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Extra-osseous Ewing sarcoma (ES) is a rare and aggressive malignant tumor found in a variety of organs. Primary ES of the thyroid is exceedingly rare and few cases have been documented to date. We describe the case of a 54-year old woman with a history of breast carcinoma in whom a unique hypermetabolic left thyroid nodule was identified during a follow-up PET-CT scan. An ultrasound examination showed a hypoechogenic nodule of 3.7 cm. A cytological diagnosis of poorly differentiated thyroid carcinoma was made, and a total thyroidectomy was performed. The surgical specimen revealed a poorly differentiated neoplasm composed of medium-sized cells with scant cytoplasm, expressing pancytokeratin, CD99 and NKX2.2 but lacking p63 and p40 expression. Molecular analysis revealed a EWSR1-FLI1 fusion transcript supporting the diagnosis of a primary extra-osseous ES of the thyroid. The patient received adjuvant chemotherapy and has no evidence of recurrent disease.

Purpose: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone. Patients and Methods: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety. Results: Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3–24.2). One DLT of T-VEC–related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0–5.8] and 5.8 months (95% Cl, 2.9–11.4), respectively. Conclusions: The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).

Purpose:Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.Patients and Methods:Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W.Results:Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12–27 months) in colorectal cancer (n = 2), non–small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3–positive staining, including one patient with NSCLC who received prior PD-1 therapy.Conclusions:Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.

Patients with cancer experience higher burden of SARS-CoV-2 infection, disease severity, complications, and mortality, compared to the general population. SARS-CoV-2 mRNA vaccines have shown to be highly effective in clinical trials; however, few data are available on the efficacy of SARS-CoV-2 vaccines in patients with cancer. Using a prospective cohort study design, we assessed the seroconversion rates and anti-SARS-CoV-2 S antibody titers following the 1st and 2nd dose of BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines in patients with cancer at centers in U.S. and Europe from January 2021 to April 2021. Among 131 patients included in the immunogenicity analysis, most (94%) developed antibody levels; however, 6% showed no seroconversion after completing the mRNA vaccination series. No differences in seroconversion rates were observed between BNT162b2 and mRNA-1273 vaccine groups. Patients with solid tumors (98%) were much more likely to seroconvert and develop higher antibody titers than those with hematological malignancy (77%). Although seroconversion rates were consistently high in patients receiving different types of anti-cancer therapy except anti-CD-20 antibody; the antibody titers were much lower in patients who received cytotoxic chemotherapy, immunotherapy, or monoclonal antibody compared to those on clinical surveillance or receiving endocrine therapy within six months prior to vaccination. None of the patients on anti-CD-20 antibody therapy developed an antibody response, even after receiving 2 doses of the vaccines. After correlating with cell-mediated immunity in a subset of patients at high-risk for antibody non-response, we propose exploring the addition of a second booster, or convalescent plasma therapy, or postpone vaccination until after completion of their specific anti-cancer treatment. Although encouraging results, we suggest high-risk vaccinated patients with cancer to continue taking safety precautions until their immune response is confirmed at 4 weeks after 2nd dose of mRNA vaccines. We also highly encourage all eligible individuals in the general population to get vaccinated to ensure the protection of the most vulnerable groups, such as those with cancer. Funding: This project has been funded in whole or in part with federal funds from National Cancer Institute grant P30 CA054174 (Mays Cancer Center at University of Texas Health San Antonio MD Anderson); and grant MRSG-16-152-01-CCE the American Cancer Society and Hope Foundation for Cancer Research. A ‘Research & Development Program’ grant from Geneva University Hospitals awarded to Natacha Bordry funded part of this study. Declaration of Interest: Dr. Addeo reported receiving personal fees for attending advisory from Bristol‐Myers Squibb, AstraZeneca, Roche, Pfizer, Merck Sharp and Dohme,Astella, Eli Lilly and Boehringer‐Ingelheim. He has received fees for speaking bureau for Eli Lilly, AstraZeneca, MSD for work performed outside of the current study. Dr. P. Shah reported receiving grant from the Biomedical Advanced Research and Development Authority outside of this work. Dr Labidi-Galy reported receiving personal fees for attending advisory from AstraZeneca. Proferssor Mach is a founder and minority shareholder of MaxiVAX SA, a private biotech company based in Geneva Switzerland, working on personalized cancer immunotherapy and infectious disease vaccines; with no impact on the current manuscript. Dr. Taylor reported funding from NIAID/NIH and the COVID-19 Prevention Network which conducts COVID-19 vaccine trials. Dr. Patel reported receiving grant support from the National Institutes of Health, Cancer Prevention Research Institute of Texas, ThriveWell Foundation and the Bill and Ella Owens Medical Foundation outside of this work Dr. Wang reported receiving grants from 80/20 Foundation, National Institute of Health, and Nancy Smith Hurd Foundation. Dr. Mesa reported receiving research support from Celgene, Incyte, Abbvie, Samus, Genotech, Promedior, and CTI; and consulting fees from Novartis, Sierra Onc, LaJolla, and Pharma. Dr. D. Shah reported receiving grants from American Cancer Society and Hope Foundation for Cancer Research during the conduct of the study. Dr. D. Shah reported receiving grant from the Biomedical Advanced Research and Development Authority outside of this work. No other disclosures were reported. All other coauthors reported no conflict of interests. Ethical Approval: This study was approved by institutional review boards at each institution.

Background Head and neck squamous cell carcinoma (HNSCC) affects health-related quality of life (HRQoL); few treatments have demonstrated clinically meaningful HRQoL benefit. KEYNOTE-040 evaluated pembrolizumab vs standard of care (SOC) in patients with recurrent and/or metastatic HNSCC whose disease recurred or progressed after platinum-containing regimen. Methods Patients received pembrolizumab 200 mg or SOC (methotrexate, docetaxel, or cetuximab). Exploratory HRQoL analyses used European Organisation for Research and Treatment of Cancer (EORTC) 30 quality-of-life, EORTC 35-question quality-of-life head and neck cancer-specific module, and EuroQoL 5-dimensions questionnaires. Results The HRQoL population comprised 469 patients (pembrolizumab = 241, SOC = 228). HRQoL compliance for patients in the study at week 15 was 75.3% (116 of 154) for pembrolizumab and 74.6% (85 of 114) for SOC. The median time to deterioration in global health status (GHS) and QoL scores were 4.8 months with pembrolizumab and 2.8 months with SOC (hazard ratio = 0.79, 95% confidence interval [CI] = 0.59 to 1.05). At week 15, GHS / QoL scores were stable for pembrolizumab (least squares mean [LSM] = 0.39, 95% CI = –3.00 to 3.78) but worsened for SOC (LSM = −5.86, 95% CI = −9.68 to −2.04); the LSM between-group difference was 6.25 points (95% CI = 1.32 to 11.18; nominal 2-sided P = .01). A greater difference in the LSM for GHS / QoL score occurred with pembrolizumab vs docetaxel (10.23, 95% CI = 3.15 to 17.30) compared with pembrolizumab vs methotrexate (6.21, 95% CI = −4.57 to 16.99) or pembrolizumab vs cetuximab (−1.44, 95% CI = −11.43 to 8.56). Pembrolizumab-treated patients had stable functioning and symptoms at week 15, with no notable differences from SOC. Conclusions GHS / QoL scores were stable with pembrolizumab but declined with SOC in patients at week 15, supporting the clinically meaningful benefit of pembrolizumab in recurrent and/or metastatic HNSCC.

