceptable toxicity. Results: Disease control (partial response [PR] + complete response [CR] + stable disease [SD]) was noted in 19 patients (54%) and overall response (CR + PR) was noted in 8 patients (23%). However, the most frequent response outcomes were progressive disease in 16 patients (46%) and SD in 11 patients (31%). The most frequent Grade 3-4 adverse events were lymphopenia in 38 patients (75%), anemia in 20 patients (39%), and infection in 16 patients (31%). Median progression-free survival was 3.6 months; median overall survival was 6.3 months. Conclusion: The biweekly GEMTAX regimen has statistically significant grade 3 and 4 adverse events and has meaningful clinical activity as a second-line treatment in patients with recurrent or metastatic SCCHN who have received prior chemotherapy. This regimen may particularly be a useful treatment option in patients who progressed in