Background: For patients with resectable stage IIIA(N2) non-small cell lung cancer (NSCLC) neoadjuvant chemotherapy with three cycles of cisplatin and docetaxel followed by surgery has been shown to yield a 1-year event-free survival (EFS) rate of 48% and is an accepted standard of care. Neoadjuvant PD-(L)1 inhibitors can result in high response rates in resectable NSCLC. Methods: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m 2 and docetaxel 85 mg/m 2 q3w followed by two cycles of durvalumab 750 mg q2w. Adjuvant durvalumab was continued for 1 year after surgery. The primary endpoint was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%. This trial is registered with ClinicialTrials.gov, NCT02572843. Findings: Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43·3% (95%CI: 31·2-56·0) after neoadjuvant chemotherapy (complete remission (CR): 2·9%, partial remission (PR): 40·3%, stable disease (SD): 44·8%) and 58·1% (95%CI: 44·8-70·5) after additional neoadjuvant immunotherapy (CR: 6·5%, PR: 51·6%, SD: 25·8%). Fifty-five patients were resected, of which 34 (61·8%) achieved a major pathological response (MPR; ≤10% viable tumour cells), and 10 (18·2%) amongst them a complete pathological response. Postoperative nodal down-staging (ypN0-1) was observed in 37 patients (67·3%). Fifty-one (92·7%) patients had an R0 resection. There was no significant effect of pre-treatment PD-L1 expression on MPR or nodal down-staging. In the entire study population, the 1-year EFS rate was 73·4% (90%CI: 62·7-81·5). Median EFS and overall survival were not reached after 28 months of median follow-up. Fifty-nine (88·1%) patients had an adverse event (AE) grade ≥3 including two fatal AEs that were not assessed to be treatment-related. Interpretation: This is thus far the largest report on perioperative PD-(L)1 inhibition in patients with resectable stage IIIA(N2) NSCLC. The addition of perioperative durvalumab to neoadjuvant chemotherapy is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73·4%. Trial Registration: This trial is registered with ClinicialTrials.gov, NCT02572843. Funding Statement: The study was supported by research agreements with the following institutions: Swiss State Secretary for Education, Research and Innovation (SERI), Swiss Cancer Research Foundation (SCS) and Swiss Cancer League (SCL). Research funding for translational research projects was granted by Gateway for Cancer Research and Rising Tide Foundation. AstraZeneca provided drug and financial support. Declaration of Interests: SIR: Honoraria for advisory boards and consulting (all paid to the institution) from Astra-Zeneca, BMS, Boehringer-Ingelheim, Eisai, Eli Lilly, Merck Serono, MSD, Novartis, Pfizer, Roche, Takeda. Research funding from AbbVie, Astra-Zeneca, BMS, Boehringer-Ingelheim, Merck. Support for travel and accommodations from Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, MSD, Roche, Takeda. Member of the Federal Drug Commission of the Federal Office of Public Health. AZ: Honoraria for advisory boards and consulting (all paid to the institution) from Bristol-Myers Squibb, Merck Sharp & Dohme, Hoffmann–La Roche, NBE Therapeutics, Secarna, ACM Pharma and Hookipa. Non-commercial research agreements with Hoffmann–La Roche, NBE Therapeutics, Secarna, ACM Pharma, Hookipa, and BeyondSpring. EIE: None SSP: Honoraria for advisory boards and consulting from Astra-Zeneca, BMS, Boehringer-Ingelheim, MSD, Novartis, Pfizer and Roche. DB: None AB: None MF: Research grants from Bristol-Myers-Squibb and Astra Zeneca (paid to the institution). Honoraria for advisory boards from Bristol-Myers Squibb, AstraZeneca, Takeda, Roche, Boehringer-Ingelheim and MSD. MJ: Research grants from Bristol-Myers Squibb, Roche and Merck. DL: None HG: None LAM: Honoraria for advisory boards from AstraZeneca, Bristol-Myers-Squibb, Takeda, Roche and MSD. Support for travel and accommodations from AstraZeneca and Roche. CB: Honoraria for advisory boards from AstraZeneca, Pfizer, Roche, Takeda, Janssen-Cilag and Boehringer-Ingelheim. Support for travel and accommodations from AstraZeneca and Takeda. WW: Honoraria for advisory boards and consulting from Astra Zeneca SP: Personal fees from Abbvie, grants and personal fees from Amgen, grants and personal fees from AstraZeneca, personal fees from Bayer, personal fees from Biocartis, grants and personal fees from Boehringer-Ingelheim, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Clovis, personal fees from Daiichi Sankyo, personal fees from Debiopharm, personal fees from Eli Lilly, grants and personal fees from F. Hoffman - La Roche, personal fees from Foundations Medicine, grants and personal fees from Illumina, personal fees from Janssen, grants and personal fees from Novartis, personal fees from Pharma Mar, grants and personal fees from Pfizer, personal fees from Regeneron, personal fees from Sanofi, personal fees from Seattle Genetics, personal fees from Takeda, grants and personal fees from Merck Sharp and Dohme, personal fees from Merck Serono, personal fees from Merrimack. MM: Honoraria for advisory boards from AstraZeneca, Bristol-Myers-Squibb, MSD, Roche and Takeda. Research grant (to the institution) from AstraZeneca. RC: Honoraria for advisory boards (all paid to the institution) from AstraZeneca, Astellas, MSD, Bristol-Myers-Squibb, Janssen-Cilag, Roche, Pfizer, Merck Serono, Ipsen and Bayer. AFO: None WDJ: None CW: None NM: None PF: Honoraria for advisory from Pfizer, Roche, Takeda, Boehringer-Ingelheim and BristolMyers Squibb. MB: None PB: None GG: None CR: None MG: Honoraria for advisory boards and consulting (all paid to the institution) from Astra-Zeneca. MP: Honoraria for advisory boards from AbbVie, AstraZeneca, Boehringer-Ingelheim, BristolMyers-Squibb, Eisai, MSD, Novartis, Pfizer, Roche, Takeda and Merck. Speakers fee from Janssen-Cilag. Support for travel and accommodations from AstraZeneca, BoehringerIngelheim, Bristol-Myers-Squibb and Vifor. Ethics Approval Statement: The trial was done in accordance with the principles of the Declaration of Helsinki. The protocol was approved by the ethics committee of each participating site. Written informed consent was obtained from all patients.

Patients with cancer experience a higher burden of SARS-CoV-2 infection, disease severity, complications, and mortality, than the general population. SARS-CoV-2 mRNA vaccines are highly effective in the general population; however, few data are available on their efficacy in patients with cancer. Using a prospective cohort, we assessed the seroconversion rates and anti-SARS-CoV-2 spike protein antibody titers following the first and second dose of BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines in patients with cancer in US and Europe from January to April 2021. Among 131 patients, most (94%) achieved seroconversion after receipt of two vaccine doses. Seroconversion rates and antibody titers in patients with hematological malignancy were significantly lower than those with solid tumors. None of the patients with history of anti-CD-20 antibody in the 6 months before vaccination developed antibody response. Antibody titers were highest for clinical surveillance or endocrine therapy groups and lowest for cytotoxic chemotherapy or monoclonal antibody groups.

TO THE EDITOR: Treatment of proteasome inhibitor (PI)–refractory multiple myeloma (MM) is challenging, with response rates of only 15% to 35% being achieved with next-generation drugs such as pomalidomide, carfilzomib, and daratumumab, alone or in combination.[1][1][⇓][2]-[3][3] The oral HIV

Objective Platinum-based chemotherapy plus the anti-EGFR monoclonal antibody (mAb) cetuximab is used to treat recurrent/metastatic (RM) head-neck squamous cell carcinoma (HNSCC). Recently, we defined Cluster3 gene-expression signature as a potential predictor of favorable progression-free survival (PFS) in cetuximab-treated RM-HNSCC patients and predictor of partial metabolic FDG-PET response in an afatinib window-of-opportunity trial. Another anti-EGFR-mAb (panitumumab) was used as the treatment agent in RM-HNSCC patients in the phase II PANI01trial. PANI01 tumor samples were analyzed using functional genomics to explore response predictors to anti-EGFR therapy. Materials and methods Whole-gene expression and real-time PCR analyses were applied to pre-treatment samples from 25 PANI01 patients. Three gene signatures (Cluster3 score, RAS onco-signature, microenvironment score) and seven selected miRNAs were separately analyzed for association with panitumumab efficacy. Results Cluster3 expression levels had a profile with a significant bimodal separation of samples (P = 3.08 E−13). Higher RAS activation, microenvironment score, and miRNA expression were associated with low-Cluster3 patients. The same biomarkers were separately associated with PFS. Patients with high-Cluster3 had significantly longer PFS than patients with low-Cluster3 (median PFS: 174 versus 51 days; log-rank P = 0.0021). ROC analysis demonstrated accuracy in predicting PFS (AUC = 0.877). Conclusions Despite differences in clinical settings and anti-EGFR inhibitors used for treatment, response prediction by the Cluster3 signature and selected miRNAs was essentially the same. Translation into a useful clinical assay requires validation in a broader setting.

Summary Background There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma. Methods We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3–6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients. Findings Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4–9·4) with pembrolizumab and 6·9 months (5·9–8·0) with standard of care (hazard ratio 0·80, 0·65–0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia). Interpretation The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co.

e18005 Background: MVX-ONCO-1 is an active, personalized cancer immunotherapy combining irradiated autologous tumor cells and encapsulated, genetically engineered allogeneic cells producing GM-CSF. The immunostimulant cytokine is released locally in a sustained manner over one week at the immunization site. All cancer types are potential candidates and more than 40 patients have been treated in two clinical trials. Here we report the data on all HNSCC patients treated, as of 31st January 2021. Methods: Eleven (11) patients with locally advanced/metastatic HNSCC relapsing after at least one line of systemic therapy were enrolled in 2 open-label, single-arm clinical trials (NCT02193503 and NCT02999646) evaluating the safety, feasibility and efficacy of MVX-ONCO-1. All patients were treated with at least 5 administrations of MVX-ONCO-1 over 8 weeks (W1,2,3,4,6,8). Each administration consists of the subcutaneous implantation in healthy skin of 2 capsules containing each 8x105 cells, producing > 20ng/24h of GM-CSF, and an injection of 4x106 irradiated autologous tumor cells between the 2 capsules. Results: Eleven (11) patients are evaluable for safety and feasibility. Ten patients (91%) with at least 6 months, respectively 9 patients (82%) with 12 months follow-up are evaluable for efficacy analysis. Eight patients (80%) failed both Cisplatin based chemotherapy and anti-PD1 therapies prior to enrolment. The most common treatment-related adverse event (AE) was local hematoma at implantation site in 3 patients (27%). None experienced > grade 2 treatment-related AE. Overall Survival is 70% (7/10pts) at 6 months, and 56% (5/9pts) at 12 months. Eight patients (80%) presented some degree of disease control with 4SDs, 2PRs and 2CRs. Both CRs are longstanding, with both patients not any longer on anticancer therapy for 24 and 6 months respectively. While 1 PR was observed on MVX-ONCO-1, 1PR and 1CR were observed on subsequent Nivolumab therapy (both CPS0), and 1 CR was observed after carboplatin-cetuximab. Two patients had progressive disease as best overall response. Conclusions: Treatment with MVX-ONCO-1 is feasible, safe and well tolerated. Preliminary efficacy data shows an encouraging rate of tumor control including prolonged CR in patients subsequently treated with nivolumab or chemotherapy. Efficacy of the concurrent use of anti-PD-1 and MVX-ONCO will be assessed in a planned clinical trial. Clinical trial information: NCT02999646.

6036 Background: T-VEC, a genetically modified herpes simplex virus-1, is the first FDA- and EMA-approved oncolytic viral immunotherapy designed to enhance systemic antitumor immune responses. R/M HNSCC is a disease with considerable clinical complexity and poor prognosis. Pembro is a PD-1-specific humanized monoclonal antibody currently approved as first-line Tx for this disease, but there is an unmet need among many patients (pts). To meet this gap, the safety and preliminary efficacy of T-VEC plus pembro in pts with R/M HNSCC was evaluated in a phase 1b study (Harrington et al. Clin Cancer Res. 2020). Here, we present results of the final analysis of this study (NCT02626000). Methods: Eligible pts (≥18 yrs) had ECOG-PS of 0 or 1; histologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx unsuitable for curative surgical resection or radiotherapy; platinum-refractory and with injectable tumors. Pts with known active CNS metastases and any systemic or local therapy 28 days before enrollment were excluded. T-VEC was injected intralesionally up to 8.0 mL of 106 PFU/mL according to lesion sizes on day 1; after 3 weeks, subsequent doses of ≤8.0 mL of 108 PFU/mL were given Q3W. Pembro was given intravenously at 200 mg Q3W. Pts were followed-up for 36 mos after the last patient was enrolled in the study. Key endpoints (irRECIST per investigator assessment) were objective response rate (ORR), best overall response (BOR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 36 pts (80.6% male) were enrolled and treated: 28 (77.8%) had confirmed PD-L1-positive tumor (CPS ≥1), 5 (13.9%) were HPV-positive, 13 (36.1%) had metastatic disease, and 19 (52.8%) had prior lines of therapy in the R/M setting. At the final analysis, 7 pts (19.4%) completed the study, and 29 (80.6%) discontinued the study due to death. Safety profile was consistent with that at 1-yr analysis (Harrington et al. Clin Cancer Res. 2020). Confirmed ORR was seen in 16.7% (95% CI, 6.4–32.8). No patient had a complete response as their BOR, 6 (16.7%) had a partial response, 8 (22.2%) had stable disease, 6 (16.7%) had progressive disease, 6 (16.7%) were unevaluable, and 10 (27.8%) died before the first response assessment. The DCR was 38.9% (95% CI, 23.1–56.5). The median DOR was 45.9 mos (95% CI, 8.5–NE). The median PFS was 3.0 mos (95% CI, 2.0–5.8), and the median OS was 5.8 mos (95% CI, 2.9–11.4). Conclusions: The safety results at 3 yrs for T-VEC plus pembro in pts with R/M HNSCC were consistent with those of the 1-yr analysis. Although the response rate was consistent with that observed with pembro alone in historical HNSCC studies, the extended DOR in responding patients warrants further investigation. Clinical trial information: NCT02626000.

e21119 Background: A substantial proportion of patients with squamous lung cell carcinoma (SQCLC) (46%) exhibit tumor overexpression of fibroblast growth factor receptor (FGFR) messenger ribonucleic acid (mRNA). Rogaratinib is a novel pan-FGFR inhibitor with anti-tumor activity in pre-clinical models as a single agent in FGFR pathway-addicted tumor models. Phase I data showed promising activity and good safety profile. The objective of the SAKK 19-18 trial was to determine clinical activity and safety of rogaratinib in patients with advanced SQCLC overexpressing tumor FGFR1-3 mRNA. Methods: Patients with metastatic SQCLC, previously treated with systemic treatment, overexpressing tumour FGFR mRNA were treated with rogaratinib 600 mg BID until progression of disease or drug intolerance. A rate ≤15% of PFS at 6 months was considered uninteresting, whereas a PFS rate at 6 months ≥38% was considered promising. Ten patients were needed in the first stage with at least 2 achieving 6 months PFS in order to continue the accrual. Results: Between May and November 2020, 49 patients were screened and 20 were classified FGFR positive. Among them15 patients were registered in the trial and the first 10 were assessed for the first stage analysis. Most commons treatment related adverse events (TRAEs) were hyperphosphatemia (60%), diarrhoea (20%), and dry mouth (20%). Grade ≥3 TRAEs occurred in 50% of the patents with Hypercalcemia being the most frequent one (20%). Among 10 first patients only 1 achieved 6 months PFS while 2 was the boundary required for continuing this trial. Conclusions: Despite preliminary signal of activity, rogaratinib failed to improve PFS in patients overexpressing tumor FGFR mRNA. Further studies on a more reliable biomarker are needed, the development of rogaratinib in SQCLC has been put on hold by Bayer and the SAKK 19/18 study was terminated early due to lack of efficacy. Clinical trial information: NCT03762122.

430 Background: The combination of cisplatin-based chemotherapy with immune checkpoint inhibitors is extensively investigated in urothelial carcinoma. Using this combination in the neoadjuvant setting for patients (pts) with MIUC might improve pathological response rate (PaR: 1 EFS at 2 years ≥ 65% compared to H0 EFS at 2 years ≤ 50%. We report the secondary endoints PaR, pathological complete remission (pCR: ypT0 N0), and safety on the full analysis set (FAS, received at least one dose of durva). Results: 61 pts were included between 7/18 and 9/19 at 12 sites. The FAS consists of 58 pts (79% male, median age 67.5 yrs) with bladder cancer (95%) or upper urinary tract/urethral cancer (5%). Clinical T2, T3, T4 stage were present at diagnosis in 69%, 21%, 10%, respectively, and 17% had cN1. 95% of pts received all 4 doses of neoadjuvant durva, 81% all 4 cycles of cis/gem and 17% switched to carboplatin. In total grade 3 and 4 adverse events (AE) during neoadjuvant treatment occurred in 48% and 27%, respectively. AEs related to durva were G3 in 7 pts (12%) and G4 in one patient (2%). Resection was performed in 53 pts (91%; 51 radical cystectomy, 2 nephroureterectomy), 4 pts refused surgery and one patient was irresectable due to a frozen pelvis. R0 resection was achieved in 52 pts (98%), one had R1. Postoperative complications included Clavien-Dindo III in 13 pts (24%) and IV in 5 pts (9%). PaR was found in 60% (95% CI 46.0%-73.5%) with 18 pts achieving pCR (34%; 95% CI 21.5%-48.3%) and 14 patients (26%) ypT1/ypTis. Conclusions: The first FAS results for neoadjuvant durvalumab in combination with cis/gem for operable MIUC confirm elevated pathological response rates and demonstrate acceptable safety. Postoperative morbidity is relevant but not exceeding the expected frequency or severity. Clinical trial information: NCT03406650.

Background Modern techniques of radiotherapy are supposed to decrease the incidence of osteoradionecrosis of the mandible (ORNM). The purpose of this study was to compare the incidence of ORNM after intensity-modulated radiotherapy (IMRT) in comparison to conventional 3D conformal radiotherapy techniques (conventional RT). Methods We conducted a retrospective study of consecutive unselected patients treated in a single institution between 2002 and 2012. To minimize confounding effects, only patients with oropharyngeal carcinoma without surgery of the primary site were included. Results The cohorts included 145 patients in the conventional RT group and 89 patients in the IMRT group. Total incidence rate of ORNM was similar for both groups with rates of 11% versus 10% (n = 16 for conventional RT and n = 9 for IMRT; p = 1.0). Subanalysis revealed more ORNM in T4 classified lesions with IMRT (p = .007). Analysis of different risk factors showed no statistically significant difference between ORNM and no-ORNM patients. Conclusion We found no reduction in ORNM with IMRT. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

An increasing number of older patients are suffering from aggressive lymphoma. Effective and more tolerable treatment regimens are urgently needed for this growing patient population. Patients with aggressive lymphoma not eligible for anthracycline-based first-line therapy or intensive salvage regimens were treated with the rituximab-bendamustine-lenalidomide (R-BL) regimen (rituximab 375 mg/m(2) day 1, bendamustine 70 mg/m(2) d 1, 2, lenalidomide 10 mg d 1-21) for six cycles every 4 weeks. Forty-one patients with a median age of 75 (range 40-94) years were enrolled: 33 patients had substantial co-morbidities. 13 patients were not eligible for anthracycline-based first-line chemotherapy, 28 patients had relapsed/refractory disease. The primary endpoint, overall response, was achieved by 25 (61%) patients (95% confidence interval 45-76%). Grade ≥ 3 toxicity comprised haematological (59%), skin (15%), constitutional (15%) and neurological (12%) events. 9 patients died during trial treatment: 5 from lymphoma progression, 2 from toxicity, 2 with sudden death. After a median follow-up of 25·9 (interquartile range 20·4-31·6) months, 13 patients were still alive. Median overall survival was 14·5 months. In conclusion, R-BL can be considered a treatment option for elderly patients with treatment naïve or relapsed/refractory aggressive lymphoma not eligible for standard aggressive regimens.

Denosumab has shown promising results in the management of giant cell tumor of bone, a primary bone tumor with locally aggressive behaviour. We report a case of premature denosumab interruption due to radiological and clinical tumor expansion of a giant cell tumor of the distal ulna. Although denosumab is known to induce tumor regression, with progressive ossification and loss of the characteristic morphology of giant cell tumor of bone, the ulnar tumor specimen showed a moderately to highly cellular proliferation of short spindle-shaped cells, and no osteoclast-like giant cells. There were no abnormal mitotic figures. We considered the surgical specimen as a giant cell tumor of bone with partial regression after prematurely interrupted denosumab treatment. This case illustrates the diagnostic issues of an initially unfavourable evolution raising concern for malignancy, and the difficulties in histological assessment of a partially treated giant cell tumor of bone, that may mimic osteosarcoma.

9016 Background: For patients (pts) with resectable stage IIIA(N2) non-small cell lung cancer (NSCLC) neoadjuvant chemotherapy (chemo) with 3 cycles cisplatin (cis)/docetaxel (doc) followed by surgery is an accepted standard of care leading to a 1-year (yr) event-free survival (EFS) of 48% and a 5-yr overall survival (OS) of 37%. PD-1/PD-L1 inhibitors have recently shown to lead to high response rates in resectable NSCLC. Methods: SAKK 16/14 is an open-label single-arm phase II study including 68 pts with resectable NSCLC stage IIIA(N2) (T1-3 N2 M0), irrespective of histological subtype, genomic aberrations or PD-L1 expression status. Neoadjuvant treatment consisted of 3 cycles of cis 100 mg/m2 and doc 85 mg/m2 q3w followed by 2 cycles of durvalumab 750 mg q2w. Durvalumab was continued after surgery q2w for 1 yr. The primary endpoint is EFS at 1 yr. The statistical hypothesis is to improve EFS at 1 yr from 48% based on the SAKK 16/00 study to 65%. Here, we report the primary endpoint and response data from 67 evaluable pts included in the study. Results: 68 pts were included from 06/16 to 01/19 and 67 pts (35 males, 32 females) were evaluable. Median age was 61 yrs (range, 41-74). 52 pts (77.6%) had a WHO PS of 0. 95.5% were current or former smokers. The majority of tumors were adenocarcinoma (55.2%) followed by squamous cell histology (32.8%). Clinical stage T1, T2 and T3 were present at diagnosis in 22.4%, 49.3% and 28.4%, respectively. 81.1% of pts underwent resection. The main reason for not undergoing surgery was disease progression (33.3%). Pneumonectomy was performed in 5 pts (9.1%), 43 pts underwent lobectomy and 7 pts bilobectomy. 30-day postoperative mortality was observed in one patient (1.8%). One patient died due to a bleeding complication after surgery most likely not related to neoadjuvant therapy. Radiographic response was 44.8% (95%CI: 32.6-57.4) after neoadjuvant chemo and 59.7% (95%CI: 46.4-71.9) after additional neoadjuvant immunotherapy. 1-yr EFS was 73.3% (90%CI: 62.5-81.4). Results for pathologic remission rate as well as correlation with PD-L1 status will be presented during the meeting. Conclusions: We report on treatment outcomes of the largest cohort of pts with resectable stage IIIA(N2) NSCLC receiving perioperative immune checkpoint inhibitor therapy. The addition of perioperative durvalumab to standard of care cis/doc is safe and leads to a high response rate and a very encouraging 1-yr EFS rate that appears substantially higher than with chemo alone. Clinical trial information: NCT 02572843.

499 Background: Cisplatin-based neoadjuvant chemotherapy followed by surgery is the standard of care for patients (pts) with MIUC but relapse rates remain high. Immune checkpoint inhibitors have demonstrated efficacy in advanced urothelial carcinoma (UC). We hypothesize that the integration of the PD-L1 inhibitor durvalumab into perioperative management of MIUC improves outcome. Methods: SAKK 06/17 is an open label single arm phase II study including 61 pts. Operable MIUC cT2-T4a cN0-1 pts without contraindication for Cis were eligible. Four cycles of preoperative Cis/Gem q3w are administered in combination with 4 cycles Durva 1500mg q3w starting at cycle 2. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival at 2 years. We report a preplanned interim analysis of the secondary endpoints safety, pathological complete remission ypT0 N0 (pCR,) and pathological response rate (PaR, defined as ≤ypT1N0) on the first 30 resected pts. Results: Among 34 eligible pts (27M, 7F; median age 70, range 41-81 years) included from 07/18 – 02/19, 33 pts (97%) had primary bladder cancer and 1 pt had upper tract UC. Clinical T2, T3, T4 and TxN1 stage were present at diagnosis in 68%, 18%, 15% and 15%, respectively. Four cycles of chemo-immunotherapy were completed per protocol in 34 pts (100%). No tumor progression was noted at preoperative restaging. AE related to Durvalumab were G3 in 5 pts (15%) and G4 in 3 pts (9%). Surgery was performed as planned in 30 pts (88%), 3 pts refused surgery and 1 pt had a frozen pelvis. Operation technique was open in 20 pts (67%) and laparoscopic/robot-assisted in 10 pts (33%). Postoperative complications included Clavien-Dindo III in 6 pts (20%) and IV in 2 pts (7%) with infections being most common (5 pts, 17%). pCR was found in 9 pts (30%) and additional 6 pts (20%) had ypT1/ypTis for a PaR of 50%. Conclusions: The combination of Cis/Gem and Durva as neoadjuvant treatment for MIUC is feasible with manageable toxicities and pCR and PaR rates in the expected range. The rate of postoperative complications warrants further close follow up. Clinical trial information: 2017-003565-10.

Background MBG453 and spartalizumab are humanized IgG4 mAbs that block binding of TIM-3 to PtdSer and PD-1 to PD-L1/2, respectively. In Ph I dose escalation, MBG453 + spartalizumab showed preliminary antitumor activity in advanced solid tumors. Here we report Ph II MBG453 + spartalizumab dose expansion in pts with NSCLC and melanoma (NCT02608268). Methods Pts with melanoma or NSCLC who had progressive disease (PD) on/after anti–PD-1/L1 therapy received MBG453 (800 mg, Q4W) + spartalizumab (400 mg, Q4W) until unacceptable toxicity, PD, or investigator/pt decision. On prior anti–PD-1/L1 therapy clinical benefit (CB) was defined as durable (DCB) if pts had a complete or partial response, or stable disease (SD) for ≥6 months, or non-durable (NDCB) if pts had SD for Results As of Feb 15, 2019, 33 pts received MBG453 + spartalizumab (melanoma: n = 16; NSCLC: n = 17); 5 (15.2%) pts were ongoing (melanoma: n = 3 [18.8%]; NSCLC: n = 2 [11.8%]); 28 (84.8%) pts discontinued, mainly due to PD (60.6%) and death due to underlying disease (12.1%). Anti–PD-1/L1 was the last therapy before enrollment in 21 (63.6%) pts (melanoma: n = 10 [62.5%]; NSCLC: n = 11 [64.7%]). On prior anti–PD-1/L1 therapy, 6 (37.5%) melanoma and 7 (41.2%) NSCLC pts had DCB and 10 (62.5%) melanoma and 9 (52.9%) NSCLC pts had NDCB; CB was unknown (UNK) in 1 NSCLC pt. On MBG453 + spartalizumab, 3/16 (18.8%) melanoma pts (prior anti-PD-1/L1: DCB n = 2; NDCB n = 1) and 7/17 (41.2%) NSCLC pts (prior anti-PD-1/L1: DCB n = 3; NDCB n = 3; UNK n = 1) had SD per RECIST 1.1. Baseline tumor PD-L1 appears higher in pts with SD vs PD. Data suggest a trend of inverse association between tumor reduction and CD163 tumor expression. Common treatment-related adverse events (TRAEs) were fatigue, nausea, and pruritus (n = 3 each [9.1%]); 0 melanoma and 2 (11.8%) NSCLC pts (pruritus, amylase, lipase, and increased ALT) had Grade 3/4 TRAEs. Conclusions MBG453 (800 mg, Q4W) + spartalizumab (400 mg, Q4W) was well tolerated but with limited efficacy in pts with melanoma and NSCLC who had PD on/after prior anti–PD-1/L1 therapy. Further evaluation of MBG453 in other indications/combinations is needed to assess the clinical relevance of TIM-3 inhibition. Editorial acknowledgement Jenny Winstanley, PhD, of Articulate Science Ltd. Legal entity responsible for the study Novartis Pharmaceuticals. Funding Novartis Pharmaceuticals. Disclosure G. Curigliano: Honoraria (self), Advisory Board: Novartis; Honoraria (self), Advisory Board: Roche; Speaker Bureau / Expert testimony, Expert talk: Pfizer; Speaker Bureau / Expert testimony, Expert talk: Eli Lilly; Advisory / Consultancy, Scientific consultation: Ellipsis. A. Santoro: Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: AbbVie; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Advisory / Consultancy, Speaker Bureau / Expert testimony: Gilead; Speaker Bureau / Expert testimony: AstraZencea; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Arquile; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Sandoz; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD. D. Kim: Research grant / Funding (institution): Alpha Biopharm; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. S. Hodi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol Mysers Squibb; Advisory / Consultancy: Merck; Advisory / Consultancy: EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Takeda; Advisory / Consultancy: Surface; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Compass Therapeutics; Advisory / Consultancy: Apricity; Advisory / Consultancy: Bayer; Advisory / Consultancy: Aduro; Advisory / Consultancy: Partners Therapeutics; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pionyr; Advisory / Consultancy: 7 Hills Pharma; Advisory / Consultancy: Verastem; Advisory / Consultancy: Torque; Advisory / Consultancy: Rheos. T. Doi: Research grant / Funding (institution): Lilly ; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Boehringer Ingelheim ; Research grant / Funding (institution): Quintiles; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Dainippon Sumitomo; Research grant / Funding (institution): Kyowa Hakko Kirin; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy: Otsuka. T. Longmire: Full / Part-time employment: Novartis. H. Sun: Full / Part-time employment: Novartis. A. Xyrafas: Full / Part-time employment: Novartis. S. Gutzwiller: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. L. Manenti: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. All other authors have declared no conflicts of interest.

We add new features to the diffusion-based codec R-EED that go beyond pure quality.Our new progressive modes for R-EED can outperform JPEG and JPEG2000.Tree-based subdivision allows efficient region of interest coding.Diffusion-based video decoding is possible in real-time without sacrificing quality.Our newly proposed features are pairwise compatible and can be used simultaneously. Compared to transform-based image compression methods such as JPEG2000, approaches based on partial-differential equations (PDEs) are in a proof-of-concept stage. Nevertheless, R-EED, a codec employing edge-enhancing anisotropic diffusion (EED) and rectangular subdivision, can surpass JPEG2000 quality-wise. However, today's requirements for compression algorithms go beyond pure compression performance. Codecs must also fulfil the feature requirements of specific applications such as online media or medical imaging. We propose three such features for the R-EED codec. By reordering grey values and exploiting the subdivision scheme, we incorporate a progressive mode into R-EED that can outperform JPEG and JPEG2000. Additionally, we show that rectangular subdivision is well-suited for region of interest coding and adapt the quality of image parts according to their importance. Finally, we propose a real-time video player that demonstrates how R-EED-based decoding can be performed efficiently. All of these extensions are compatible with each other and can be used simultaneously.

Chordoma is a rare tumor of notochordal origin, currently principally treated by surgery and/or irradiation. Here, we describe the clinical outcome of 3 consecutive patients with metastatic and locally advanced chordoma, treated with different immunotherapeutic approaches. All patients presented fast growing tumors and failure of standard therapies. One was treated with a tumor-based vaccine, the 2 others with anti-PD1 antibodies, all with impressive clinical and radiological responses. We therefore propose that chordoma is an immunogenic tumor and thus that translational and clinical research is necessary to develop rationally designed immunotherapy approaches.

Background Pemetrexed and bevacizumab as single agents have been approved for maintenance therapy after platinum-based induction in patients with advanced nonsquamous non–small-cell lung cancer. It is currently unknown whether bevacizumab plus pemetrexed is superior to pemetrexed alone. Patients and Methods We conducted a nonrandomized phase II trial with 2 sequential cohorts. In the first cohort, 77 patients were treated with 4 cycles of cisplatin, bevacizumab, and pemetrexed every 3 weeks, followed by bevacizumab plus pemetrexed maintenance until progression. In the second cohort, we treated 52 patients without bevacizumab, using maintenance with pemetrexed alone. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), adverse events, and the treatment costs of the 2 cohorts were compared. Results The median PFS from the time of registration was 6.9 months in cohort 1 and 5.6 months in cohort 2. The ORR was 62.3% in cohort 1% and 44.2% in cohort 2. The PFS (hazard ratio, 0.7; 95% confidence interval [CI], 0.5-1.0; P = .041) and ORR (odds ratio, 2.1; 95% CI, 1.0-4.3; P = .049) were better in cohort 1 than in cohort 2. No OS difference was found (hazard ratio, 1.0; 95% CI, 0.7-1.6; P = .890) after a median follow-up period of 47 months for cohort 1 and 27 months for cohort 2. The rate of grade ≥ 3 adverse events was greater in cohort 1. The treatment costs per patient were on average 1.4 times greater for cohort 1. Conclusion The addition of bevacizumab increased the ORR and PFS, but not OS, in our nonrandomized trial. Furthermore, the addition of bevacizumab was associated with greater toxicity and higher costs.

PURPOSE Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses. EXPERIMENTAL DESIGN This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide(®) ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy. RESULTS In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event. CONCLUSIONS Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.

Background: MBG453 and spartalizumab, humanized IgG4 mAbs, block binding of TIM-3 to PtdSer and PD-1 to PD-L1/2, respectively. Preclinical studies show synergistic anti-tumor activity of TIM-3 and PD-1 co-blockade. Here we report the dose escalation results from a Ph I-Ib/II study of MBG453 ± spartalizumab in metastatic solid tumors (NCT02608268). Methods: Metastatic cancer pts received intravenous MBG453 alone at 80-1200 mg Q2W or Q4W, or combination therapy (Q2W/Q4W) with MBG453 (20-800/80-1200 mg) + spartalizumab (80-240 mg/80-400 mg). The recommended Ph II dose (RP2D) was determined using an adaptive Bayesian logistic regression model guided by escalation with overdose control together with Ph I-Ib endpoints (dose-limiting toxicity [DLT] at 8 weeks). Results: As of July 26, 2018, 87 pts received MBG453 alone (14% were anti-PD-1/PD-L1 pre-treated; common tumors [≥9%]: pancreatic cancer [11%], sarcoma [10%], and colorectal cancer [CRC; 9%]) and 86 pts received MBG453 + spartalizumab (27% were anti-PD-1/PD-L1 pre-treated; common tumors [≥6%]: melanoma [8%], NSCLC [7%], CRC [7%], and ovarian cancer [6%]). One DLT (myasthenia gravis grade [G] 4) was reported in a pt with thymoma treated with MBG453 (240 mg Q4W) + spartalizumab (80 mg Q4W). Treatment-related adverse events (AEs) were reported in 40% and 59% of pts treated with MBG453 and MBG453 + spartalizumab, and G3/4 AEs in 0% and 11% of pts; the most common AE (≥10%) was fatigue in 10% and 15% of pts, respectively. MBG453 exposure generally increased in a dose-proportional manner. Maximum tolerated doses were not identified with the tested dose/schedule. MBG453 800 mg Q4W (n=9 pts treated) and MBG453 800 mg + spartalizumab 400 mg Q4W (n=6 pts treated) were declared as RP2Ds. Stable disease (SD) was seen in 25/87 (29%) pts treated with MBG453 alone (common tumors [≥2 pts]: sarcoma [n=5], and breast cancer, CRC, ovarian cancer, cholangiocarcinoma, and NSCLC [n=2 pts each]); 4 of 25 pts with SD were anti-PD-1/PD-L1 pre-treated. Of 86 MBG453 + spartalizumab pts, partial responses were seen in 4 pts (5%); 1 anti-PD-1/PD-L1 pre-treated pt (out of 6 with NSCLC; DOR: 392 d), 3 anti-PD-1/PD-L1 naïve pts (CRC [n=2 out of 6, DOR: 223 d, 109 d]; SCLC [n=1 out of 3; DOR: 112 d]). SD was seen in 34/86 (40%) MBG453 + spartalizumab pts (common tumors [≥3 pts]: melanoma [n=5; 2 cutaneous, 2 uveal, and 1 non-cutaneous], ovarian cancer [n=3], and urothelial carcinoma [n=3]); 10 of 34 pts with SD were anti-PD-1/PD-L1 pre-treated. RNAseq analysis of screening and on-treatment biopsies revealed a pharmacodynamic trend of increased IFN-γ-associated gene signatures following MBG453 + spartalizumab treatment. Conclusions: MBG453 + spartalizumab was well tolerated with preliminary signs of anti-tumor activity. MBG453 800 mg Q4W and MBG453 800 mg + spartalizumab 400 mg Q4W were selected as the RP2Ds; dose expansion is ongoing in pts with melanoma or NSCLC resistant to anti-PD-1/PD-L1. Citation Format: Giuseppe Curigliano, Hans Gelderblom, Nicolas Mach, Toshihiko Doi, Wai Meng David Tai, Patrick Forde, John Sarantopoulos, Philippe L. Bedard, Chia-Chi Lin, Stephen Hodi, Sofie Wilgenhof, Armando Santoro, Catherine Sabatos-Peyton, Tyler Longmire, Kitty Wan, Panagiotis Nikolopoulos, Luigi Manenti, Aung Naing. Phase (Ph) I/II study of MBG453± spartalizumab (PDR001) in patients (pts) with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT183.

e20661 Background: FGFR1 gene amplifications are observed in squamous (sq) non-small cell lung cancer (NSCLC) and may suggest tractable oncogenic dependency. However, their value in predicting clinical activity of FGFR inhibitors is unclear. We explored tumor FGFR1-3 mRNA expression levels to select patients (pts) for treatment with rogaratinib, an oral, potent, small-molecule inhibitor of FGFR1-4. The first-in-human study of rogaratinib included pts with all NSCLC histologies. Methods: Pts with refractory advanced NSCLC were screened for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples, and FGFR1-3 overexpression was defined by pre-specified cut-offs. Pts received rogaratinib 800 mg BID on a continuous 21-day cycle. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1 after cycles 2, 5, and 8. Results: 260 NSCLC biopsies were screened for FGFR1-3 tumor mRNA expression; 244 (93.8%) were evaluable. FGFR1-3 mRNA overexpression was found in 47% of sq NSCLC, and only 14% of non-sq NSCLC, with FGFR3 being the most commonly overexpressed subtype. 40 FGFR mRNA-positive pts were enrolled and treated. Rogaratinib was well tolerated; hyperphosphatemia (75%), diarrhea (53%), and decreased appetite (35%) were the most frequent treatment-emergent adverse events. Events were mostly mild or moderate. 36 treated pts were evaluable for response. The overall response rate was 5.6% (2 partial responses, 1 lasting for > 16 months). Disease control rate was 64%. Disease stabilization was seen in pts with mRNA overexpression across all FGFR subtypes and also in pts who failed prior lines of therapy, including anti-PD-L1. Molecular studies are ongoing to identify additional predictors of response to improve pt selection. Conclusions: Rogaratinib has a favorable safety and tolerability profile and clinical activity in pts with refractory FGFR1-3 tumor mRNA-positive NSCLC. It has potential for further exploration in combination with other agents. A clinical trial is currently enrolling FGFR mRNA-overexpressing pts with advanced and pre-treated sq NSCLC. Clinical trial information: NCT03762122.

6026 Background: The open-label, randomized, phase 3 KEYNOTE-040 study (NCT02252042) showed that pembro vs standard of care (SOC) chemotherapy prolonged survival in patients (pts) with recurrent and/or metastatic HNSCC whose disease progressed during/after platinum-based therapy. Post hoc analyses were conducted to evaluate pembro vs SOC by prior RT and disease state (metastatic, locoregionally recurrent [referred to as recurrent herein], or recurrent and metastatic [R/M]). Methods: Pts (N = 495) were randomly assigned (1:1) to receive pembro (200 mg Q3W) or investigator choice of methotrexate (40 mg/m2 QW), docetaxel (75 mg/m2 Q3W), or cetuximab (400 mg/m2 loading dose, then 250 mg/m2 QW). Primary end point was OS; PFS and ORR were secondary end points. Results: 175, 97, and 195 pts had metastatic, recurrent, and R/M disease, respectively (28 pts had unknown disease state); 64 pts had no prior RT; 431 pts had prior RT. As in the ITT population, prolonged survival benefit and trend toward improved PFS and ORR was observed with pembro vs SOC in pts with prior RT (Table), and prolonged survival benefit was observed with pembro vs SOC in pts with metastatic and R/M, but not recurrent, disease. Conclusions: In this post hoc analysis, patients with prior RT benefited from treatment with pembro vs SOC. For patients without RT, sample sizes are too small to draw any definitive conclusions. Survival benefit of pembro vs SOC was observed in pts with metastatic and R/M disease. Clinical trial information: NCT02252042. [Table: see text]

TPS725 Background: T-VEC is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and produce GM-CSF to enhance systemic antitumor immune responses. Atezolizumab is a monoclonal antibody checkpoint inhibitor (CPI) that targets PD-L1. The safety of intrahepatic administration of T-VEC has been demonstrated in a prior clinical trial (NCT02509507). A previous trial of T-VEC in combination with a CPI in advanced melanoma demonstrated improved responses compared to those with a CPI alone (Puzanov et al. JCO. 2016; 34:2619-26). We hypothesize that T-VEC combined with a CPI may also be effective in other tumor types. This phase 1b, multicenter study evaluates the safety of intrahepatic injection of T-VEC in combination with IV atezolizumab in pts with TNBC or CRC with LMs. Methods: The study will enroll up to 36 pts in two parallel cohorts (18 TNBC, 18 CRC) at sites in the USA, Europe, and Australia. The primary objective is to evaluate the incidence of dose-limiting toxicities (DLTs). Secondary objectives include objective response rate, lesion-level responses in injected and uninjected tumors, progression-free survival, and overall survival. Key eligibility criteria include age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG performance status 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable, injectable LM. T-VEC will be given by image-guided intralesional injection of up to 4 mL of 106 plaque forming units (PFU)/mL on day 1 and up to 4 mL of 108 PFU/mL every 21 days thereafter; atezolizumab 1,200 mg IV will be given on day 1 and every 21 days thereafter. The DLT-evaluation period is the first two cycles (1 cycle = 21 days). Interim safety analysis will occur after the first 4–6 pts have become DLT evaluable. Up to six cycles of T-VEC will be given with an additional 6 cycles allowed. After cycle three, nonhepatic lesions may be injected, subject to protocol-defined criteria. The study opened for enrollment in January 2018. (NCT03256344) Clinical trial information: NCT03256344.

Background: It was known that survival data were outstanding on several patients (pts) when the final analysis of the multinational, open-label, phase 3 KEYNOTE-040 study (NCT02252042) of pembro vs SOC for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) was performed. This abstract presents OS and PFS data using the same data cutoff date but with full survival acquisition. Methods: 495 pts with SCC of the oral cavity, oropharynx, hypopharynx, or larynx who had recurrence or PD after a platinum-containing regimen were randomized 1:1 to pembro 200 mg Q3W for 24 mo or investigator's choice of methotrexate, docetaxel, or cetuximab. Primary end point was OS in the ITT population. Key secondary end points included OS in the PD-L1 combined positive score (CPS) ≥1 population and PFS in the ITT and CPS ≥1 populations. OS and PFS in the PD-L1 tumor proportion score (TPS) ≥50% population were prespecified exploratory end points. Response was assessed per RECIST v1.1 by blinded, independent central review. Results: With full acquisition of survival data, HR was 0.80 (95% CI, 0.65-0.98) (nominal P = 0.0161) for OS and 0.96 (95% CI, 0.79-1.16) (nominal P = 0.33) for PFS in the ITT population. Median (95% CI) OS was 8.4 mo (6.4-9.4) for pembro vs 6.9 mo (5.9-8.0) for SOC; median PFS was 2.1 mo (2.1-2.3) vs 2.3 mo (2.1-2.8). Pembro benefit was greater in pts with PD-L1 CPS ≥1 and TPS ≥50% (Table). Conclusions: Pembro provided a clinically meaningful prolongation of OS compared with SOC in pts with R/M HNSCC. With full acquisition of survival data and compared with the previous analysis, the HR for OS decreased from 0.81 to 0.80, and the P value decreased from 0.0204 to 0.0161. There continued to be an enhanced benefit for pembro in pts with PD-L1–expressing tumors. Along with previously presented safety data, these results provide stronger support for the benefit of pembro in pts with R/M HNSCC. Table. OS and PFS in the PD-L1 CPS ≥1 and TPS ≥50% Populations CPS ≥1TPS ≥50%Pembron = 196SOCn = 191Pembro n = 64SOCn = 65OSMedian (95% CI), mo8.7 (6.9-11.4)7.1 (5.7-8.3)11.6(8.3-19.5)6.6(4.8-9.2)HR (95% CI)0.74 (0.58-0.93)0.53 (0.35-0.81)Pa0.00490.0014PFSMedian (95% CI), mo2.2 (2.1-3.0)2.3 (2.1-3.0)3.5(2.1-6.3)2.1(2.0-2.4)HR (95% CI)0.86 (0.69-1.06)0.58 (0.39-0.86)Pa0.080.003aNominal one-sided P value stratified by the randomization stratification factors. Citation Format: Denis Soulieres, Ezra Cohen, Christophe Le Tourneau, Jose Dinis, Lisa Licitra, Myung-Ju Ahn, Ainara Soria, Jean-Pascal Machiels, Nicolas Mach, Ranee Mehra, Barbara Burtness, Pingye Zhang, Jonathan Cheng, Ramona Swaby, Kevin J. Harrington. Updated survival results of the KEYNOTE-040 study of pembrolizumab vs standard-of-care chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT115.

6036Background: We evaluated the safety and efficacy of the combo of T-VEC, the first FDA-approved oncolytic immunotherapy that enhances systemic antitumor immune responses, and Pembro, an immune c...

6013Background: In KEYNOTE-040 (NCT02252042) (N = 495), pembro 200 mg Q3W for 24 mo yielded a clinically meaningful improvement in overall survival over SOC choice of methotrexate (Mtx), docetaxel ...

Previous cancer vaccination trials often aimed to activate CD8+ cytotoxic T-cell (CTL) responses with short (8–10mer) peptides and targeted CD4+ helper T cells (TH) with HLA class II–binding longer peptides (12–16 mer) that were derived from tumor antigens. Accordingly, a study of immunomonitoring focused on the detection of CTL responses to the short, and TH responses to the long, peptides. The possible induction of concurrent TH responses to short peptides was widely neglected. In a recent phase I vaccination trial, 53 patients with different solid cancers were vaccinated with EMD640744, a cocktail of five survivin-derived short (9- or 10-mer) peptides in Montanide ISA 51VG. We monitored 49 patients and found strong CD8+ T-cell responses in 63% of the patients. In addition, we unexpectedly found CD4+ TH cell responses against at least two of the five short peptides in 61% (23/38) of the patients analyzed. The two peptides were recognized by HLA-DP4– and HLA-DR–restricted TH1 cells. Some short peptide–reactive (sp)CD4 T cells showed high functional avidity. Here, we show that a short peptide vaccine is able to activate a specific CD4+ T-cell repertoire in many patients, facilitating a strong combined CD4+/CD8+ T-cell response. Cancer Immunol Res; 4(1); 18–25. ©2015 AACR.

Ex vivo gene therapy using retrievable encapsulated cellular implants is an effective strategy for the local and/or chronic delivery of therapeutic proteins. In particular, it is considered an innovative approach to modulate the activity of the immune system. Two recently proposed therapeutic schemes using genetically engineered encapsulated cells are discussed here: the chronic administration of monoclonal antibodies for passive immunization against neurodegenerative diseases and the local delivery of a cytokine as an adjuvant for anti-cancer vaccines.

This study was conducted to determine the maximum tolerated dose of docetaxel when administered concomitantly with radical hyperfractionated radiotherapy and cisplatin in patients with locally advanced head and neck cancer.Patients with stage III-IV tumors received radical radiotherapy of 74.4 Gy given in two daily fractions of 1.2 Gy for 6 weeks. Cisplatin was given once weekly on day 1 at a constant dose of 15 mg/m2. The starting dose of docetaxel was 10 mg/m2 once weekly on day 3, with planned escalation steps of 5 mg/m2. Main endpoints of the study were the maximum tolerated dose of docetaxel, acute toxicities, and the preliminary efficacy results.Twenty-five patients were enrolled. Median follow-up was 15 months (range: 4-40 months). Two of three patients presented with dose-limiting toxicities at the 15-mg/m2 dose of docetaxel (one patient presented with multiple grade 3-4 toxicities requiring hospitalization for management and another presented with multiple toxicities including life-threatening bronchoaspiration). Thus, the weekly docetaxel dose of 10 mg/m2 was considered the maximum tolerated dose. Nineteen patients were then treated with the maximum tolerated dose and no dose-limiting toxicities were observed. Radiotherapy was completed in all patients except one (median dose: 74.4; range: 73.2-74.4), and at least 80% of the scheduled cisplatin and docetaxel doses were given in 92% of the patients. Acute toxicities were dominated by grade 3 mucositis (92%) and grade 3-4 dysphagia (68%). The 2.5 year actuarial local control rate was 87.5%, and the disease-free survival rate was 75%. At the time of last follow-up, 23 patients were alive and two had died from cancer. No distant metastases were observed.In patients with locally advanced head and neck cancer, this study determined the maximum tolerated dose of docetaxel to be 10 mg/m2 administered once weekly when given concurrently with 74.4 Gy hyperfractionated radiotherapy and a weekly 15-mg/m2 dose of cisplatin. The toxicity profile and the encouraging results suggest that this new combination merits further investigation in a multi-institutional phase II trial.

Background. In oropharyngeal carcinomas, it is as- sumed that the effectiveness of the different treatment ap- proaches is roughly equivalent, whereas the functional outcome after radical radiotherapy (RT) is superior to that associated with primary surgery. The aim of this study is to assess quality of life (QoL) outcomes of patients after two treatment strategies: radical surgery with postoperative RT and accelerated concomitant boost RT with or without chemotherapy. Methods. Sixty patients who were disease free at least 1 year after treatment of oropharynx carcinoma were studied. Forty had been treated with radical RT (median tumor dose, 69.9 Gy in 5.5 weeks), and 20 had been treated with primary surgery and postoperative monofractionated RT (median dose, 60.2 Gy). Seven of the former patients received chemotherapy concomi- tantly with, and one before, RT. Functional outcome was as- sessed by the subjective Performance Status Scale for Head and Neck cancer (PSSHN) and the general QoL by the European Organization for Research and Treatment of Cancer Core QoL questionnaire (EORTC QLQ-C30). The unpaired t test was used to assess for significant differences between means. Results. By use of the PSSHN module, scores were gener- ally higher in the RT group, with a significant difference in the speech subscale (p = .005), a trend for a significant difference for the eating in public subscale (p = .08), and an insignificant dif- ference for the normalcy of diet subscale (p = .25). When ana- lyzed by tumor stage, no significant differences were observed for T1-2 tumors, whereas for patients with T3-4 tumors highly significant differences favoring the RT group became evident for all three subscales. Although no significant differences were ob- served using the EORTC QLQ C-30 functional scales, patients treated with primary surgery reported significantly more dyspnea (28 vs 12,p = .04) and appetite loss (30 vs 13, p =. 05). In patients with T3-4 tumors, trends toward better scores favoring the RT group were observed for physical, role, emotional, and social functions, as well as a significantly better score for pain symptoms. Conclusions. Although for early stages no clear advantage in QoL outcome was noted for the RT group compared with the surgery group, for advanced-stage disease an advantage favor- ing radical RT seemed apparent. For those patients, if an equiva- lency between the two treatment strategies could be assumed regarding oncologic results, then nonsurgical treatment should

Lessons Learned Panitumumab shows activity in terms of disease control rate and preventing disease progression but not for tumor shrinkage in head and neck squamous cell cancer for second-line treatment. Epidermal growth factor receptor (EGFR) copy number gain, a property of tumor cells that theoretically could identify patients more likely to experience disease response, was common among patients having disease control. Our trial, given the lower toxicity with an every-2-week schedule, provides guidance for future trials, for example, in combinations of immune therapies and anti-EGFR-antibodies. Background The objective of this study was to investigate the efficacy and safety of panitumumab (anti-epidermal growth factor receptor [EGFR] antibody) given as a single agent in platinum-pretreated head and neck squamous cell cancer (HNSCC). Methods Patients with advanced HNSCC previously treated with platinum-containing therapy were included. Panitumumab was administered intravenously every 2 weeks at a dose of 6 mg/kg. Primary endpoint was overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; secondary endpoints were progression-free survival (PFS) and safety. A Simon's two-step design was chosen; 4 partial remissions (PR) in the first 32 patients were required for continuing to step two. An exploratory biomarker analysis was performed. Results Thirty-three patients were enrolled. Two patients obtained a PR for an ORR of 6%, and 15 (45%) showed stable disease (SD) for at least 2 months, resulting in a 51% disease control rate. Median PFS was 2.6 months (95% confidence interval [CI]: 1.7–3.7), while median OS was 9.7 months (95% CI: 6.3–17.2). The most frequent adverse drug reactions were cutaneous rash (64%) and hypomagnesemia (55%). Overall, 30% of patients experienced grade 3/4 adverse events. No infusion-related reactions occurred. EGFR copy number gain (CNG) was more frequent in patients who benefitted from panitumumab. Two uncommon KRAS mutations (G48E, T50I) and 3 canonical PIK3CA mutations (all E545K) were detected. High-risk HPV16 was found in 10 patients and EGFR CNG in 13 treated patients. EGFR CNG seems to be more frequent in individuals with at least SD compared with patients with progressive disease (59% vs. 30%). PFS for patients with EGFR CNG was 4.6 months (95% CI: 1.0–9.2 months) and 1.9 months (95% CI: 1.0–3.2 months) for patients without CNG (p = .02). Conclusion Panitumumab monotherapy in pretreated HNSCC patients was well tolerated but moderately active. We observed a considerable disease control rate. Future strategies with this agent comprise right patient selection through the identification of reliable biomarkers and gene signatures predicting response and, considering good tolerability and convenience, combination strategies with novel agents and immune therapeutic agents.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings.

Algorithms based on partial differential equations (PDEs) constitute a relatively novel class of lossy image compression methods. In this paper we introduce a practically relevant extension: We demonstrate how to incorporate progressive modes into these codecs. Since the data in PDE-based codecs is only available at irregular locations, this is a challenging task. We propose two progressive modes: The first one changes the order in which the grey values are stored, while the second additionally distributes the stored information more evenly over the file. Our experiments show that the novel codecs can outperform JPEG and even JPEG 2000 for high compression ratios.

Important advances in non small cell lung cancer (NSCLC) diagnosis, staging and treatment have been made over the last decade. Minimally-invasive endoscopic techniques including endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) and navigational bronchoscopy have emerged as valid alternatives to transthoracic and/or surgical approaches, providing aspiration cytology material instead of histological material for diagnosis and staging of mediastinal and lung lesions. Several drugs designed to target molecular pathways involved in cancer-cell growth and survival have been shown to be effective in a selected fraction of NSCLC patients, mostly with adenocarcinoma (targeted therapy). Somatic activating mutations in several genes involved in those pathways (EGFR/KRAS) can predict patients’ responses to targeted therapies (individualized therapy). Those mutations are commonly detected in histopathological samples (core-needle biopsy/surgical resection). However, when histological tissues are not available, molecular testing can be performed on cytological specimens. This scenario is increasing in frequency, due to the use of less invasive procedure for diagnosis and staging such EBUS-TBNA and/or patients in advanced stage of disease who are not candidates for surgery. Several strategies exist and may be combined to ensure that the less abundant material that results from minimally invasive techniques can be used efficiently for molecular analyses. These include Rapid On-Site Evaluation (ROSE) of EBUS-TBNA cytological material, to ensure optimal sampling and triage of the material (e.g. cell-block preparation), and microdissection techniques, to select an adequate population of tumor cells. Major issues raised by cytological diagnosis of NSCLC and molecular testing on cytological specimen are discussed in this article.

Rationale: Proteasome inhibitor-refractory multiple myeloma (MM) patients are a difficult to treat population with a very poor prognosis. The activity of registered, current or next generation MM drugs (pomalidomide, carfilzomib, daratumumab) in heavily pretreated, proteasome inhibitor-refractory MM is in the range of 30%. The biology of proteasome inhibitor resistance is driven by adaptive downregulation of the unfolded protein response (UPR), which regulates plasma cell maturation and sensitivity to proteasome inhibitor treatment (Leung-HagesteijnC. et al., Cancer Cell 2013 Sep 9;24(3):289-304). The oral HIV protease inhibitor nelfinavir (NFV) has anti-MM activity in vivo, triggers UPR activation, sensitizes MM to proteasome inhibitors and overcomes proteasome inhibitor resistance in vitro. Combination therapy with NFV and bortezomib (BTZ) showed UPR activation in vivo and strong signals of activity in bortezomib-refractory MM in the SAKK 65/08 phase I trial (Driessen C. et al.,Haematologica 2016 Mar;101(3):346-55). Objective: We performed a prospective, multicenter phase II trial to assess the activity ofnelfinavir,bortezomiband dexamethasone (NVd) in proteasome inhibitor-refractory MM. Methods: Patients with progressing, measurable, proteasome inhibitor-refractory MM (IMWG criteria) were included in this multicenter phase II trial. Further selection criteria included WHO performance status ≤ 3, platelets ≥ 50 x 109/L, hemoglobin ≥ 80 g/L (both may be achieved by transfusion) and adequate hepatic function. Concomitant use of other anti-cancer medication or radiotherapy, except for local pain control, was excluded. Patient age or prior number or types of therapy were not limited. Simon's two stage design was used to differentiate a promising activity (best response at any time point, partial response (PR) or better, ≥ 35 %) from an uninteresting activity (≤ 15% PR; power 80%, alpha 5%). Results: 34 patients were treated with oral nelfinavir 2500 mg days 1-14 b.i.d. in combination with bortezomib + dexamethasone (BTZ 1.3 mg/m2 days 1, 4, 8, 11, dexamethasone 20 mg p.o. days 1-2, 4-5, 8-9, 11-12) for a maximum of 6 21-day cycles at 9 SAKK trial sites throughout Switzerland. Patients (median age 67.5 years, range 42-82 years) had a median of 5 (range 2-12) prior therapy lines, 26 (76%) patients had prior high dose chemotherapy, and 13 (39%) had known poor prognosis cytogenetic abnormalities. All treated patients had proteasome inhibitor refractory MM according to IMWG criteria, i.e. they had progressed during or within 60 days after adequately dosed proteasome inhibitor-containing therapy. Moreover, 26 (76%) patients werelenalidomide-refractory by IMWG criteria (double refractory). Trial therapy is still ongoing in 2 patients. The median number of treatment cycles delivered per patient is 4. 22 patients achieved an objective response with a PR or better, resulting in an overall response rate (OR) of 65% (90% CI 49.2%-75.7%) to date. VGPR was reached in 5 patients, PR in 17 patients, MR in 3 patients, SD in 4 patients and PD in 3. Inpatients double-refractory for proteasome inhibitors andlenalidomide, the OR was 69%, in patients with poor prognosis cytogenetic abnormalities it was 77%. The OR was independent from the number of prior therapy lines (OR rate 69% with < 5 prior therapy lines, OR rate 61% with ≥ 5 prior lines). Most frequent > grade (G) 2 adverse events to date were anemia (G3 29%), thrombocytopenia (G3 24%, G4 18%), infections (G3 24%, G4 9%, G5 3%), hyperglycemia (G3 18%, G4 3%) and fatigue (G3 12%). Six patients maintained their PR or better for the full 6 cycles per protocol while on study. Four patients continuedNVd therapy on a compassionate use basis after completing the study. Updated final data will be provided at the meeting. Conclusion: Nelfinavir in combination with bortezomib and dexamethasone (NVd) is a reasonable, active, safe and widely available treatment option for patients with proteasome inhibitor-refractory multiple myeloma. The objective response rate of 65% observed in this very advanced, heavily pretreated, mostly dual-refractory patient population is exceptional. Our results warrant further development of nelfinavir as a sensitizing drug for proteasome inhibitor-based treatments and promising new agent for MM therapy. Figure Maximum relative change in serum M-protein or serum free light chain concentration in individual evaluable patients. Figure. Maximum relative change in serum M-protein or serum free light chain concentration in individual evaluable patients. Disclosures Driessen: Mundipharma-EDO: Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy; janssen: Consultancy. Samaras:Celgene (Adboard, educational talk), Amgen (adboard), Takeda (Adboard), Roche (Adboard), Sanofi (Adboard), Novartis (Adboard): Consultancy, Honoraria. Zander:Bristol Myers, Celgene, Amgen, Mundipharma, Janssen-Cilag, Takeda Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant in autologous cell-based anti-tumor immunotherapy has recently been approved for clinical application. To avoid the need for individualized processing of autologous cells, we developed a novel strategy based on the encapsulation of GM-CSF-secreting human allogeneic cells. GM-CSF-producing K562 cells showed high, stable and reproducible cytokine secretion when enclosed into macrocapsules. For clinical development, the cryopreservation of these devices is critical. Thawing of capsules frozen at different time points displayed differences in GM-CSF release shortly after thawing. However, similar secretion values to those of non-frozen control capsules were obtained 8 days after thawing at a rate of >1000 ng GM-CSF per capsule every 24 h. For future human application, longer and reinforced capsules were designed. After irradiation and cryopreservation, these capsules produced >300 ng GM-CSF per capsule every 24 h 1 week after thawing. The in vivo implantation of encapsulated K562 cells was evaluated in mice and showed preserved cell survival. Finally, as a proof of principle of biological activity, capsules containing B16-GM-CSF allogeneic cells implanted in mice induced a prompt inflammatory reaction. The ability to reliably achieve high adjuvant release using a standardized procedure may lead to a new clinical application of GM-CSF in cell-based cancer immunization. Cancer Gene Therapy (2011) 18, 553-562; doi:10.1038/cgt.2011.22; published online 13 May 2011

The aim of the study is to evaluate the outcome of low-dose bifractionated up-front radiotherapy (RT) followed by chemotherapy (CHT) in limited-disease small cell lung cancer (LD-SCLC). From December 1999 to February 2002, 20 LD-SCLC consecutive patients were treated by initial involved-field thoracic irradiation of 2 Gy twice daily to a total dose of 20 Gy, and concomitant prophylactic cranial irradiation (PCI) of 1.8 Gy twice daily to a total dose of 18 Gy followed 3 days later by 4-6 cycles of CHT with cisplatin and etoposide. Median follow-up was 66 months (52-77). There were no Grade 3-4 esophagitis or pneumonitis. Response rate was 90%, 45% of the patients showing a complete and 45% a partial response. Median time to first event was 13 months. Forty percent showed local infield recurrence, while 55% presented distant metastasis, 4 of them in the brain. Median survival time was 28 months. The Kaplan-Meier 1-, 3-, and 5-years survival rates were 95%, 35%, and 21%, respectively. Salvage RT was applied for local recurrence in 7 patients and for distant metastasis in 7 patients. The rate of brain recurrence with up-front low-dose PCI is favorable and should be further evaluated. Although the response and survival rates are promising, the high number of local recurrences indicates that the irradiation dose is insufficient for patients whose disease can be encompassed within a radical radiation portal.

Summary Decision support, order entry, drug and care administration with their respective documentations cannot be seen as independent actions, especially in terms of medical approach and patient safety. Chemotherapy offers a good illustration of the varied implications of technology information in these multifaceted and intricate processes. Chemotherapy administration can be a highly complex process. It can take place over a variable period of time ranging from hours to several months. Usually it involves numerous actors around the patient, such as physicians, pharmacists and nurses. Chemotherapies can be produced specifically for a given patient and can have dramatic effects if errors occur. Chemotherapy depends on various information, including patient-specific data such as temperature, weight or laboratory findings; drug-specific knowledge such as side effects or administration directives amongst others. At the University Hospitals of Geneva (HUG), critical process reengineering accompanied by new applications covering the whole chain of processes involved in chemotherapy, from prescription to administration including preparation, have been developed. This paper presents the overall approach leading to computerisation of these processes.

Objective. To perform a risk analysis of the cancer chemotherapy process, by comparing five different organizations. To quantitatively demonstrate the usefulness of centralization and information technologies, to identify residual risks that may be the target of additional actions. Study design. A reengineering of the process started in 1999 and was planned to be finished in 2006. The analysis was performed after the centralization and at the beginning of information technologies integration. Setting. Two thousand two hundred beds university hospital, with medical, surgical, haematological, gynaecological, geriatric, paediatric oncological departments. Twelve thousand cancer chemotherapies each year. Methods. According to the failure modes, effects and criticality analysis (FMECA) method, the failure modes were defined and their criticality indexes were calculated on the basis of the likelihood of occurrence, the potential severity for the patients, and the detection probability. Criticality indexes were compared and the acceptability of residual risks was evaluated. Results. The sum of criticality indexes of 27 identified failure modes was 3596 for the decentralized phase, 2682 for centralization, 2385 for electronic prescription, 2081 for electronic production control, and 1824 for bedside scanning (49% global reduction). The greatest improvements concerned the risk of errors in the production protocols (by a factor of 48), followed by readability problems during transmission (14) and product/dose errors during the production (8). Among the six criticality indexes remaining superior to 100 in the final process, two were judged to be acceptable, whereas further improvements were planned for the four others. Conclusions. Centralization to the pharmacy was associated with a strong improvement but additional developments involving information technologies also contributed to a major risk reduction. A cost-effect analysis confirmed the pertinence of all developments, as the cost per gained criticality point remained stable all over the different phases.